Amelioration of oxidative stress-mediated cytotoxicity and genotoxicity induced by copper and flubendiamide in-vivo and in- vitro by potent antioxidants

Present study was designed to assess the toxicity of copper @ 33 mg/kg and flubendiamide @ 200 mg/kg in vivo in male Wistar rats orally once daily for 90 days and protective effect of α-tocopherol, resveratrol, curcumin and catechin and in vitro cyto-genotoxicity in primary cell culture of thymocytes. In vivo study showed significant (p<0.05) increase in AST, total bilirubin and uric acid, creatinine and BUN levels while decrease in total proteins, GSH, SOD and GST levels and increased LPO and GPx with severe degenerative changes were observed in liver and kidney tissues in intoxicated groups. In vitro thymocytes were exposed to 40 µM concentration of flubendiamide and/or showed significant increase in TUNEL+ve cells, micronuclei, DNA shearing, and comet formation per 100 cells. Concurrent treatment with α-tocopherol in xenobiotics intoxicated groups showed almost normal values of the biochemical parameters and decreased LPO production and improved antioxidant enzymes activities and histoarchitecture of liver and kidney tissues suggest ameliorative potential of α-tocopherol whereas, resveratrol, curcumin, catechin or α-tocopherol in vitro decreased TUNEL+ve cells, micronuclei induction and comet formation and effect of antioxidants was concentration-dependent and their order of potency on equimolar concentration (10 µM) basis is: curcumin > resveratrol >catechin = α-tocopherol.

Better outcomes of COVID-19 in vaccinated compared to unvaccinated patients with systemic rheumatic diseases

ObjectiveΤo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs).MethodsPatients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients.ResultsBetween 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and <14 days after the second vaccine dose (partially vaccinated). Despite no differences in demographics, SRD type, treatment or comorbidities between unvaccinated and vaccinated patients, hospitalisation and mortality rates were higher in unvaccinated (29.3% and 4.1%, respectively) compared with partially vaccinated (21% and 0%) or fully vaccinated (10.3% and 0%) patients.ConclusionsVaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics.

Lactic acidosis and hyperlactatemia associated with lamivudine accumulation and sepsis in a kidney transplant recipient—a case report and review of the literature

Background We report a case of sudden, lethal metabolic acidosis in a 70-year-old man on long-term nucleoside reverse transcriptase inhibitor (NRTI) -based antiretroviral therapy (ART) who had developed atypical necrotizing fasciitis 1 month after kidney transplantation. Case presentation The HIV infection of the patient was treated for the last four months with an integrase strand inhibitor (dolutegravir 50 mg/d) plus a NRTI backbone including lamivudine (150 mg/d) and abacavir (600 mg/d). In this renal transplant patient we hypothesize that the co-existence of sepsis, renal failure and an accumulation of lamivudine led to the development of fatal metabolic acidosis and hyperlactatemia. Although lamivudine is only rarely associated with hyperlactatemia, there is evidence that overdose may be a risk factor for developing it. In our patient the lamivudine concentration two days after stopping and during hemodiafiltration was more than 50 times higher than therapeutic target trough concentrations. Likely reasons for this were renal impairment and concurrent treatment with trimethoprim, known to inhibit the renal elimination of lamivudine. Conclusions NRTIs could trigger the development of hyperlactatemia in septic patients. The use of NRTI sparing regimens might be considered in the presence of this critical condition.

Concurrent treatment of HIV, disseminated Mycobacterium avium complex and HCV-infection

Patients with HIV-infection diagnosed at late stages usually have significant immunosuppression and demand simultaneous antiretroviral therapy and treatment of opportunistic infections. The presence of HCV coinfection makes treatment even more challenging because of possible adverse effects and drug-drug interactions. HCV cure in such clinical situations not only prevents fibrosis progression, but can also enhance virologic and/or immunologic response to antiretrovirals and thus effective treatment of opportunistic infections. Thorough consideration of all existing diseases and drug interactions of the combined therapy makes simultaneous treatment of HIV, chronic hepatitis C, and opportunistic infections not only possible but the best way to improve outcomes in a complex clinical situation.

