Protective Role of Quercetin in Carbon Tetrachloride Induced Toxicity in Rat Brain: Biochemical, Spectrophotometric Assays and Computational Approach

Carbon tetrachloride (CCL4) induces oxidative stress by free radical toxicities, inflammation, and neurotoxicity. Quercetin (Q), on the other hand, has a role as anti-inflammatory, antioxidant, antibacterial, and free radical-scavenging. This study explored protection given by quercetin against CCL4 induced neurotoxicity in rats at given concentrations. Male Wistar rats were divided into four groups Group C: control group; Group CCL4: given a single oral dose of 1 mL/kg bw CCL4; Group Q: given a single i.p injection of 100 mg/kg bw quercetin; and Group Q + CCL4: given a single i.p injection of 100 mg/kg bw quercetin before two hours of a single oral dose of 1 mL/kg bw CCL4. The results from brain-to-body weight ratio, morphology, lipid peroxidation, brain urea, ascorbic acid, reduced glutathione, sodium, and enzyme alterations (aspartate aminotransferase (AST), alanine aminotransferase (ALT), catalase, and superoxide dismutase) suggested alterations by CCL4 and a significant reversal of these parameters by quercetin. In silico analysis of quercetin with various proteins was conducted to understand the molecular mechanism of its protection. The results identified by BzScore4 D showed moderate binding between quercetin and the following receptors: glucocorticoids, estrogen beta, and androgens and weak binding between quercetin and the following proteins: estrogen alpha, Peroxisome proliferator-activated receptors (PPARγ), Herg k+ channel, Liver x, mineralocorticoid, progesterone, Thyroid α, and Thyroid β. Three-dimensional/four-dimensional visualization of binding modes of quercetin with glucocorticoids, estrogen beta, and androgen receptors was performed. Based on the results, a possible mechanism is hypothesized for quercetin protection against CCL4 toxicity in the rat brain.

Clinical evaluation of the effects of a single oral dose of gabapentin on fear-based aggressive behaviors in cats during veterinary examinations

OBJECTIVE To investigate the effects of a single oral dose of gabapentin on fear-based aggressive behaviors (FABs) in cats during veterinary examinations. ANIMALS 55 healthy pet cats (26 with and 29 without a history of FAB during veterinary visits [FAB and untreated control groups, respectively]). PROCEDURES A standardized 9-step clinical examination protocol (with patient compliance scored from 0 to 9 according to the highest completed step) was tested on untreated control group cats. The protocol was then used in a double-blind, randomized, placebo-controlled, crossover-design trial in which FAB-group cats received owner-administered gabapentin (100 or 200 mg/cat) or placebo capsules 2 hours before the first of 2 veterinary visits and received the alternate treatment before the second visit ≥ 1 day later. Ease of administration (scored from 1 [very difficult] to 4 [very easy]) and adverse effects were recorded. Compliance scores were compared between treatments for the FAB group and between FAB and untreated control groups. Changes in scores between treatments for the FAB group were used to investigate associations between selected variables and the outcome of interest. RESULTS FAB group compliance scores after gabapentin administration (median, 9; range, 0 to 9) were significantly higher than scores after placebo administration (median 0.5; range, 0 to 7) and did not differ from scores for the untreated control group. Owner scores indicated capsule administration was easy. Adverse effects (most commonly drowsiness, myorelaxation, and ataxia) resolved ≤ 10 hours after detection. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested oral administration of gabapentin to cats 2 hours before a veterinary visit can reduce FAB during physical examination, enabling more complete evaluation.

1122. Effect of Aluminum Hydroxide/Magnesium Hydroxide/Simethicone and Omeprazole on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects

Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety being developed for treating complication urinary tract infections. Antacids and proton pump inhibitors are known to change gastric pH after administration, which could affect the absorption of oral medications. This study evaluated the effect of a single dose of aluminum hydroxide/magnesium hydroxide/simethicone and the effect of multiple doses of omeprazole on the PK of TBP, following a single dose of TBP-PI-HBr. Methods This was an open-label, 3-period, fixed sequence drug-drug interaction study. On Day 1, Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 x 300 mg tablets) at Hour 0. On Day 1, Period 2, subjects received a single oral 20 mL dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension per 10 mL (Maalox® Advanced Maximum Strength oral suspension) with a single oral dose of TBP-PI-HBr 600 mg at Hour 0. In Period 3, on Days 1 through 5, subjects received a single oral dose of omeprazole 40 mg (Prilosec®) once daily (QD), at Hour -2. On Day 5, a single oral dose of 600 mg TBP-PI-HBr was administered at Hour 0. Whole blood sampling for TBP PK occurred pre-dose and up to 24 hours post dose. Whole blood samples were assayed for TBP by liquid chromatography-tandem mass spectrometry. Results Twenty subject were enrolled and completed the study. Geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 22% lower for TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone vs. TBP-PI-HBr alone (Figure). Similarly, geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 43% lower for TBP-PI-HBr in combination with omeprazole vs. TBP-PI-HBr alone. Because the PK/PD driver for TBP efficacy is AUC dependent, concomitant administration is not expected to impact the efficacy of oral TBP-PI-HBr. Figure 1. Arithmetic mean plasma TBP concentrations following a 600 mg dose of clinical study drug product (A1 and A2) and registrational drug product (B) – PK population. Conclusion Administration of TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole QD had no meaningful effect on plasma TBP exposure; Cmax decreased with both agents. Co-administration was generally safe and well tolerated. Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gina Patel, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Floni Bajraktari, MSc, Spero Therapeutics, Inc. (Employee) Yang Lei, PhD, Spero Therapeutics, Inc. (Employee) Akash Jain, PhD, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

1120. Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Following a Single Oral Dose in Healthy Male Subjects

Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety, with activity against multidrug-resistant gram-negative pathogens, including extended-spectrum-β-lactamase (ESBL)-producing Enterobacterales. TBP-PI-HBr is the first oral carbapenem intended for treating complicated urinary tract infections and acute pyelonephritis. This study evaluated the absorption, metabolism, and excretion (AME) of TBP-PI-HBr following a single oral dose of [14C]-TBP-PI-HBr to healthy males and characterized metabolites in plasma, urine, and feces. Methods This was a Phase 1, open-label, single-dose study in healthy subjects. Study drug was provided as radiolabeled and non-radiolabeled active pharmaceutical ingredient containing approximately 150 μCi of [14C]-TBP-PI-HBr. On Day 1, each subject received a 600 mg dose of TBP-PI-HBr. administered with 240 mL of water and fasted overnight for at least 10 hours. Blood samples were collected to determine TBP concentrations (whole blood), total radioactivity (whole blood and plasma), and metabolite profiling and identification were determined from plasma, urine, and feces. For mass balance, total radioactivity derived from urine and feces collections were determined. PK parameters were calculated using noncompartmental methods. Results Total radioactivity in plasma and whole blood decreased rapidly with geometric mean t½ values of 6.0 hours and 3.5 hours, respectively and Tmax of 1 hour. The cumulative mean recovery of radioactivity was 38.7% in urine and 44.6% in feces. Most of the administered radioactivity was recovered in the first 144 hours post dose in urine and feces (80.0%). Six of 8 subjects achieved a mass balance recovery ranging from 80.1% to 85.0%. The TBP plasma to total radioactivity ratio of 0.536 indicated that other metabolites contribute to the total radioactivity AUC in plasma. Metabolite profiling and identification results indicated that TBP was the major component in plasma and urine. The inactive ring open metabolite of TBP (LJC 11,562) was also found in plasma ( >10%), urine (5.27%), and feces ( >10%) as a secondary metabolite. Conclusion This study adequately characterized the AME of TBP-PI-HBr in humans. Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gary Maier, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Amanda Ek, MS, Spero Therapeutics, Inc. (Employee) Mary Fudeman, BA, MBA, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

Chloroquine Induced Hepatotoxicity in Male Albino Mice: RCT

Many drugs have been found to induce hepatotoxicity and acute liver failure. Chloroquine is one of those drugs, which can induce hepatotoxicity when it is given at higher dose Purpose: To find the effect of chloroquine on liver function tests (LFTs) Study Design: Randomized clinical trial Methodology: Sixty male albino mice were taken into this randomized controlled study. Those were divided into two groups of 30 each. Group A was the control group while group B mice were given single oral dose of 970 mg/kg of body weight of chloroquine on 9th day of experiment. Terminal intracardiac blood sample was obtained on 17th day of experiment Statistical analysis: SPSS version 23 was used for data analysis Results: When results of group B were compared with those of group A, they depicted highly significant (p=0.000) rise in serum ALP. Serum albumin decreased significantly (p= 0.007). Serum AST increased significantly (p=0.005). Serum ALT, however, did not rise significantly (p=0.285) in group B. Similarly, serum total proteins did not decrease significantly ( p=0.530) in group B Conclusion: It was concluded that chloroquine induced mild hepatotoxicity in male albino mice when a single oral dose of 970 mg/kg of body weight of it is given Key Words: Chloroquine, Hepatotoxicity and Alkaline Phosphatase.