Macromolecular Prodrugs of Ribavirin: Structure-Function Correlation as Inhibitors of Influenza Infectivity.

The requirement for new antiviral therapeutics is an ever present need. Particularly lacking are broad spectrum antivirals that have low toxicity. We develop such agents based on macromolecular prodrugs whereby both the polymer chain and the drug released from the polymer upon cell entry have antiviral effects. Specifically, macromolecular prodrugs were designed herein based on poly(methacrylic acid) and ribavirin. Structure-function parameter space was analyzed via the synthesis of 10 polymer compositions varied by molar mass and drug content. Antiviral activity was tested in cell culture against both low and high pathogenic strains of influenza. Lead compounds were successfully used to counter infectivity of influenza in chicken embryos. The lead composition with the highest activity against influenza was also active against another respiratory pathogen, respiratory syncytial virus, providing opportunity to potentially treat infection by the two pathogens with one antiviral agent. In contrast, structure-function activity against the herpes simplex virus was drastically different, revealing limitations of the broad spectrum antiviral agents based on macromolecular prodrugs.

Post-discharge occurrence of surgical site infections after hip or knee arthroplasty surgery in Poland, a population-based study.

Arthroplasty is a common procedure improving functioning of patients and their quality of life. Infection is a serious complication that determines subsequent management of the prosthesis and the patient. The aim of the study was to investigate the incidence of post-discharge surgical site infections (SSI) and their risk factors. A retrospective analysis of an anonymized database from the National Health Found for 2017 of 56,068 adult patients undergoing hip replacement surgery (HPRO) and 27,457 patients undergoing knee replacement surgery (KPRO). The cumulative incidence of post-discharge SSI was 0.92% for HPRO and 0.95% for KPRO. The main risk factors for hip SSI were male gender, diseases of hematopoietic, musculoskeletal and nervous system. The risk factor for knee SSI was male gender. All comorbidities significantly increased the risk of SSI. The ICU stay and antibiotics administered at discharge in studied population increased the risk of detection of SSI after HPRO and KPRO by up to four and seven times, respectively. For both procedures rehabilitation after surgery and total endoprosthesis decreased incidence of SSIs. The lower experience of the center was related to higher SSI incidence in HPRO in primary (1.5% vs. 0.9%) and in revision surgeries (3.8% vs. 2.1%), but in KPRO, lower experience only in primary surgeries was significantly associated with SSI. The cumulative incidence of post-discharge SSI in Poland is higher than in other European countries. Special attention should be paid to patients with chronic diseases.

Vaginal Secretion Epithelium Count as a Prognostic Indicator of High Abundance of Ureaplasmas in Women with a Normal Nugent Score.

Genital tract ureaplasma infections are associated with numerous complications, ranging from inflammation, through infertility, to problematic pregnancy. In the course of ureaplasma infection, the risk of human papillomavirus infection increases. Diagnostic tests for urea-plasma infections are not always carried out, especially in women with the normal Nugent test results. The study attempts to check whether it is possible to find a prognostic indicator that could suggest a high abundance of ureaplasmas (≥ 104 CFU/ml) at the stage of the initial examination of vaginal discharge. Such a prognostic factor could qualify women for further tests to detect infections with these atypical bacteria. Six hundred twenty-seven white women with a score of 0-3 on the Nugent scale were tested, including 322 patients with a high abundance of ureaplasmas (≥ 104 CFU/ml) and 305 who tested negative for these bacteria. Ureaplasma infections were detected statistically significant in women who had few or no epithelial cells in the genital swab specimens compared to the results obtained for women with numerous or very numerous epithelial cells (p < 0.001). The risk of the high density of ureaplasmas was 38.7% higher with fewer or no epithelial cells than with high numbers. In patients aged 18-40 years with few or no epithelial cells, a high density of ureaplasmas (≥ 104 CFU/ml) was observed significantly more frequently (p = 0.003). Determining the number of epithelial cells in Gram-stained slides may be the prognostic indicator of ureaplasma infection. Testing for genital ureaplasma infection should be considered, especially in women of childbearing age (18-40 years), even if the Nugent test value is normal and pH ≤ 4.6.

