Advances and challenges in the prevention and treatment of COVID-19.

Since the end of 2019, a new type of coronavirus pneumonia (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been spreading rapidly throughout the world. Previously, there were two outbreaks of severe coronavirus caused by different coronaviruses worldwide, namely Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). This article introduced the origin, virological characteristics and epidemiological overview of SARS-CoV-2, reviewed the currently known drugs that may prevent and treat coronavirus, explained the characteristics of the new coronavirus and provided novel information for the prevention and treatment of COVID-19.

Double-Stranded Structure of the Polyinosinic-Polycytidylic Acid Molecule to Elicit TLR3 Signaling and Adjuvant Activity in Murine Intranasal A(H1N1)pdm09 Influenza Vaccination.

Polyinosinic-polycytidylic acid (PIC) is a potent double-stranded RNA (dsRNA) adjuvant useful in intranasal influenza vaccination. In mice, the intensity and duration of immune responses to PIC correlated with the double-stranded chain length. A rational method to avoid PIC chain extension in PIC production is to use multiple short poly(I) molecules and one long poly(C) molecule for PIC assembly. In this study, we elucidate that a newly developed uPIC100-400 molecule comprising multiple 0.1 kb poly(I) molecules and one 0.4 kb poly(C) molecule effectively enhanced the immune responses in mice, by preventing the challenged viral propagation and inducing hemagglutinin-specific IgA, after intranasal A(H1N1)pdm09 influenza vaccination. Reduced intraperitoneal toxicity of PIC prepared with multiple short poly(I) molecules in mice indicates the widened effective range of uPIC100-400 as an adjuvant. In contrast to uPIC100-400, the PIC molecule comprising multiple 0.05 kb poly(I) molecules failed to elicit mouse mucosal immunity. These results were consistent with TLR3 response but not retinoic acid inducible gene I (RIG-I)-like receptor response in the cell assays, which suggests that the adjuvant effect of PIC in mouse intranasal immunization depends on TLR3 signaling. In conclusion, the double-stranded PIC with reduced toxicity developed in this study would contribute to the development of PIC-adjuvanted vaccines.

Transcriptomic Analysis Reveals Priming of The Host Antiviral Interferon Signaling Pathway by Bronchobini® Resulting in Balanced Immune Response to Rhinovirus Infection in Mouse Lung Tissue Slices.

Rhinovirus (RV) is the predominant virus causing respiratory tract infections. Bronchobini® is a low dose multi component, multi target preparation used to treat inflammatory respiratory diseases such as the common cold, described to ease severity of symptoms such as cough and viscous mucus production. The aim of the study was to assess the efficacy of Bronchobini® in RV infection and to elucidate its mode of action. Therefore, Bronchobini®'s ingredients (BRO) were assessed in an ex vivo model of RV infection using mouse precision-cut lung slices, an organotypic tissue capable to reflect the host immune response to RV infection. Cytokine profiles were assessed using enzyme-linked immunosorbent assay (ELISA) and mesoscale discovery (MSD). Gene expression analysis was performed using Affymetrix microarrays and ingenuity pathway analysis. BRO treatment resulted in the significant suppression of RV-induced antiviral and pro-inflammatory cytokine release. Transcriptome analysis revealed a multifactorial mode of action of BRO, with a strong inhibition of the RV-induced pro-inflammatory and antiviral host response mediated by nuclear factor kappa B (NFkB) and interferon signaling pathways. Interestingly, this was due to priming of these pathways in the absence of virus. Overall, BRO exerted its beneficial anti-inflammatory effect by priming the antiviral host response resulting in a reduced inflammatory response to RV infection, thereby balancing an otherwise excessive inflammatory response.

Alternative pre-approved and novel therapies for the treatment of anthrax.

