Progress, pitfalls, and path forward of drug repurposing for COVID-19 treatment

On 30 January 2020, the World Health Organization (WHO) declared the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic a public health emergency of international concern. The viral outbreak led in turn to an exponential growth of coronavirus disease 2019 (COVID-19) cases, that is, a multiorgan disease that has led to more than 6.3 million deaths worldwide, as of June 2022. There are currently few effective drugs approved for treatment of SARS-CoV-2/COVID-19 patients. Many of the compounds tested so far have been selected through a drug repurposing approach, that is, by identifying novel indications for drugs already approved for other conditions. We here present an up-to-date review of the main Food and Drug Administration (FDA)–approved drugs repurposed against SARS-CoV-2 infection, discussing their mechanism of action and their most important preclinical and clinical results. Reviewed compounds were chosen to privilege those that have been approved for use in SARS-CoV-2 patients or that have completed phase III clinical trials. Moreover, we also summarize the evidence on some novel and promising repurposed drugs in the pipeline. Finally, we discuss the current stage and possible steps toward the development of broadly effective drug combinations to suppress the onset or progression of COVID-19

Pharmacologic topoisomerase-I inhibition causes DNA damage and mortality in activated CD4+ T cells

Topoisomerase-I is required for DNA replication. It acts by preventing torsional stress caused by DNA winding during replication fork progression.  Topoisomerase-I inhibitors are widely used in many cancer therapies, in light of their anti-proliferative activity. However, their use as chemotherapeutics is associated with significant toxicity due to the off-target effects on healthy cells. We analyzed the dose-time-toxicity profile of a clinically employed topoisomerase-I inhibitor, i.e. topotecan, on primary CD4+T cells. This cell type was chosen to model a typical in-vivo interaction, due to the wide use of topotecan in the treatment of T-cell lymphomas. Our results show that a clinically achievable concentration of topotecan can induce toxic effects in healthy CD4+ T cells as early as 7 hours of the in vitro treatment. Toxicity of the drug was markedly increased by prolonging the post-treatment follow-up, but not by increasing concentrations, suggesting that clinical doses of topotecan can induce cell death and DNA damage in non-cancerous activated CD4+ T lymphocytes

Proteasomal degradation of PML protein is a stress response to HIV-1 replication and reactivation

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Bone Marrow Concentrate in the Treatment of Aneurysmal Bone Cysts: A Case Series Study

Introduction. A recent attractive option regarding mesenchymal stem cells (MSC) application is the treatment of bone cystic lesions and in particular aneurysmal bone cysts (ABC), in order to stimulate intrinsic healing. We performed a retrospective evaluation of the results obtained at our institution.Methods. The study group consisted of 46 cases with an average follow-up of 33 months. Forty-two patients underwent percutaneous treatment as the first approach; four patients had curettage as first treatment. In all cases, autologous bone marrow concentrate (BMC) was associated too. The healing status was followed up through a plain radiograph 45 days and 2 months after the procedure.Results and Conclusions.At the final follow-up, thirty-six patients healed with a Neer type II aspect, nine healed with a type I aspect, and one patient was not classified having total hip arthroplasty. Bone marrow concentrate is easy to obtain and to manipulate and can be immediately available in a clinical setting. We can assert that the use of BMC must be encouraged being harmless and having an unquestionable high osteogenic and healing potential in bone def

Surgical management of villonodular-pigmented synovitis of knee: decisional algorithm

Pigmented villonodular synovitis (PVNS) of knee is an uncommon disease defined as benign despite presenting local aggressiveness and high propensity to recurrence. Etiology is still not completely understood. It seems to be a chronic inflammation process involving synovial membranes characterized by hemosiderin deposition which leads to pain, limitation of range of motion and, if not treated, bone erosion and osteoarthritis of knee. The gold standard for treatment is surgical excision; other adjuvant or alternative therapies are described, too. We present a case series of PVNS of the knee treated with surgical excision at our institution. Functionality was assessed using the Muscoloskeletal Tumor Society (MSTS) Score for lower limbs and Oxford Knee Score (OKS). Statistical analysis were performed. At the latest follow-up, our patients' mean MSTS score was 26.4 (30-18): 27.4 for those treated with posterior approach and 26.1 for the anterior ones. Only 5% of patients suffered local complications and 15% had a local recurrence of the disease. Adequate pre-operative study and careful surgical excision, that should be tailored to each patient are the key to obtain a low recurrence rate

Upregulation of the Nrf2 antioxidant pathway characterizes the transition from productive to latent infection in CD4+ T cells

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Two-year follow-up of macaques developing intermittent control of the human immunodeficiency virus homolog simian immunodeficiency virus SIVmac251 in the chronic phase of infection

Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4(+) T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir

A NEGLECTED ZOONOSIS IN ALBANIA: WHY ECHINOCOCCOSIS IS BECOMING A SURGEON’S EXCLUSIVITY?

Echinococcosis is an endemic zoonosis in the Mediterranean area, with Albania interested actually to a level that is becoming a public health concern. Authors describe preliminary data from the only tertiary (university) medical facility of Albania, positioned in the capital of the country (Tirana), with 333 new cases diagnosed and treated during the period 2005 – 2011. Out of all these 333 new cases an impressive majority of 91% had a surgical treatment right from the first admission, rendering the disease almost a surgical exclusivity. Even more, 80% of all patients from the study group were hospitalized straightforwardly in surgical wards, with options of surgical intervention’s percentages outrunning figures from other sources and authors of the same geographical area. Such a situation, together with a very important level of patients’ origin from highly urbanized areas such as those of the capital, suggest the necessity of well-organized interventions, among which might be the mandatory notification of all human cases with Echinococcus infection

Unstable lateral femoral fractures: elements predictable of failure. Analysis of critical aspects related to the fracture pattern and nailing in order to obtain healing

Objective. Lateral femoral fractures are common events, especially in old frail patients. They can be stable or unstable on the basis of specific features. Optimal treatment requires preoperative evaluation of the fracture pattern and appropriate choice of implant and surgical technique. The aim of this study was to detect variables related to fixation failure in unstable lateral femoral fracture. Methods. We retrospectively evaluated 136 patients treated with intramedullary proximal femur nail (PFN) between January 2016 and December 2017 at our hospital. All fractures were classified according to the AO/OTA classification; the type and length of nail, nail collodiaphyseal angle, type of distal locking and use of steel wire cerclage were recorded. These variables were statistically analysed to evaluate any correlation with the onset of complications, i.e., biological and/or mechanical failure. Results. At the first follow-up at three months, we found 13 failures (9.6%). At 6 months, 38 patients were lost to follow-up and we identified 3 failures as pseudoartrosis. Statistical analysis showed a significant correlation between the type of fracture and failure. No significant differences were detected for the other parameters. Conclusions. When treating a lateral unstable femoral fracture with proximal femoral nail, the only variable significantly related to failure seems to be the fracture pattern. Thorough knowledge of the implant still remains essential to obtain a good result

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies