Curcumin Along With Fe3O4 Nanoparticles Improved Sperm Parameters In Rats With Testicular Ischemia

Background: Ischemic/reperfusion (I/R) in testicular tissue is one reason for the worldwide increase in male infertility. In the present study, we assessed the effects of curcumin and Fe3O4 nanoparticles (NPs) on sperm parameters in rats with I/R damage. Materials and Methods: Forty-eight adult male rats were divided into two groups (n=24 per group): control and torsion/detorsion. The control and torsion/detorsion groups were divided into four subgroups include sham, Fe3O4 NPs, curcumin, and Fe3O4 NPs+curcumin. After the rats were sacrificed, semen was collected from their epididymal tissues to assess sperm viability, motility, concentration, and morphology. Results: Curcumin significantly improved viability, motility, and normal sperm morphology in rats with I/R damage compared to the control group; however, it did not have a significant effect on sperm concentration (P<0.001). Fe3O4 NPs alone decreased all sperm parameters in the control and I/R rats (P<0.001). However, concomitant administration of Fe3O4 nanoparticles with curcumin significantly improved sperm parameters in rats with I/R damage (P<0.001). Conclusion: The increase in all semen parameters in the experimental groups with concomitant use of Fe3O4 NPs plus curcumin indicated that green synthesis of NPs could be recommended for future clinical studies.

Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation

The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3H-indole-3,2′-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2.

Fe2O3 Magnetic Nanoparticles and Curcumin Improved Sperm Parameters in Rats with Scrotal Hyperthermia

Background: Testicular function depends on temperature, and it has been shown that scrotal hyperthermia causes a sharp decrease in sperm parameters due to oxidative stress. In recent years, the use of natural materials from the plant and nanoparticles has attracted much attention. Therefore, the present study aimed to investigate the effect of curcumin and Fe2O3 nanoparticles on sperm parameters in rats. Materials and Methods: After preparing the rats, they were placed in a hot water bath at 43°C for 30 minutes for six consecutive days. The 48 rats were then divided into eight groups. A concentration of 0.03 mg/kg body weight magnetic Fe2O3 nanoparticles and curcumin at the concentration of 0.02 mg/kg body weight were used. After killing animals, the semen parameters such as viability, concentration, motility, and morphology of sperm were studied. Results: Significant differences were observed in all groups of rats in terms of semen parameters (P<0.001). The results showed a positive effect of curcumin on improving semen parameters in scrotal hyperthermia rats and a negative and toxic effect of Fe2O3 magnetic nanoparticles. However, significant improvement in sperm parameters was observed when Fe2O3 magnetic nanoparticles were given to rats along with curcumin. Conclusion: Curcumin has a positive and significant effect on improving sperm parameters in scrotal hyperthermia conditions. Fe2O3 magnetic nanoparticles, if co-administered with curcumin, can significantly improve sperm parameters. In this regard, green synthesis of nanoparticles and concomitant administration of antioxidants such as curcumin in scrotal hyperthermia conditions is recommended. [GMJ.2021;10:e2014]

Clinical Pharmacology of Sildenafil in Infants and Children

Sildenafil is a competitive and selective inhibitor of phosphodiesterase 5. Sildenafil is cleared by hepatic CYP3A (major route) and CYP2C9 (minor route) and concomitant administration of potent CYP3A inducers (e.g., bosentan) causes decreases in plasma levels of sildenafil. CYP3A4 inhibitors (erythromycin and cimetidine) inhibit sildenafil metabolism prolonging the half-life and elevating blood levels of sildenafil. Sildenafil is a pulmonary arterial vasodilator and it has been used in the treatment of persistent pulmonary hypertension. The initial oral dose is 250 to 500 µg/kg 4 times-daily in infants and the oral dose is 10 to 20 mg thrice-daily in children with a body-weight up to 20 kg or > 20 kg, respectively. Sildenafil has been found efficacy and safe in infants and children but it may induce adverse-effects. Following an oral dosing, the absorption rate constant is 0.343 h-1, and the elimination half-life is 2.41 hours in children suggesting that sildenafil is rapidly absorbed and eliminated. The interaction of sildenafil with drugs and the metabolism of sildenafil have been extensively studied. The principal routes of sildenafil metabolism are: N-demethylation, oxidation, and aliphatic dihydroxylation, and the major metabolite is N-desmethyl sildenafil. The treatment of infants and children with sildenafil has been extensively studied. Sildenafil citrate and sildenafil cross the human placenta and sildenafil migrates into the breast-milk in significant amounts. The aim of this study is to review the sildenafil dosing, efficacy and safety, effects, adverse-effects, pharmacokinetics, interaction with drugs, metabolism, treatments, and sildenafil placental transfer and migration into the breast-milk.