BACKGROUND: Bacillus anthracis, the causative agent of anthrax, is a spore forming and toxin producing rod-shaped bacterium that is classified as a category A bioterror agent. This pathogenic microbe can be transmitted to both animals and humans. Clinical presentation depends on the route of entry (direct contact, ingestion, injection or aerosolization) with symptoms ranging from isolated skin infections to more severe manifestations such as cardiac or pulmonary shock, meningitis, and death. To date, anthrax is treatable if antibiotics are administered promptly and continued for 60 days. However, if treatment is delayed or administered improperly, the patient's chances of survival are decreased drastically. In addition, antibiotics are ineffective against the harmful anthrax toxins and spores. Therefore, alternative therapeutics are essential. In this review article, we explore and discuss advances that have been made in anthrax therapy with a primary focus on alternative pre-approved and novel antibiotics as well as anti-toxin therapies. METHODS: A literature search was conducted using the University of Manitoba search engine. Using this search engine allowed access to a greater variety of journals/articles that would have otherwise been restricted for general use. In order to be considered for discussion for this review, all articles must have been published later than 2009. RESULTS: The alternative pre-approved antibiotics demonstrated high efficacy against B. anthracis both in vitro and in vivo. In addition, the safety profile and clinical pharmacology of these drugs were already known. Compounds that targeted underexploited bacterial processes (DNA replication, RNA synthesis, and cell division) were also very effective in combatting B. anthracis. In addition, these novel compounds prevented bacterial resistance. Targeting B. anthracis virulence, more specifically the anthrax toxins, increased the length of which treatment could be administered. CONCLUSIONS: Several novel and pre-existing antibiotics, as well as toxin inhibitors, have shown increasing promise. A combination treatment that targets both bacterial growth and toxin production would be ideal and probably necessary for effectively combatting this armed bacterium.

Fractional Laser-Assisted Topical Imiquimod 5% Cream Treatment for Recalcitrant Common Warts in Children: A Pilot Study.

BACKGROUND: Conventional treatments for warts like cryotherapy are limited by the pain during procedures, especially in pediatric patients. Imiquimod is a topical immune response modifier, but the thick stratum corneum of common warts prevents drug permeation through skin. OBJECTIVE: To evaluate the efficacy and safety of fractional laser/topical 5% imiquimod cream for the treatment of warts in children. METHODS: Eleven pediatric patients with multiple recalcitrant common warts were included. Lesions were treated using an ablative fractional 2,940-nm Er:YAG laser at 1- or 2-week interval. After each laser treatment session, imiquimod 5% cream was self-applied once daily 5 days a week. Response and adverse effects were assessed 2 weekly until complete clearance or up to maximum of 48 weeks. Pain during fractional laser was assessed using a visual analogue scale (0-10). RESULTS: Eight of the 11 (72.7%) children experienced complete clearance. Mean duration was 29.7 (16-48) weeks, and the mean number of fractional laser was 17.5 (8-37). No significant adverse effect was observed. Pain visual analogue scale during fractional laser was 2.4 (1-4) compared to 6.2 (5-8) during cryotherapy. CONCLUSION: This pilot study indicates that fractional laser-assisted topical imiquimod may provide benefit for recalcitrant warts in children.

[Stimulating Type I interferon response with small molecules: revival of an old idea]. / Stimuler la réponse interféron de type I avec des petites molécules : le renouveau d'une vieille idée.

Type I interferons play a central role in the establishment of an innate immune response against viral infections and tumor cells. Shortly after their discovery in 1957, several groups have looked for small molecules capable of inducing the expression of these cytokines with therapeutic applications in mind. A set of active compounds in mice were identified, but because of their relative inefficiency in humans for reasons not understood at the time, these studies fell into oblivion. In recent years, the characterization of pathogen recognition receptors and the signaling pathways they activate, together with the discovery of plasmacytoid dendritic cells, have revolutionized our understanding of innate immunity. These discoveries and the popularization of high-throughput screening technologies have renewed the interest for small molecules that can induce type I interferons. Proofs about their therapeutic potency in humans are expected very soon.

Polymeric nanoparticles for co-delivery of synthetic long peptide antigen and poly IC as therapeutic cancer vaccine formulation.