Balloon assisted, ultrasound guided percutaneous thrombin injection of a large radial artery pseudoaneurysm using a trans-venous approach via an Ipsilateral Arteriovenous Fistula

Background Pseudoaneurysm formation is known to complicate arteriovenous haemodialysis access. Ultrasound guided thrombin injection is a recognised treatment option, but is not possible in pseudoaneurysms with no measurable neck. Balloon assisted techniques have been described in such cases, which transiently obstruct flow out of the pseudoaneurysm and thereby prevent non-target embolization during ultrasound guided percutaneous thrombin injection. We describe a balloon assisted technique for the treatment of a radial artery pseudoaneurysm, via retrograde access from the draining cephalic vein of an arteriovenous fistula. Method A 61-year-old male with a radio-cephalic fistula was found on duplex ultrasound to have a large radial artery pseudoaneurysm with no measurable neck, as well as a juxta-anastomotic cephalic vein stenosis. Endovascular treatment was selected over open surgery. Retrograde cephalic venous access was established, which allowed for concurrent treatment of both the venous stenosis and the arterial pseudoaneurysm. After balloon dilation of the juxta-anastomotic stenosis, a percutaneous transluminal angioplasty balloon catheter was advanced across the arteriovenous anastomosis and inflated across the neck of the radial artery pseudoaneurysm, to transiently obstruct blood flow. This allowed for safe injection of thrombin into the pseudoaneurysm by direct ultrasound guided sac puncture; thereby achieving thrombosis. Conclusions Balloon assisted ultrasound guided thrombin injection is an endovascular treatment option that can obviate the need for open surgery in cases involving pseudoaneurysms with no measurable neck. The technique described allowed both concurrent treatment of a juxta-anastomotic venous stenosis and treatment of an arterial pseudoaneurysm from a single venous puncture. This technique avoided arterial access and its inherent complications.

A Synergistic Combination of Niclosamide and Doxorubicin as an Efficacious Therapy for All Clinical Subtypes of Breast Cancer

Drug resistance is one of the major hurdles in the success of cancer chemotherapy. Notably, aberrantly expressed Wnt/β-catenin signaling plays a major role in the initiation and maintenance of oncogenesis along with development of chemoresistance. Therefore, the combinatorial approach of targeting Wnt/β-catenin pathway along with using a chemotherapeutic agent seems to be a promising strategy to improve cancer therapy. In the present study, we evaluated the combination of niclosamide (Nic), an FDA-approved antihelminthic drug repurposed as a Wnt signaling inhibitor, and doxorubicin (Dox), a conventional anticancer agent, in all clinical subtypes of breast cancer viz. triple negative breast cancer, HER2 positive breast cancer, and hormone receptor positive breast cancer. The results demonstrated that the combination induced apoptosis and caused synergistically enhanced death of all breast cancer cell types at multiple combinatorial concentrations using both the sequential and concurrent treatment regimens. Mechanistically, downregulation of Wnt/β-catenin signaling and cell cycle arrest at G0/G1 phase by Nic and increase in reactive oxygen species by both Nic and Dox along with the inherent cytotoxicity of Dox mediated the synergism between the two drugs in both the treatment regimens. Overall, the combination of Nic and Dox holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of its clinical subtype.

Is the Concurrent Use of Sorafenib and External Radiotherapy Feasible for Advanced Hepatocellular Carcinoma? A Meta-Analysis

We evaluate the feasibility of a concurrent application of sorafenib and external beam radiation therapy (EBRT) for advanced hepatocellular carcinoma (HCC). PubMed, Embase, Medline, and Cochrane Library were searched up to 9 April 2021. The primary endpoint was grade ≥3 complications, and the secondary endpoint was overall survival (OS). Subgroup analyses were performed for studies with the EBRT targets, intrahepatic vs. non-intrahepatic lesions (e.g., extrahepatic metastases or malignant vessel involvement only). Eleven studies involving 512 patients were included in this meta-analysis. Pooled rates of gastrointestinal, hepatologic, hematologic, and dermatologic grade ≥3 toxicities were 8.1% (95% confidence interval (CI): 4.8–13.5, I2 = ~0%), 12.9% (95% CI: 7.1–22.1, I2 = 22.4%), 9.1% (95% CI: 3.8–20.3, I2 = 51.3%), and 6.8% (95% CI: 3.8–11.7, I2 = ~0%), respectively. Pooled grade ≥3 hepatologic and hematologic toxicity rates were lower in studies targeting non-intrahepatic lesions than those targeting intrahepatic lesions (hepatologic: 3.3% vs. 17.1%, p = 0.041; hematologic: 3.3% vs. 16.0%, p = 0.078). Gastrointestinal and dermatologic grade ≥3 complications were not significantly different between the subgroups. Regarding OS, concurrent treatment was more beneficial than non-concurrent treatment (odds ratio: 3.3, 95% CI: 1.3–8.59, p = 0.015). One study reported a case of lethal toxicity due to tumor rupture and gastrointestinal bleeding. Concurrent treatment can be considered and applied to target metastatic lesions or local vessel involvement. Intrahepatic lesions should be treated cautiously by considering the target size and hepatic reserve.