Rotavirus Vaccine Safety and Effectiveness in Infants With High-Risk Medical Conditions

OBJECTIVES Rotavirus vaccination has 87% to 100% effectiveness against severe rotavirus acute gastroenteritis (AGE) in healthy infants in high-income countries. Little is known whether infants with medical risk conditions (MRCs) are equally protected and if the vaccine is equally well tolerated. We conducted a quasi-experimental prospective multicenter before-after cohort study to assess the vaccine effectiveness (VE) and safety profile of the human rotavirus vaccine (HRV) among MRC infants that required prolonged or frequent postnatal care. METHODS The Netherlands has no national rotavirus immunization program, but HRV was implemented in routine care for MRC infants in 13 Dutch hospitals. Participants in the before and after cohort, HRV unvaccinated and vaccinated, respectively, were followed for occurrence of (rotavirus) AGE. VE of at least 1 dose was estimated by using time-to-event analysis for severe rotavirus AGE. Vaccine-related serious adverse event (AEs) after HRV were retrieved systematically from medical charts. Solicited AEs after vaccinations were prospectively collected and compared between vaccination time points with or without HRV. RESULTS In total, 1482 high-risk infants with MRC were enrolled, including 631 in the before and 851 in the after cohorts; 1302 infants were premature (88.3%), 447 were small for gestational age (30.2%), and 251 had at least 1 congenital disorder (17.0%). VE against severe rotavirus AGE was 30% (95% confidence interval [CI]: −36% to 65%). Overall, the observed number of rotavirus hospitalizations was low and not significantly different between the cohorts (2 and 2, respectively). The rate of vaccine-related serious AE was 0.24 per 100 vaccine doses. The adjusted risk ratio for any AE after HRV vaccination compared with other routine vaccinations was 1.09 (95% CI: 1.05 to 1.12) for concomitant administration and 0.91 (95% CI: 0.81 to 0.99) for single HRV administration. Gastrointestinal AEs were 10% more frequent after HRV. CONCLUSIONS In contrast to previous findings among healthy term infants, in routine use, HRV offered limited protection to vulnerable medical risk infants. HRV is generally well tolerated in this group in single administration, but when coadministered with routine vaccines, it is associated with higher risk of (mostly gastrointestinal) AE. Our study highlights the importance of studying vaccine performance in subgroups of medically vulnerable infants.

Protective effect of resveratrol against hexavalent chromium-induced genotoxic damage in Hsd:ICR male mice

It is well-established that exposure to hexavalent chromium [Cr(VI)] induces genotoxic damage. The aim of this study was to examine the ability of resveratrol to counteract hexavalent chromium [Cr(VI)]-induced genetic damage, as well as possible pathways that may be associated with this protection. Hsd:ICR male mice were divided into groups of 5 each and treated as follows: a) control 1, distilled water; b) control 2, ethanol 30%; c) resveratrol, 50 mg/kg by gavage; d) CrO3, 20 mg/kg intraperitoneally; and e) resveratrol in addition to CrO3 (resveratrol+CrO3), with resveratrol administered 4 hr prior to CrO3. The frequency of micronuclei (MN) and cytotoxicity were measured in peripheral blood at 0, 24, 48 and 72 hr, while 8-hydroxydeoxyguanosine (8-OHdG, 7,8-dihydro-8-oxodeoxyguanosine) adduct repair levels, endogenous antioxidant system biomarkers and apoptosis at 48 hr after treatments. Resveratrol administration increased activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). CrO3 treatment elevated GPx and CAT activities. Resveratrol reduced the frequency of Cr(VI)-induced rise in MN and without significant effect on levels of 8-OHdG adduct when administered alone, suggesting that this polyphenol-mediated cellular repair does not involve 8-OHdG adduct formation. Concomitant administration of resveratrol and Cr(VI)-resulted in return of activities of SOD, GPx and CAT to control levels accompanied by decreased glutathione levels suggesting that the endogenous antioxidant system might play an important role in resveratrol-mediated inhibition of Cr(VI)-induced oxidant toxicity. The increase in apoptotic cell number in resveratrol+CrO3 group as well as diminished necrosis further affirms that resveratrol effectively blocked the actions of Cr(VI).