The aim of the current study was to develop a cancer vaccine formulation for treatment of human papillomavirus (HPV)-induced malignancies. Synthetic long peptides (SLPs) derived from HPV16 E6 and E7 oncoproteins have been used for therapeutic vaccination in clinical trials with promising results. In preclinical and clinical studies adjuvants based on mineral oils (such as incomplete Freund's adjuvant (IFA) and Montanide) are used to create a sustained release depot at the injection site. While the depot effect of mineral oils is important for induction of robust immune responses, their administration is accompanied with severe adverse and long lasting side effects. In order to develop an alternative for IFA family of adjuvants, polymeric nanoparticles (NPs) based on hydrophilic polyester (poly(d,l lactic-co-hydroxymethyl glycolic acid) (pLHMGA)) were prepared. These NPs were loaded with a synthetic long peptide (SLP) derived from HPV16 E7 oncoprotein and a toll like receptor 3 (TLR3) ligand (poly IC) by double emulsion solvent evaporation technique. The therapeutic efficacy of the nanoparticulate formulations was compared to that of HPV SLP+poly IC formulated in IFA. Encapsulation of HPV SLP antigen in NPs substantially enhanced the population of HPV-specific CD8+ T cells when combined with poly IC either co-encapsulated with the antigen or in its soluble form. The therapeutic efficacy of NPs containing poly IC in tumor eradication was equivalent to that of the IFA formulation. Importantly, administration of pLHMGA nanoparticles was not associated with adverse effects and therefore these biodegradable nanoparticles are excellent substitutes for IFA in cancer vaccines.

[THE INFLUENCE OF A COMBINATION OF MODERN DRUGS NUCLEINAT AND ALFAGIN ON THE CONCENTRATION OF CIRCULATING IMMUNE COMPLEXES AND THEIR MOLECULAR COMPOSITION IN THE SERUM OF PATIENTS WITH IRRITABLE BOWEL SYNDROME ON THE BACKGROUND OF NEUROCIRCULATORY DYSTONIA IN COMPLEX MEDICAL REHABILITATION].

The effect of the combination nucleinat and alfagin in a complex of medical rehabilitation at the level of circulating immune complexes (CIC) in serum of patients and their molecular composition with irritable bowel syndrome (IBS), against neurocirculatory dystonia (NeD). It is established that the combination of nucleinat and alfagin in medical rehabilitation of patients with this comorbid disorders contributes to the normalization of the total concentration of the CEC and their molecular composition, which indicates the validity of the application of the pathogenesis combinations of drugs in complex medical rehabilitation of patients with lBS against NCD.

Imiquimod for anogenital warts in non-immunocompromised adults.