Postdischarge pneumonia after hip arthroplasty: a population­based study of 55 842 patients in Poland.

INTRODUCTION: Alloplasty is one of the most frequently performed procedures, as it hugely improves the quality of life. OBJECTIVES: The purpose of this study was to determine the incidence, risk factors, and clinical implications of postdischarge pneumonia after hip endoprosthesis in Polish adults. PATIENTS AND METHODS: This retrospective study was conducted using the database of the National Health Fund (Narodowy Fundusz Zdrowia) containing data from 55 842 hip arthroplasties performed in 2017. RESULTS: Postdischarge pneumonia was identified in 371 patients and accounted for 26.6% of all postdischarge infections, with incidence rate of 0.7%. Multivariable analysis showed a significantly higher risk of pneumonia in patients aged 65 and older (odds ratio [OR], 3.5; 95% CI, 2.40-5.03), urgently admitted (OR, 4.0; 95% CI, 3.16-4.98), operated in winter (OR, 1.7; 95% CI, 1.37-2.11), and hospitalized in the intensive care unit (OR, 5.9; 95% CI, 3.65-9.46). Preventative factors were pre­surgery treatment for diseases of the musculoskeletal system (OR, 0.7; 95% CI, 0.59-0.91) and postoperative rehabilitation (both outpatient and inpatient; OR, 0.3; 95% CI, 0.10-0.99 and OR, 0.7; 95% CI, 0.42-0.99, respectively). Seventy patients (18.9% of pneumonia cases) required inpatient pneumonia treatment. The in­hospital case fatality rate observed in postdischarge pneumonia was 21.4%. CONCLUSIONS: Pneumonia is one of the most common postoperative infections after hip endoprosthesis, especially in winter, requiring rehospitalization. Efforts should be made to prepare patients in the perioperative period.

Lipoic Acid Does Not Affect The Growth of Mycoplasma hominis Cells In Vitro.

Mycoplasma hominis is associated with various infections, for which the treatment can be complex. Lipoic acid (LA) plays a role as a cofactor in eukaryotes, most Bacteria, and some Archea. Research of recent years has increasingly pointed to the therapeutic properties of exogenously supplemented LA. The present study was conducted on 40 strains of M. hominis cultured with the following LA concentrations: 1,200 µg/ml, 120 µg/ml, and 12 µg/ml. The bacterial colonies of each strain were counted and expressed as the number of colony-forming units/ml (CFU). The number of CFU in M. hominis strains obtained in the presence of LA was compared with the number of CFU in the strains grown in the media without LA. The obtained results indicated that the presence of LA in the medium did not affect the growth of M. hominis. The investigation of the influence of LA on the growth and survival of microbial cells not only allows for obtaining an answer to the question of whether LA has antimicrobial activity and, therefore, can be used as a drug supporting the treatment of patients infected with a given pathogenic microorganism. Such studies are also crucial for a better understanding of LA metabolism in the microbial cells, which is also important for the search for new antimicrobial drugs. This research is, therefore, an introduction to such further studies.

Patients Undergoing Hip or Knee Arthroplasty in Poland Based on National Data-Challenge for Healthcare in Aging Society.

Arthroplasty procedures are more frequently performed due to their impact on the quality of life. The aim of this study was to evaluate and analyze the Polish national datasets and registries for hip and knee arthroplasty across Poland in order to describe and understand the challenges for healthcare in an aging society. The study included national data on 83,525 hip or knee arthroplasties performed in 2017. Of those, 78,388 (93.8%, 63.0% females) were primary operations: 66.6% underwent hip replacement surgery (HPRO, mean age 68.43 years, SD 11.9), and 5137 were secondary operations (females: 62.9%), with 75.2% of those being HPRO (mean age 69.0 years, SD 12.0). The mean age of the patients undergoing knee surgery (KPRO) was 68.50 years (SD 8.2). The majority (79.9%) were scheduled. The main reason for hospitalization was arthrosis (84.2% in total, HPRO-76.5%, and KPRO-99.5%), then trauma (15.1%; p < 0.001). In 5137 cases (6.2%, 62.9% females) in revision surgery group, 75.2% underwent HPRO (mean age 69.0 years; SD12.0), and 24.8% KPRO (mean age 68.0 years; SD 10.5). Similarly, 71.1% were scheduled. The main reason for hospitalization was complications (total-90.9%, HPRO-91.4%, and KPRO-89.4%) (p < 0.001). Comorbidities were present (over 80%) with the level of influenza, hepatitis B vaccination, and pre-hospital rehabilitation not exceeding 8% each in both groups. Due to the increasing age of patients, implicating comorbidities, there is a need for better preparation prior to surgery.