Presynaptic Release-Regulating Alpha2 Autoreceptors: Potential Molecular Target for Ellagic Acid Nutraceutical Properties

Polyphenol ellagic acid (EA) possesses antioxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic and cardio protection activities, making it an interesting multi-targeting profile. EA also controls the central nervous system (CNS), since it was proven to reduce the immobility time of mice in both the forced swimming and the tail-suspension tests, with an efficiency comparable to that of classic antidepressants. Interestingly, the anti-depressant-like effect was almost nulled by the concomitant administration of selective antagonists of the noradrenergic receptors, suggesting the involvement of these cellular targets in the central effects elicited by EA and its derivatives. By in silico and in vitro studies, we discuss how EA engages with human α2A-ARs and α2C-AR catalytic pockets, comparing EA behaviour with that of known agonists and antagonists. Structurally, the hydrophobic residues surrounding the α2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α2A-AR, with respect to α2C-AR. Moreover, EA seems to better accommodate within α2A-ARs into the TM5 area, close to S200 and S204, which play a crucial role for activation of aminergic GPCRs such as the α2-AR, highlighting its promising role as a partial agonist. Consistently, EA mimics clonidine in inhibiting noradrenaline exocytosis from hippocampal nerve endings in a yohimbine-sensitive fashion that confirms the engagement of naïve α2-ARs in the EA-mediated effect.

628. Pharmacokinetics, Safety and Tolerability of Co-administration of Nacubactam and β-lactams after Multiple Doses in Japanese Healthy Subjects

Background Increase of carbapenem-resistant Enterobacterales (CRE) is a serious problem in the clinical setting and drugs which can treat patients with CRE are still limited. Nacubactam (OP0595) is a novel diazabicyclooctane-type β-lactamase inhibitor and being developed as a standalone drug to be co-administered with cefepime or aztreonam. Methods A randomized, double-blind multiple dose study of nacubactam in co-administration with cefepime (Cohort 1) or aztreonam (Cohort 2) in Japanese healthy subjects was performed to assess pharmacokinetics, safety, and tolerability of co-administrations of nacubactam and cefepime or aztreonam. In each cohort, 6 subjects received 2 g of nacubactam and 2 g of concomitant drug (cefepime or aztreonam) and 2 subjects received placebo (saline) intravenously over 60 minutes, three times daily every 8 hours for 7 days. Plasma samples were collected and concentrations of each drug were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and the evaluation of changes from baseline in safety laboratory test results, 12-lead electrocardiograms (ECGs), vital signs, and physical examinations. Results Profiles of Cmax, tmax, AUC0-8, AUC0-∞ and t1/2 for nacubactam, cefepime and aztreonam are summarized in Table 1. Summary of Ctrough for nacubactam, cefepime and aztreonam are summarized in Table 2. Plasma concentrations of nacubactam, cefepime and aztreonam reached the steady-state by Day 4, and the mean accumulation ratios of Cmax and AUC0-8 on Day 7 to those of Day 1 were in the range of 0.91 to 1.10. As for the safety, no serious adverse event was observed in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the discontinuation in 1 subject in nacubactam/cefepime group, but it was judged as “Not related to study drug”. Table 1. PK profiles of nacubactam and concomitant drugs on Day 1 and Day 7 Table 2. Summary of Ctrough of nacubactam and concomitant drugs Conclusion In conclusion, no remarkable change in pharmacokinetics was observed in each drug with multiple concomitant administration for 7 days and safety and tolerability of co-administrations of nacubactam and cefepime or aztreonam were confirmed. Based on these results, nacubactam is currently under further development. Disclosures All Authors: No reported disclosures