BACKGROUND: 30% of people with anogenital warts (AGW) have spontaneous regression of lesions but there is no way to determine whether a specific lesion will remain. There are a wide range of options available for treating people with AGW and selection is based on clinician's experience, patient preferences and adverse effects. The imiquimod could offer the advantages of patient-applied therapies without incurring the limitations of provider-administered treatments. OBJECTIVES: To assess the effectiveness and safety of imiquimod for the treatment of AGW in non-immunocompromised adults. SEARCH METHODS: We searched the Cochrane Sexually Transmitted Infections Group Specialized Register (15 April 2014), CENTRAL (1991 to 15 April 2014), MEDLINE (1946 to 15 April 2014), EMBASE (1947 to 15 April 2014), LILACS (1982 to 15 April 2014), World Health Organization International Clinical Trials Registry (ICTRP) (15 April 2014), ClinicalTrials.gov (15 April 2014), Web of Science (2001 to 15 April 2014) and OpenGrey (15 April 2014). We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing the use of imiquimod with placebo, any other patient-applied or any other provider-administered treatment (excluding interferon and 5-fluorouracil which are assessed in other Cochrane Reviews) for the treatment of AGW in non-immunocompromised adults. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. We resolved any disagreements through consensus. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Ten RCTs (1734 participants) met our inclusion criteria of which six were funded by industry. We judged the risk of bias of the included trials as high. Six trials (1294 participants) compared the use of imiquimod versus placebo. There was very low quality evidence that imiquimod was superior to placebo in achieving complete and partial regression (RR 4.03, 95% CI 2.03 to 7.99; RR 2.56, 95% CI 2.05 to 3.20, respectively). When compared with placebo, the effects of imiquimod on recurrence (RR 2.76, 95% CI 0.70 to 10.91), appearance of new warts (RR 0.76, 95% CI 0.58 to 1.00) and frequency of systemic adverse reactions (RR 0.91, 95% CI 0.63 to 1.32) were imprecise. We downgraded the quality of evidence to low or very low. There was low quality evidence that imiquimod led to more local adverse reactions (RR 1.73, 95% CI 1.18 to 2.53) and pain (RR 11.84, 95% CI 3.36 to 41.63).Two trials (105 participants) compared the use of imiquimod versus any other patient-applied treatment (podophyllotoxin and podophyllin). The estimated effects of imiquimod on complete regression (RR 1.09, 95% CI 0.80 to 1.48), partial regression (RR 0.77, 95% CI 0.40 to 1.47), recurrence (RR 0.49, 95% CI 0.21 to 1.11) or the presence of local adverse reactions (RR 1.24, 95% CI 1.00 to 1.54) were imprecise (very low quality evidence). There was low quality evidence that systemic adverse reactions were less frequent with imiquimod (RR 0.30, 95% CI 0.09 to 0.98).Finally, two trials (335 participants) compared imiquimod with any other provider-administered treatment (ablative methods and cryotherapy). There was very low quality of evidence that imiquimod did not have a lower frequency of complete regression (RR 0.84, 95% CI 0.56 to 1.28). There was very low quality evidence that imiquimod led to a lower rate of recurrence during six-month follow-up (RR 0.24, 95% CI 0.10 to 0.56) but this did not translate in to a lower recurrence from six to 12 months (RR 0.71, 95% CI 0.40 to 1.25; very low quality evidence). There was very low quality evidence that imiquimod was associated with less pain (RR 0.30, 95% CI 0.17 to 0.54) and fewer local reactions (RR 0.55, 95% CI 0.40 to 0.74). AUTHORS' CONCLUSIONS: The benefits and harms of imiquimod compared with placebo should be regarded with caution due to the risk of bias, imprecision and inconsistency for many of the outcomes we assessed in this Cochrane Review. The evidence for many of the outcomes that show imiquimod and patient-applied treatment (podophyllotoxin or podophyllin) confer similar benefits but fewer systematic reactions with the Imiquimod, is of low or very low quality. The quality of evidence for the outcomes assessing imiquimod and other provider-administered treatment were of very low quality.

Efficacy of combination therapy of oral zinc sulfate with imiquimod, podophyllin or cryotherapy in the treatment of vulvar warts.

AIM: Zinc sulfate is beneficial in the treatment of epithelial warts. We conducted this study to compare the efficacy of combination therapy of oral zinc sulfate with conventional treatments in the treatment of vulvar warts. MATERIAL AND METHODS: This study was a randomized controlled trial. The sample size was 42 in each group. Women aged 20-50 years were placed by the block randomized method into six groups: the podophyllin-, imiquimod- and cryotherapy-treated groups, and another three groups receiving 8-week combination therapy of 400 mg oral zinc sulfate with one of the above-mentioned treatments. Data were analyzed using anova and Fischer's exact test with spss16. RESULTS: A total of 228 patients were recruited and completed the study in six treatment groups. No significant difference was observed in the response to treatment among these groups. Relapse after 6 months was significantly higher in the podophyllin-, imiquimod- and cryotherapy-treated patients compared to patients receiving these treatments in combination with oral zinc sulfate (P<0.05). CONCLUSIONS: Combined therapy of oral zinc sulfate with conventional treatments of vulvar warts appears to reduce the relapse rate.

[POSITIVE EFFECTS OF MODERN IMMUNOCORRECTION ACCORDING TO THE ANALYSIS OF CYTOKINES AND SLPI IN PATIENTS WITH PYELONEPHRITIS].

