ABSTRACT
Background: An outbreak of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection or COVID 19 has caused serious threats to all around the world. Until an effective and safe vaccine for novel coronavirus is developed by scientists, current drug therapy should be optimized for the control and treatment of COVID 19. Objective(s): In this manuscript, we present a perspective on possible benefits of reformulating antiviral drug dosage form with nanoemulsion system against novel coronavirus infection. Method(s): Literature review has been done on COVID 19, treatment strategies, novel drug delivery sys-tems and the role of pulmonary surfactant in lung protection. Result(s): Nanoemulsion system and its components have certain biophysical properties which could in-crease the efficacy of drug therapy. Antiviral drugs, delivered through a nanoemulsion system contain-ing P-gp inhibitor (surfactant and co-solvent), can minimize the cellular resistance to drugs and would potentiate the antiviral action of drugs. Pulmonary Surfactant (PS) assisted antiviral drug delivery by nanoemulsion system could be another effective approach for the treatment of COVID 19. The use of functional excipients like Pulmonary Surfactant (PS) and Surfactant Proteins (SPs) in the formulation of the antiviral drug-loaded nanoemulsion system can improve the treatment of coronavirus infection. Conclusion(s): In our opinion, for synergizing antiviral action, lipid and protein portion of PS and their commercial analogs should be explored by pharmaceutical scientists to use them as a functional excipi-ent in the formulation of antiviral drug-loaded nanoemulsion system.Copyright © 2021 Bentham Science Publishers.
ABSTRACT
CASE: An 84-year-old woman with atrial fibrillation on Digoxin presented with acute onset of confusion associated with a week history of abdominal pain, vomiting, and poor fluid intake. A few days prior, Amiodarone was added to her drug regimen which included Lasix. Additionally, she received the COVID-19 booster vaccine which led to a viral-like syndrome resulting in dehydration. The patient was afebrile, normotensive, but bradycardic. EKG showed a prolonged PR interval and scooped ST segments. Labs showed hyperkalemia, pre-renal acute kidney injury (AKI), and a Digoxin level of 4.3 ng/mL (therapeutic range: 0.8-2.0 ng/mL). Digoxin and Lasix were held and Digoxin antidote, Digibind, was administered with normalizing heart rate, potassium, and clinical improvement. IMPACT/DISCUSSION: Digoxin is used to slow conduction in atrial fibrillation and increase cardiac contractility in heart failure. It inhibits the membrane sodium-potassium-adenosine triphosphatase pump (Na/K ATPase), resulting in increased cytosolic calcium and subsequent cardiac contractility and automaticity. In turn, this can also cause premature ventricular contractions and tachycardia. In the carotid sinus, increased baroreceptor firing and subsequent increased vagal tone occurs which can cause bradycardia, atrioventricular blocks, hypotension, and GI symptoms. In skeletal muscle, hyperkalemia can result due to the abundance of Na/K ATPase pumps. Digoxin has a narrow therapeutic index with serum levels easily affected by many commonly prescribed drugs by way of decreasing renal clearance, inhibiting P-glycoprotein, and inducing secondary electrolyte disturbances. That said, drug dosing should be individualized with close monitoring to avoid potentially life-threatening effects that may result with even mildly increased digoxin levels. Acute toxicity manifests as non-specific GI, and neurologic symptoms (confusion, lethargy, visual changes), hyperkalemia, and brady or tachy-arrhythmias. Treatment is with digoxin specific fragment antigen binding (Fab) antibody, Digibind, which binds digoxin, inactivating it within 6-8 hours. Postadministration, digoxin serum testing cannot distinguish free verse bound drug;therefore, drug levels remain elevated for days to weeks until the FabDigoxin complex is excreted. In the case above, the viral-like-syndrome after the booster vaccine with subsequent AKI secondary to dehydration likely precipitated Digoxin toxicity. Accompanying drug interactions of diuretics causing dehydration and hypokalemia, P-glycoprotein inhibitors (Amiodarone, Verapamil, Diltiazem, Quinidine), and ACE inhibitors can further worsen renal clearance and culminate in Digoxin toxicity. CONCLUSION: Given Digoxin's narrow therapeutic index, small clinical changes such as post COVID-19 vaccine flu-like symptoms, dehydration, and medication changes can manifest drug toxicity. Therefore, attentive monitoring of accompanying comorbidities and drug interactions is imperative at preventing catastrophic toxic effects.
ABSTRACT
The ability to control the proliferation and cell death by inhibiting specific target kinase offers the opportunity to apply targeted therapies in the treatment of cancer. It has been found that (S)-valine-thiazole-derived compounds such as NEOS-223 are effective inhibitors of one or more of these kinases. NEOS 223 was developed, synthesized, and tested in the NCI 60 human tumor cell-screening panel demonstrating inhibition of colon (-53%), melanoma (-41%), and breast cancers (-9%). Microsomal clearance was determined in mouse, rat, dog, and human, and analyzed by LC-MS/MS by percent of parent material. IC50 values for CYP inhibition of >10 μM were calculated for 1A2, 2C19, and 3A4 with IC50 values of 4.86, 4.31, and 7.84 μM for 2C9 and 2D6. Microsomal clearance was high in all species with clearance rates ranging from 69-136 mL/min/kg. Plasma protein binding was determined by Rapid Equilibrium Dialysis in mice, rats, dogs, and humans. High plasma protein binding (>70%) was observed across all species. Based on the NCI results several cell lines were assayed in an MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) to determine cell viability in the presence of NEOS-223 resulting in <20% viability in colon, breast, melanoma, pancreatic and prostate human cancer cell lines at a 10 uM concentration. Maximum tolerated dose studies were conducted by both intraperitoneal and oral administration in mice. NEOS-223 delivered up to 80 mg/kg was well tolerated. Minimal or no toxicity was observed in acute and repeat dose animal studies. Pharmacokinetics of oral administration demonstrated adequate systemic exposure at therapeutic levels in mice, rats, and dogs. Preliminary in vivo mouse xenograft studies were performed on colon (COLO 205, HT-29 red FLUC), breast (MDA-Sumathi Chittamuru;Timothy M. Murphy;Sara A. Little;Andrew A. Taylor;Roseanne Wexler;Laxman Desai MB-468), melanoma (M-14), pancreatic (PANC-1), and prostate (PC3) human cancer cells with significant tumor inhibition observed compared to positive control agent groups with twice daily dosing of NEOS-223. In addition, a five-day pilot oral toxicity study in rats with dose range-finding studies and a 28-day repeat dose toxicity study performed in both rats and dogs provided favorable results. NEOS-223 has demonstrated active in vitro activity along with a favorable safety profile. in vivo efficacy resulted in inhibition of growth of multiple cell line. As a novel effective structure possibly targeting multiple kinases and transporters in one hybrid molecule, NEOS-223 may be a preferred monotherapy or combined therapy for multiple cancers. If upon further development, this drug is effective in humans, it would advance clinical practice and could improve current therapy significantly.