Sex Differences in Spironolactone and the Active Metabolite Canrenone Concentrations and Adherence

We aim to investigate sex differences in blood concentrations of spironolactone and the active metabolite canrenone in resistant hypertension patients. Furthermore, sex differences in adherence for spironolactone and other antihypertensive drugs (AHDs) were studied. The patients in this post hoc study had all participated in a single-blind randomized controlled trial called RHYME-RCT (Dutch Trial Register, NL6736). Concentrations in blood of several AHDs were assessed in RHYME-RCT to investigate adherence to treatment. This allowed for a comparison of drug exposure to spironolactone and canrenone between males and females. In linear regression models, no statistically significant sex differences (N = 35) in spironolactone (B =−10.23, SE = 7.92, p = 0.206) or canrenone (B = 1.24, SE = 10.96, p = 0.911) concentrations after adjustment for dose and time between sampling and intake were found. Furthermore, no statistically significant differences in non-adherence to spironolactone were found between sexes (N = 54, male 15% vs. female 38%, p = 0.100), but non-adherence to spironolactone was associated with non-adherence to other AHDs (p ≤ 0.001). Spironolactone and canrenone concentrations were not different between males and females with resistant hypertension. Although not statistically significant, females were twice as likely to be non-adherent to spironolactone compared to males, and thereby also more likely to be non-adherent to other AHDs.

Pre-clinical evaluation of antiviral activity of nitazoxanide against Sars-CoV-2

To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.

Toxicodynamic aspects and new tools for assessing acetaminophen toxicity: a review

Acetaminophen (Tylenol®) or APAP is a widely used non-steroidal anti-inflammatory drug responsible for many cases of intoxication, suicide, and liver toxicity. Due to its toxicity mechanisms are not yet fully elucidated and this literature review aims to objectively bring some of the most recent and relevant scientific discoveries that can help in the understanding of the subject. After being ingested, paracetamol is absorbed and begins to be digested in the stomach, then being metabolized by the liver through phase I and phase II (glucuronyltransferases and sulfotransferases). When present in excess in the body, APAP forms an active metabolite known as N-acetyl-para-benzoquinone-imine (NAPQI). This metabolite is a reactive species capable of binding to living cells and proteins causing damages, which are largely responsible for injuries, especially in the liver. As a conclusion of this study, it can be inferred that the lesions caused by acetaminophen, in addition to protein adducts, also extend to mitochondria and proteins. New markers, in addition to enzymes already known from the CYP families, also include proteins and cytokines, in addition to molecular methods, messenger RNA and micro RNA have been used to study hepatotoxicity by APAP. This makes it easier to deeply understand the mechanisms of toxicity induced by acetaminophen and then to advance in studies with new therapies.

Acetaminophen pharmacokinetic and toxicological aspects: a review

Paracetamol (Tylenol®) is a widely used non-steroidal anti-inflammatory drug responsible for many cases of intoxication and liver failure. When taken orally, it is absorbed and begins to be digested in the stomach. Paracetamol is primarily metabolized by the liver via phase I and phase II enzymes (glucuronyltransferases and sulfotransferases). When present in excess in the body, it forms an active metabolite known as N-acetyl-para-benzoquinone-imine (NAPQI). This metabolite is a reactive species capable of binding to living cells and proteins causing injuries and adducts, which are largely responsible for damage, especially the liver. The study of paracetamol pharmacokinetics is important to understand its toxicity pathways and thus develop new therapies to prevent or minimize the damage caused by this drug. This review sought some of the most relevant works that address the pharmacokinetics of paracetamol to facilitate a general understanding of what has been discovered so far on the subject. This study also aims to make patients aware of the possible harm that can occur when this drug is indiscriminately used.

Carvone Attenuates Irinotecan-Induced Intestinal Mucositis and Diarrhea in Mice

Intestinal mucositis is referring to inflammatory or ulcerative lesions of the oral or gastrointestinal tract; one of the main reasons is treatment with cancer chemotherapy. The prodrug Irinotecan is converted by carboxylesterase to the active metabolite SN-38, conjugated by UGT enzyme to SN-38G and then deconjugated by ?-glucoronidase produced by intestinal bacterial flora to produce SN-38. Irinotecan induces intestinal mucositis and diarrhea due to increased concentration of its active metabolite (SN-38).To evaluate the protective effect of carvone, I.P injection of (75mg/kg/day) of irinotecan for 4 days to induce intestinal mucositis, carvone administered to mice orally for 6 days starting from day 1. Results showed that carvone (50mg/Kg and 100mg/Kg) significantly and by dose-dependent manner attenuated body weight loss (-9.39±1.56 vs. -23.21±1.65 %), diarrhea scores (0.50±0.244 vs. 2.67±0.211) and serum TNF-? level (1361.44±55.075 vs. 3402.12±321.56 ng/ml) compared to experimental model group. In conclusion, carvone exerted a dose dependent anti-inflammatory and protective effect by attenuation irinotecan-induced intestinal mucositis.

Understanding the Role of the Antioxidant Drug Erdosteine and Its Active Metabolite on Staphylococcus aureus Methicillin Resistant Biofilm Formation

Increasing numbers of researches have suggested that some drugs with reactive oxygen species (ROS)-mediated mechanisms of action modulate biofilm formation of some pathogenic strains. However, the full contribution of ROS to biofilm development is still an open question. In this paper, the correlations between the antioxidant drug Erdosteine (Er) and its active Metabolite I (Met I), ROS and biofilm development of two strains of methicillin resistant Staphylococcus aureus are presented. Experiments revealed that Er and Met I at 2 and 5 mg/L increased up to three orders of magnitude the number of biofilm-dwelling cells, while the content of ROS within the biofilms was reduced above the 87%, with a major effect of Met I in comparison to Er. Comparative proteomics showed that, 5 mg/L Met I modified the expression of 30% and 65% of total proteins in the two strains respectively. Some proteins involved in cell replication were upregulated, and a nitric oxide-based mechanism is assumed to modulate the biofilm development by changing quorum sensitive pathways. Additionally, several proteins involved in virulence were downregulated in the presence of Met I, suggesting that treated cells, despite being greater in number, might have lost part of their virulence.