The peculiarities of cytokines as compounds of immunogenesis are shown in the patients having acute (A) and chronic (Ch) pyelonephritis (PN). The combination of antibacterial therapy with Nukleinat and Galavit promotes the positive changes of cytokin-producing ability of immunocompetent cells and decrease in the level of proinflammation cytokines in blood and urine, secretory leucocyte protease inhibitor (SLPI) in urine. In children with PN and adult patients with diagnostically elevated titres of antibodies (IgG) to Herpes simplex virus, Cytomegalovirus are shown the positive effects of Kanephron® H and Proteflazidum, accordingly. Clinico-immunological effects of immunomodulators testify to the expediency of this usage in complex therapy with the aim to modulate the cytokine link of immunity for improvement of the effective treatment in APN and the protection against aggravation of kidney functioning in ChPN.

[Syndrome "sickly child"].

Scientific review is devoted to the urgent problem of child health care--Syndrome "sickly child" described in detail the category of "frequently ill children" repeated respiratory diseases, the pathogens that cause diseases of the respiratory tract. Paying attention to factors contributing to re-respiratory morbidity, including genetically determined causes (disturbances in the state of health of the mother), is represented by the genetic determinism of repeated and recurrent diseases related to blood groups. The development of an immune imbalance is manifested by changes in the cellular, humoral immune response and nonspecific resistance factors characterizing the changes of local immunity in this category of children that shape the development of chronic disease. We describe the effect of an allergic component to the severity of respiratory disease and the relationship with the mechanisms of neuroendocrine and immune systems. Correction of the immune resistance of sickly children was conducted cycloferon contributing to reduce the incidence and duration of repeated episodes of acute respiratory infections per year.

Scar revision review.

Scars are a natural part of dermal healing following lacerations, incisions, or tissue loss. They can vary in quality depending on the individual's racial characteristics, the mechanism of the trauma, and conditions in which the wound healed-all of which are factors beyond the surgeon's control. A scar on the face can have significant implications for the patient. What may seem like an insignificant issue to the casual observer can cause continuous frustration for the patient, affecting their daily lives. These can include psychological as well as social consequences, leading to a diminished quality of life. Factors that the surgeon can control include the favorable repositioning of the scar, proper alignment of the wound edges, and meticulous handling of the tissues.

The role of imiquimod 3.75% cream in the treatment of external genital warts.

Imiquimod 3.75% cream has recently been approved by both the U.S. Federal Drug Administration and Health Canada for the treatment of external genital warts. Herein, we provide an overview of external genital warts, review the phase 3 clinical trials leading to the approval of imiquimod 3.75% cream, and compare its efficacy and clinical use with imiquimod 5% cream. Moreover, therapeutic options have further expanded with the relatively recent introduction of sinecatechins 15% ointment, an extract of green tea leaves.

[Monitoring of side effects and estimation of cycloferon efficacy in treatment of children with frequent and prolonged diseases].

Two hundred fifty patients, including 100 children with frequent and prolonged diseases at the age of 4 to 7 years, 76 children at the age of 7 to 18 years and 74 subjects at the age of 22 to 57 years were observed. The patients were treated with cycloferon in two courses with a 2-week interval according to the standard scheme. The tonsil surface microflora and its susceptibility to antibiotics were determined. Cycloferon lowered the Staphylococcus aureus titre and increased the culture susceptibility to benzylpenicillin, oxacillin, rifampicin, and erythromycin, reducing the variety of the fauces nonpathogenic microflora. The use of cycloferon induced no adverse (pathologic) reactions in 94.8% of the cases. In 4.4% of the children under school age the adverse reactions were transitory and did not require discontinuation of the drug use. Unforeseen reactions were recorded in 0.8% of the children and the use of the drug in them was discontinued. The use of cycloferon in two courses with a 2-week interval according to the standard scheme is recommended for prophylaxis of acute respiratory diseases in the group of children with frequent and prolonged diseases during epidemiologically unfavourable periods and for complex therapy of rhinopharinx infections as an agent increasing efficacy of other antibacterials.

[Comparative assessment of the methods of treatment of Condylomata acuminata].

