Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

Pharmacokinetics and Pharmacodynamics of Anthocyanins after Administration of Tart Cherry Juice to Individuals with Gout.

SCOPE: Tart cherries (TCs) contain high levels of anthocyanins that exert potent antioxidant and antiinflammatory effects and potentially benefit individuals with gout. METHODS AND RESULTS: This study aims to quantitate the major anthocyanins in TC Juice Concentrate (TCJC) and identify the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the major anthocyanin cyanidin-3-glucosylrutinoside (C3GR). A PK-PD study enrolling human subjects with a history of gout is performed. Subjects are randomized to receive either 60 or 120 mL of TCJC. Anthocyanins are quantitated using liquid chromatography-mass spectroscopy (LCMS). Antioxidant and antiinflammatory mRNA expression is measured using real-time qPCR before and after the administration of TCJC. A population PK model (popPK) is fit to the experimental data, and an indirect PD model (IDR) is constructed in Monolix. CONCLUSION: Of the bioavailable anthocyanins, C3GR achieves the highest plasma concentration in a dose-dependent manner. A popPK predicts anthocyanin exposure, and an IDR produces reasonable approximations of PD effects.

Colchicine to Weather the Cytokine Storm in Hospitalized Patients with COVID-19.

The repurposing of colchicine for the treatment of COVID-19 was suggested based in its immunomodulatory, anti-inflammatory, and anti-viral properties. We performed a single-center propensity score matched cohort study, including all consecutive COVID-19 patients admitted to a community hospital between 1 March 2020 and 30 May 2020. Patients were stratified according to the receipt of colchicine. The primary endpoint was defined as in-hospital death within 28-days follow-up. Secondary endpoints included favorable change in the Ordinal Scale for Clinical Improvement on days 14 and 28 versus baseline, proportion of patients not requiring supplemental oxygen on days 14 and 28, and proportion of patients discharged by day 28. In total data for 303 PCR positive COVID-19 patients were extracted and 66 patients were included in the 1:1 matched cohort study. At the end of the 28 day follow-up, patients receiving colchicine were approximately five times more likely to be discharged (odds ratio, 5.0; 95% confidence interval, 1.25-20.1; p = 0.023) and when comparing mortality, there were 3 deaths (9.1%) in patients receiving colchicine versus 11 deaths (33.3%) in the groups receiving standard of care (odds ratio, 0.20; 95% confidence interval, 0.05-0.80; p = 0.023). These observations warrant further investigation in large controlled clinical trials.

An Update on Current Therapeutic Drugs Treating COVID-19.

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.

Clinical outcomes and treatment cost comparison of levalbuterol versus albuterol in hospitalized adults with chronic obstructive pulmonary disease or asthma.

PURPOSE: Results of a prospective study comparing clinical outcomes and costs of levalbuterol versus albuterol therapy for exacerbations of asthma or chronic obstructive pulmonary disease (COPD) are presented. METHODS: In a single-center open-label study, selected adults hospitalized for asthma or COPD exacerbations over a 21-month period were randomly assigned to receive levalbuterol 1.25 mg three times daily (n = 55) or albuterol 2.5 mg four times daily (n = 57); dosage reductions and other respiratory therapies were permitted. Study outcomes included scheduled and rescue nebulizations, total treatment costs, hospital length of stay, and change in heart rate from baseline. RESULTS: The numbers of scheduled nebulizations were similar in the levalbuterol and albuterol groups (mean ± S.D., 19.6 ± 13.4 versus 20.7 ± 14.4; p = 0.692), as were the numbers of rescue nebulizations (mean ± S.D., 0.7 ± 1.4 versus 0.8 ± 2.0; p = 0.849). The mean change from baseline in heart rate did not differ significantly between groups. Mean total treatment costs per patient were significantly greater with the use of levalbuterol ($8003, bootstrap 95% confidence interval [CI], $6628-$9379) versus albuterol ($5772, bootstrap 95% CI, $5051-$6494; p = 0.006). Hospital length of stay was significantly greater in the levalbuterol group (mean ± S.D., 8.5 ± 5.2 days versus 6.8 ± 3.6 days with albuterol use; p = 0.040). CONCLUSION: Clinical outcomes were similar with the use of levalbuterol versus albuterol for exacerbations of COPD or asthma. On average, patients receiving levalbuterol had longer and more costly hospital stays.

Prodrug of proline analogue reduces hypoxic pulmonary hypertension in rats.

A polymeric prodrug of the proline analogue cis-4-hydroxy-l-proline (CHOP), poly(ethylene glycol)-lysine-CHOP or CHOP-PEG, prevents hypoxic pulmonary hypertension in rats by inhibiting collagen accumulation. A more potent prodrug was synthesized by increasing the loading of CHOP on the carrier from 14 to 100%. Pulmonary antihypertensive efficacy and pharmacokinetics are described in the rat hypoxia model. The antihypertensive effect of CHOP-PEG in rats exposed to 10% O2 for 7d showed approximately 2 x 10(2)-fold greater potency than monomeric CHOP. Routes of administration were compared to determine the lowest dose of CHOP-PEG that reduced right ventricular pressure approximately 50% vs. untreated hypoxic controls at 7d. Total doses required were: continuous s.c. via an osmotic minipump, 0.8 mg; single s.c., 10mg; single i.v., 40 mg; and single intratracheal 90 mg. Efficacy for at least 7d postdosing in pre-established pulmonary hypertension was shown. Using an ELISA-based assay, biphasic i.v. and stable s.c. pharmacokinetic profiles were observed 72 h after single injections and 7d after continuous s.c. infusion. Thus, this CHOP-PEG formulation prevents and reverses chronic hypoxic pulmonary hypertension in rats, is most effective when given by continuous s.c. infusion, and has favorable pharmacokinetic properties. Potent inhibitors of fibrosis appear to be promising agents in treating pulmonary hypertension and possibly other fibrosing diseases.

Recombinant human relaxin reduces hypoxic pulmonary hypertension in the rat.

The fibroproliferative changes in pulmonary artery (PA) remodeling are partially prevented by antifibrotic agents. Relaxin (Rlx), a hormone involved in loosening collagen bundles in ligaments during parturition, has antifibrotic and vasodilator properties that may prevent pulmonary vascular remodeling. In the hypoxia model of pulmonary hypertension, two doses of recombinant human relaxin (rhRlx 24 [high] or 5 [low] mg X 10(-2)/kg d(-1)) were administered subcutaneously continuously for 10d to hypoxic (10% O2) rats. At day 11, right ventricular pressure (Pa X 10(2)) was reduced by rhRlx in a dose-dependent manner (15 +/- 1* control; 28 +/- 1 hypoxia; 23 +/- 1* low; 20+/-1* high; n = 10-14/group, *P < 0.05 vs. hypoxia). High rhRlx ameliorated increased collagen accumulation (mug hydroxyproline/vessel) in main PAs (87 +/- 6) vs. untreated hypoxia (102 +/- 2) (n=5/group, P < 0.05). Infusion of rhRlx had no effect on air-breathing rats, and acute administration did not alter blood pressure in hypoxic rats. Fibroblasts cultured from rat PAs spontaneously expressed collagen and fibronectin, and treatment with TGF-beta increased secretion 26- and 25 X 10(-1)-fold, respectively. Addition of rhRlx to transforming growth factor-beta-stimulated fibroblasts inhibited collagen (37%) and fibronectin (38%) secretion vs. vehicle (n = 4 per group, both P < 0.05). We conclude that rhRlx inhibits the early fibroproliferative response in hypoxic pulmonary hypertension and the mechanism may be due in part to suppression of collagen synthesis.