Glycine-modified growth hormone secretagogues identified in seized doping material.

A number of unknown pharmaceutical preparations seized by Danish customs authorities were submitted for liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis. Comparison with reference standards unequivocally identified the content of the powders as analogs of the growth hormone secretagogues GHRP-2 (Pralmorelin), GHRP-6, Ipamorelin, and modified growth hormone releasing factor (modified GRF 1-29), which can be used as performance-enhancing substances in sports. In all cases, the detected modification involved the addition of an extra glycine amino acid at the N-terminus, and analytical methods targeting growth hormone secretagogues should hence be updated accordingly.

Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects.

Macromolecular (pro)drugs hold much promise as broad-spectrum antiviral agents as either microbicides or carriers for intracellular delivery of antiviral drugs. Intriguing opportunity exists in combining the two modes of antiviral activity in the same polymer structure such that the same polymer acts as a microbicide and also serves to deliver the conjugated drug (ribavirin) into the cells. We explore this opportunity in detail and focus on the polymer backbone as a decisive constituent of such formulations. Fourteen polyanions (polycarboxylates, polyphosphates and polyphosphonates, and polysulfonates) were analyzed for blood pro/anti coagulation effects, albumin binding and albumin aggregation, inhibitory activity on polymerases, cytotoxicity, and anti-inflammatory activity in stimulated macrophages. Ribavirin containing monomers were designed to accommodate the synthesis of macromolecular prodrugs with disulfide-exchange triggered drug release. Kinetics of drug release was fast in all cases however enhanced hydrophobicity of the polymer significantly slowed release of ribavirin. Results of this study present a comprehensive view on polyanions as backbone for macromolecular prodrugs of ribavirin as broad-spectrum antiviral agents.

Macromolecular Antiviral Agents against Zika, Ebola, SARS, and Other Pathogenic Viruses.

Viral pathogens continue to constitute a heavy burden on healthcare and socioeconomic systems. Efforts to create antiviral drugs repeatedly lag behind the advent of pathogens and growing understanding is that broad-spectrum antiviral agents will make strongest impact in future antiviral efforts. This work performs selection of synthetic polymers as novel broadly active agents and demonstrates activity of these polymers against Zika, Ebola, Lassa, Lyssa, Rabies, Marburg, Ebola, influenza, herpes simplex, and human immunodeficiency viruses. Results presented herein offer structure-activity relationships for these pathogens in terms of their susceptibility to inhibition by polymers, and for polymers in terms of their anionic charge and hydrophobicity that make up broad-spectrum antiviral agents. The identified leads cannot be predicted based on prior data on polymer-based antivirals and represent promising candidates for further development as preventive microbicides.

Synthetic Polymer with a Structure-Driven Hepatic Deposition and Curative Pharmacological Activity in Hepatic Cells.

Synthetic polymers make strong contributions as tools for delivery of biological drugs and chemotherapeutics. The most praised characteristic of polymers in these applications is complete lack of pharmacological function such as to minimize the side effects within the human body. In contrast, synthetic polymers with curative pharmacological activity are truly rare. Moreover, such activity is typically nonspecific rather than structure-defined. In this work, we present the discovery of poly(ethylacrylic acid) (PEAA) as a polymer with a suit of structure-defined, unexpected, pharmacological, and pharmacokinetic properties not observed in close structural analogues. Specifically, PEAA reveals capacity to bind to albumin with ensuing natural hepatic deposition in vivo and exhibits concurrent inhibitory activity against the hepatitis C virus and inflammation in hepatic cells. Our findings provide a view on synthetic polymers as curative, functional agents and present PEAA as a unique biomedical tool with applications related to health of the human liver.