The treatment of Condylomata acuminata often causes disappointment to both the physician and the patient since most of the current medical approaches require multiple examines while on the other hand success rates are low and recurrence rates remain high. The treatment approaches include surgical as well as non-surgical methods. The non-surgical treatment includes the application of local agents such as imiquimod, podophyllotoxin, and 5-fluorouracil. Other local agents, used in outpatient treatment settings, include trichloroacetic acid (TCA), podophyllin, or the intralesional application of agents such as interferon and bleomycin. The surgical methods include cryotherapy, electrosurgery, excision and laser therapy. Their major goal is the removal of the visible lesions. The development of the laser systems and the new HPV vaccines are a significant progress in the treatment and prevention of the HPV infections.

[Characteristics of immune response to etiotropic and pathogenetic therapy in children with chronic hepatitis C].

Features of the immune response of children with chronic hepatitis C to the antiviral and pathogenetic therapy have been studied. It is shown that the antiviral therapy is accompanied by stimulation of the immune response as manifested by the synthesis of cytokines (IL-4, IFN-alpha, IFN-gamma) with retention of increased production of IFN-a for more than two years after the end of the course of treatment. In children that previously received interferon inductor (cycloferon) for 12 months, high level of IFN-a production is retained, which ensures antiviral protection. Phytotherapy did not influence the production of cytokines.

Synergistic benefit in inflammatory arthritis by targeting I kappaB kinase epsilon and interferon beta.

OBJECTIVES: The I kappaB kinase (IKK)-related kinase IKKepsilon regulates type I interferon expression and responses as well as proinflammatory mediator production. We examined the role of IKKepsilon in arthritis and its ability to enhance the therapeutic response to systemic interferon (IFN) beta therapy in passive murine K/BxN arthritis. METHODS: IKKepsilon(-/-), IFN alpha(approximately)beta R(-/-) and wild type mice were given K/BxN serum and treated with polyinosinic polycytidylic acid (poly(I:C)), IFN beta, or normal saline. Clinical response and histological scores were assessed. Gene expression in the paws was measured by quantitative PCR. Serum interleukin 1a receptor agonist (IL1Ra) and IL10 were measured by ELISA and multiplex bead array. RESULTS: Arthritis was almost completely blocked in wild type mice if arthritogenic K/BxN serum and the Toll-like receptor (TLR)3 ligand, poly(I:C), were coadministered at the onset of the model, but not in established disease. Mice deficient in IFN alpha(approximately)beta R had an accelerated course of arthritis, and did not respond to poly(I:C). IKKepsilon null mice had a modest decrease in clinical arthritis compared with heterozygous mice. Low doses of IFN beta that were ineffective in wild type mice significantly decreased clinical arthritis in IKKepsilon null mice. Articular chemokine gene expression was reduced in the IKKepsilon(-/-) mice with arthritis and secreted IL1Ra (sIL1Ra) mRNA was significantly increased. Serum levels of IL1Ra were increased in low dose IFN beta-treated IKKepsilon(-/-) mice. CONCLUSIONS: Subtherapeutic doses of IFN beta enhance the anti-inflammatory effects of IKKepsilon deficiency, possibly by increasing production of IL1Ra and unmasking the antichemokine effects. Combination therapy with low dose IFN beta and an IKKepsilon inhibitor might improve efficacy of either agent alone and offers a novel approach to RA.

[Immunological and microbiological aspects of low intensity laser effect on the factors of local immunity of the reproductive tract in women with chlamydia infection].

Assessment of immunological and microbiological efficacy of Chlamydia cervicitis management was made by a complex method with a low intensity laser. The total number of leukocytes, percentage of viable cells and the number of neutrophils were detected in cervical secrets. Functional status of neutrophils was studied by a content of lysosomes on the ground of spontaneous and induced by latex HCT-reducing capacity, phagocytic activity. A system of cytokines was studied by interleukine level (IL-1 alpha, IL-1 beta, TNF-alpha, IL-8) and IFN-gamma content in cervical mucus. Positive clinical effect of the local use of the low intensity laser for Chlamydia cervicitis treatment was accompanied by positive changes in immunological indices of cervical secret, normal concentration of cytokines in cervical secret, restoration of the number and functions of neutrophils. Local use of the low intensity laser contributed to decreased number of opportunistic pathogenic microorganisms and their associations, and restored local flora.