Substandard and falsified ivermectin tablets obtained for self-medication during the COVID-19 pandemic as a source of potential harm.

In 2019, a global viral pandemic, due to the SARS-CoV-2 virus, broke out. Soon after, the search for a vaccine and/or antiviral medicine began. One of the candidate antiviral medicines tested was ivermectin. Although several health authorities warned the public against the use of this medicine outside clinical trials, the drug was widely used at the end of 2020 and in 2021. Simultaneously, several reports started to emerge demonstrating serious adverse effects after self-medicating with ivermectin. It stands to reason that the self-administration of substandard or falsified (SF) medicines bearing harmful quality deficiencies have contributed to this phenomenon. In order to have a better view on the nature of these harmful quality deficiencies, SF ivermectin samples, intercepted in large quantities by the Belgian regulatory agencies during the period 2021-2022, were analyzed in our official medicines control laboratory. None of the samples (n = 19) were compliant to the quality criteria applicable to medicinal products. These SF products either suffered from a systematic underdosing of the active pharmaceutical ingredient or were severely contaminated with bacteria, two of which were contaminated with known pathogens that cause gastrointestinal illness upon oral intake. In addition to the direct risks of self-medicating with such a product, the improper usage and dosage of ivermectin medication might also facilitate ivermectin tolerance or resistance in parasites. This may have detrimental consequences on a global scale, certainly as the number of newly developed active pharmaceutical ingredients that can safely be used to combat parasites is rather scarce.

Increased oxidative stress in the mouse adriamycin model of glomerulosclerosis is accompanied by deposition of ferric iron and altered GGT activity in renal cortex.

Chronic renal failure evolves inevitable towards glomerular and tubulo-interstitial sclerosis. This pathological process involves a disturbed redox status of the kidney tissue, leading to irreversible damage. In this study we investigate in an adriamycin model of chronic renal failure in mice the evolution of in vivo hydrogen peroxide production, and the possible role of gamma-glutamyl transpeptidase and ferric iron in the process. Histological changes and ferric iron deposits are evaluated by histochemical staining. To evaluate oxidative stress residual catalase activity, TBARS formation and gamma-glutamyl transpeptidase activity are measured spectrophotometrically. While catalase activity remains the same, a decreased residual catalase activity indicates an increased formation of hydrogen peroxide. Both the activity of gamma-glutamyl transpeptidase and TBARS formation is increased at early stages of the disease. Ferric iron is clearly present in the proximal tubule. Twenty days after adriamycin injection all parameters decrease, probably due to the destruction of the tissue. Our data show the involvement of oxidative stress in the progression of adriamycin induced renal failure in mice. Both radical production and oxidative damage are measurable, while the altered activity of gamma-glutamyl transpeptidase and the deposition of ferric iron suggest the involvement of these factors in the development of a disturbed redox status in the kidney cortex.

Effect of mycophenolate mofetil on glomerulosclerosis and renal oxidative stress in rats.

BACKGROUND/AIMS: Mycophenolate mofetil (MMF) is known to attenuate glomerulosclerosis in experimental models of renal failure. We investigated whether this is mediated by reduction of oxidative stress. METHODS: Effects of MMF on oxidative stress are studied in an experimental rat model (NA model) involving unilateral nephrectomy and two intravenous injections with adriamycin (2 mg/kg). Rats are sacrificed after 2 and 6 weeks. Glomerulosclerosis and tubulointerstitial lesions are demonstrated by histological techniques. Presence of macrophages/monocytes (ED1) and myofibroblasts (alpha-SMA) is demonstrated by immunohistochemistry. Oxidative stress is evaluated by enzymatic measurements (AOE), spectrofluorometry (TBARS), immunohistochemistry (MDA and HNE) and histology (ferric iron deposition). RESULTS: The NA model shows proteinuria, hypercholesterolemia, beginning glomerulosclerosis, tubulointerstitial sclerosis and tubular dilatation, glomerular, periglomerular and interstitial presence of alpha-SMA and increased presence of macrophages/monocytes after 6 weeks. Oxidative stress in renal cortex is apparent (increased cortex TBARS concentration, increased glomerular presence of MDA and HNE, decreased activity of antioxidant enzymes, ferric iron deposition in proximal tubules) after 6 weeks. MMF administration results in a decrease of glomerulosclerosis, interstitial sclerosis, glomerular and periglomerular expression of alpha-SMA and the number of ED1-positive cells in tubulointerstitium and glomeruli. Proteinuria and cholesterolemia are not decreased. TBARS level, and activities of catalase, Mn and Cu/Zn superoxide dismutase as well as the presence of ferric iron in the proximal tubules are not changed by MMF treatment. Cortex activity of glutathione peroxidase returns to normal. CONCLUSION: MMF has a favorable effect on glomerular and interstitial fibrosis in the NA model of kidney disease, but not on proteinuria and cholesterolemia. Improvement of fibrosis cannot be explained by major changes in oxidative stress or antioxidant defense.

Vitamin E protects renal antioxidant enzymes and attenuates glomerulosclerosis in Adriamycin-treated rats.

BACKGROUND/AIMS: In the rat Adriamycin model of chronic renal failure, the development of glomerulosclerosis and tubulointerstitial lesions is accompanied by decreased activities and mRNA levels of the antioxidant enzymes. In this study, we investigated the effect of oral vitamin E supplementation on antioxidant enzyme activities in both the cortex and isolated glomeruli from Adriamycin-treated rats. METHODS: Glomerulosclerosis, tubulointerstitial lesions and ferric iron deposits were evaluated by histochemical staining methods, and antioxidant enzyme activities were measured by spectrophotometry. RESULTS: Vitamin E supplementation of the normal diet attenuates Adriamycin-induced glomerulosclerosis and tubulointerstitial lesions, but not proteinuria and serum total cholesterol, low-density lipoprotein cholesterol, triglycerides and total protein concentrations. In the cortex, vitamin E completely prevented a decrease in enzyme activity for Cu/Zn superoxide dismutase and catalase, and partly for Mn superoxide dismutase and glutathione peroxidase. In the glomeruli, vitamin E completely prevented a decrease in activity for Cu/Zn superoxide dismutase, catalase and glutathione peroxidase, and partly for Mn superoxide dismutase. CONCLUSION: Dietary supplementation of vitamin E protects the activities of antioxidant enzymes in the kidney cortex and glomeruli, and attenuates the evolution towards terminal renal failure in rats treated with Adriamycin.