SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papainlike protease (PL pro) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PL pro strongly were three cell protectives and antioxidants (NADþ, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine, and zanamivir), two antimicrobials (doripenem and sulfaguanidine), two anticancer drugs, three benzimidazole anthelmintics, one antacid (famotidine), three anti-hypertensive ACE receptor blockers (candesartan, losartan, and valsartan) and other miscellaneous systemically or topically acting drugs. The binding patterns of these drugs were superior to the previously identified SARS CoV PL pro inhibitor, 6-mercaptopurine (6-MP), suggesting a potential for repurposing these drugs to treat COVID-19. The objective of drug repurposing is the rapid relocation of safe and approved drugs by bypassing the lengthy pharmacokinetic, toxicity, and preclinical phases. The ten drugs with the highest estimated docking scores with favorable pharmacokinetics were subjected to molecular dynamics (MD) simulations followed by molecular mechanics/generalized Born surface area (MM/GBSA) binding energy calculations. Phenformin, quercetin, and ritonavir all demonstrated prospective binding affinities for COVID-19 PL pro over 50 ns MD simulations, with binding energy values of À56.6, À40.9, and À37.6 kcal/mol, respectively. Energetic and structural analyses showed phenformin was more stable than quercetin and ritonavir. The list of the drugs provided herein constitutes a primer for clinical application in COVID-19 patients and guidance for further antiviral studies.
Nanoemulsion is one of the potential drug delivery strategies used in topical ocular therapy. The purpose of this study was to design and optimize a nanoemulsion-based system to improve therapeutic efficacy of moxifloxacin in ophthalmic delivery. Moxifloxacin nanoemulsions were prepared by testing their solubility in oil, surfactants, and cosurfactants. A pseudoternary phase diagram was constructed by titration technique and nanoemulsions were obtained with four component mixtures of Tween 80, Soluphor® P, ethyl oleate and water. An experiment with simplex lattice design was conducted to assess the influence of formulation parameters in seven nanoemulsion formulations (MM1–MM7) containing moxifloxacin. Physicochemical characteristics and in vitro release of MM1–MM7 were examined and optimized formulation (MM3) was further evaluated for ex vivo permeation, antimicrobial activity, ocular irritation and stability. Drug pharmacokinetics in rabbit aqueous humor was assessed for MM3 and compared with conventional commercial eye drop formulation (control). MM3 exhibited complete drug release in 3 h by Higuchi diffusion controlled mechanism. Corneal steady state flux of MM3 (~32.01 µg/cm2/h) and control (~31.53 µg/cm2/h) were comparable. Ocular irritation study indicated good tolerance of MM3 and its safety for ophthalmic use. No significant changes were observed in the physicochemical properties of MM3 when stored in the refrigerator for 3 months. The greater aqueous humor concentration (Cmax; 555.73 ± 133.34 ng/mL) and delayed Tmax value (2 h) observed in MM3 suggest a reduced dosing frequency and increased therapeutic efficacy relative to control. The area under the aqueous humor concentration versus time curve (AUC0–8 h) of MM3 (1859.76 ± 424.51 ng·h/mL) was ~2 fold higher (p < 0.0005) than the control, suggesting a significant improvement in aqueous humor bioavailability. Our findings suggest that optimized nanoemulsion (MM3) enhanced the therapeutic effect of moxifloxacin and can therefore be used as a safe and effective delivery vehicle for ophthalmic therapy.
The arteriovenous fistula used for vascular access for hemodialysis may contribute to development of congestive heart failure. Theses patients can present with frequent episodes of congestive hear failure. Traditional management of high-inflow, a high-cardiac-output fistula generally involves either closure or banding. Although high-output state can be controlled, the lifeline of the patient is lost. We describe a series of 17 hemodialysis patients (10 men and 7 women) in whom a novel inflow reduction method was employed. All patients had symptoms of heart failure (15 brachiocephalic fistulas and two brachioaxillary bypass grafts) and a fistula inflow rate above 1600 ml/min. The inflow reduction procedure included ligation of the brachial anastomosis and reconstruction of the fistula by using an expanded polytetrafluoroethylene (Gore-Tex Intering) vascular graft in a bypass from the radial artery. The mean (+/- SD) time between fistula creation and the inflow reduction procedure was 30 +/- 17 months. The mean access inflow rate decreased significantly after the inflow reduction procedure, from 3135 +/- 692 to 1025 +/- 551 ml/min (p =0.0001). The mean cardiac output rate decreased from 8 +/- 3.1 to 5.6 +/- 1.7 l/min (p = 0.001) with resolution of symptoms. During the follow-up period thrombosis or stenosis developed in seven patients, three of whom underwent surgical revision. Thirteen of the seventeen accesses (77%) subjected to the inflow reduction procedure remained patent. Access loss was due to failed fistuloplasty or thrombosis. To our knowledge, this is the first report demonstrating that inflow reduction obtained by distalization of the anastomosis of the access fistula is feasible and safe for managing high-inflow, high-cardiac-output fistulas. Longer and larger studies of the inflow reduction procedure and its benefits are needed.
Tissue repair and wound healing are complex processes that involve inflammation, granulation, and remodeling of the tissue. The potential of various statins including atorvastatin (ATR) to improve the wound healing effect was established. The aim of this study was to formulate and evaluate the efficacy of topical application of ATR-based nanoemulgel on wound healing. The prepared formulations (ATR gel, ATR emulgel, and ATR nanoemulgel) were evaluated for their physical appearance, rheological behavior, in vitro drug release and ex vivo drug permeation. The in vivo wound healing effect was evaluated in wound-induced rats. The prepared ATR gel formulations showed good physical properties and were comparable. The release profiles of drugs from gel, emulgel, and nanoemulgel were distinct. Skin permeation potential of ATR was significantly (p < 0.05) enhanced when formulated into nanoemulgel. In vivo wound healing studies showed that ATR nanoemulgel exhibited the highest percent wound contraction. Histopathological assessment showed marked improvement in the skin histological architecture after 21 days of ATR nanoemulgel treatment. In conclusion, the data demonstrated here signify the prospective of ATR nanoemulgel as an innovative therapeutic approach in wound healing.
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