08. Concomitant Administration of the Adjuvanted Recombinant Zoster Vaccine (RZV) with 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Is Safe and Does Not Interfere with Immunogenicity of Either Vaccine in Adults Aged ≥ 50 Years

Background This study assessed non-inferiority of humoral immunogenicity, reactogenicity, and safety of RZV when the 1st dose was co-administered with PCV13 in adults ≥ 50 years of age (YOA) compared to sequential administration. Methods In this phase 3b, open-label, multi-center study (NCT03439657), adults were randomized 1:1 to receive either the 1st RZV dose co-administered with PCV13 at day (D)1 and the 2nd RZV dose at month (M)2 (Co-Ad group), or PCV13 at D1, the 1st RZV dose at M2 and the 2nd RZV dose at M4 (Control group). Co-primary confirmatory objectives were: (i) vaccine response rate (VRR) to RZV at 1 month post-dose 2 in Co-Ad group; (ii) non-inferiority of humoral responses to RZV (1 month post-RZV dose 2) and PCV13 (1 month post-PCV13) in Co-Ad group compared to Control group. Solicited adverse events (AEs) until D7 post-vaccination and unsolicited AEs until D30 post-vaccination were recorded. Serious AEs (SAEs) and potential immune-mediated diseases (pIMDs) were collected through 12 months post-RZV dose 2. Immunogenicity was performed in the per-protocol set (PPS) and safety analyses in the exposed set. Results Of 912 vaccinated adults, 863 were included in PPS (Co-Ad: 427; Control: 436). VRR for anti-glycoprotein E antibody concentrations was 99.1% in Co-Ad group. The predefined non-inferiority criteria for the humoral immune responses to RZV and PCV13 were met (Table 1). The overall frequency of solicited local AEs after RZV and PCV13 was comparable between Co-Ad and Control groups. Pain was the most common solicited local AE (Figure 1). The frequency of solicited general AEs was similar for the 1st RZV dose when co-administered with PCV13 or alone (57.4% vs 54.6%). Myalgia and fatigue were the most common solicited general AEs (Figure 2). The frequency (Co-Ad: 21.2%; Control: 23.1%) and nature of unsolicited AEs were balanced between groups. None of the reported SAEs, fatal SAEs, or pIMDs were vaccine-related. Table 1. Co-primary confirmatory objectives: vaccine response rate (VRR), and non-inferiority of the immune responses to RZV (1 month post-dose 2) and to PCV13 (1 month post-vaccination) in the Co-Ad group vs the Control group (per-protocol set) Figure 1. The incidence of solicited local adverse events (AEs) occurring within 7 days post-vaccination (overall/adult, exposed set) Figure 2. The incidence of solicited general adverse events (AEs) post-dose 1 occurring within 7 days post-vaccination (exposed set) Conclusion Co-administration of the 1st RZV dose with PCV13 showed non-inferior immune responses to sequential administration. The reactogenicity and safety of RZV in the Co-Ad group were within the range of the established safety profile of RZV. Co-administration of RZV with PCV13 may improve vaccination rates in ≥ 50 YOA population. Funding GlaxoSmithKline Biologicals SA Disclosures Ji-Young Min, PhD, GSK group of companies (Employee) Agnes Mwakingwe-Omar, MD, PhD, GSK group of companies (Employee) Megan Riley, PhD, GSK group of companies (Employee, Shareholder) Lifeter Yenwo Molo, BsC(hons) MSc(hons), GSK group of companies (Employee) Jyoti Soni, MA, GSK group of companies (Employee) Ginette Girard, MD, Diex Recherche Inc. Sherbrooke (Scientific Research Study Investigator) Jasur Danier, MD, GSK group of companies (Employee, Shareholder)