Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability

<p>Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation that can generate bio-inactive or toxic metabolites. As an example, the cough suppressant dextromethorphan undergoes such a P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan. This metabolite antagonizes the NMDA receptor causing hallucinations, which encourages recreational abuse. To circumvent this undesired metabolism, we have designed, synthesized, and evaluated <i>in vitro </i>and <i>in vivo</i> new fluoroalkyl analogs of dextromethorphan that display improved pharmacokinetic profiles relative to dextromethorphan and related analogs currently in clinical trials. Specifically, the fluorinated analogs minimized metabolic degradation and increased CNS exposure relative to DXM <i>in vivo</i>. Ultimately, these fluorinated motifs might be applicable to other aryl-methyl ether containing compounds as a strategy to improve pharmacokinetic profiles.<b></b></p>

Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability

<p>Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation that can generate bio-inactive or toxic metabolites. As an example, the cough suppressant dextromethorphan undergoes such a P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan. This metabolite antagonizes the NMDA receptor causing hallucinations, which encourages recreational abuse. To circumvent this undesired metabolism, we have designed, synthesized, and evaluated <i>in vitro </i>and <i>in vivo</i> new fluoroalkyl analogs of dextromethorphan that display improved pharmacokinetic profiles relative to dextromethorphan and related analogs currently in clinical trials. Specifically, the fluorinated analogs minimized metabolic degradation and increased CNS exposure relative to DXM <i>in vivo</i>. Ultimately, these fluorinated motifs might be applicable to other aryl-methyl ether containing compounds as a strategy to improve pharmacokinetic profiles.<b></b></p>

AN ANALYSIS OF BANNED FIXED-DOSE COMBINATIONS IN INDIA

Objective: The objective of the study was to analyze the nonsteroidal anti-inflammatory drugs (NSAIDs) and respiratory fixed-dose combinations (FDCs) recently banned in India. Methods: This observational study was conducted at the Department of Pharmacology, B. J. Medical College, Ahmedabad, Gujarat. The data were collected from the report on the banned FDCs submitted by the drug technical advisory board subcommittee. Total 195 FDCs belonging to NSAIDs (33) and respiratory group (162) were assessed for class, number of active pharmacological ingredients, formulations, indications, and reasons for banning. Results: The mean number of drugs in FDCs of NSAIDs was 2.6, while in respiratory FDCs, it was 3.6. The most common NSAID formulation was uncoated tablet (15, 30%) while it was syrup in respiratory (49, 30%). The most common reasons for banning these FDCs were safety concerns (153, 78.4%), followed by mismatched pharmacodynamics in respiratory FDCs and mismatched pharmacokinetics in NSAIDs FDCs. The NSAIDs FDCs were marketed for pain (70%) while respiratory FDCs were marketed for cough and cold (62%). Most common NSAIDs FDCs contained NSAID with NSAID (18%), while in respiratory FDCs combinations of a cough suppressant, expectorant, and soothing agents (10%) were present. Conclusion: Evaluation of FDCs is essential to prevent the marketing of irrational FDCs.

An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19

SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of pre-clinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry into a host cell would be an effective antiviral strategy. One mechanism for SARS-CoV-2 entry occurs when the spike protein on the surface of SARS-CoV-2 binds to an ACE2 receptor followed by cleavage at two cut sites (“priming”) that causes a conformational change allowing for viral and host membrane fusion. TMPRSS2 has an extracellular protease domain capable of cleaving the spike protein to initiate membrane fusion. A validated inhibitor of TMPRSS2 protease activity would be a valuable tool for studying the impact TMPRSS2 has in viral entry and potentially be an effective antiviral therapeutic. To enable inhibitor discovery and profiling of FDA-approved therapeutics, we describe an assay for the biochemical screening of recombinant TMPRSS2 suitable for high throughput application. We demonstrate effectiveness to quantify inhibition down to subnanomolar concentrations by assessing the inhibition of camostat, nafamostat and gabexate, clinically approved agents in Japan. Also, we profiled a camostat metabolite, FOY-251, and bromhexine hydrochloride, an FDA-approved mucolytic cough suppressant. The rank order potency for the compounds tested are: nafamostat (IC50 = 0.27 nM), camostat (IC50 = 6.2 nM), FOY-251 (IC50 = 33.3 nM) and gabexate (IC50 = 130 nM). Bromhexine hydrochloride showed no inhibition of TMPRSS2. Further profiling of camostat, nafamostat and gabexate against a panel of recombinant proteases provides insight into selectivity and potency.

Effect of intravenous lignocaine infusion on the quality of emergence in patients undergoing transsphenoidal resection of pituitary tumors – A prospective, randomized controlled trial

Background: Emergence from anesthesia is a critical step in patients undergoing transsphenoidal pituitary surgery (TSS). The cough suppressant and anesthetic sparing properties of lignocaine makes it a favorable option for smooth extubation and maintaining stable hemodynamics intraoperatively. We aimed to evaluate the effect of lignocaine infusion on the quality of emergence (QOE) and intraoperative hemodynamics in patients undergoing transsphenoidal resection of pituitary tumors. Methods: Fifty patients scheduled to undergo TSS were randomly divided into ligocaine group (n = 25), receiving 1.5 mg/kg bolus dose of lignocaine followed by continuous infusion of 1.5 mg/kg/h and saline group (n = 25). Patients assigned to the control group received equal volume of saline receiving equal volume of saline. The four emergence parameters (mean arterial pressure [MAP], heart rate (HR), cough, and agitation) were abbreviated into an aggregated score for QOE. Time to emergence and intraoperative hemodynamics were also recorded. Results: The QOE was not found to be different between the two groups (P = 0.294). Lignocaine did not increase the time to emergence (P = 0.166). The intraoperative HR and MAP were comparable between the two groups. A lower minimum alveolar concentration of desflurane was required in lignocaine group during insertion of nasal speculum (P = 0.018) and at the time of seller ridge dissection (P = 0.043) compared to the saline group. Conclusion: Intraoperative lignocaine infusion of 1.5 mg/kg/h did not significantly improve the QOE with respect to hemodynamics, cough, and emergence agitation in patients undergoing transsphenoidal resection of pituitary tumors.

Should Cough Syrups be Used In children?

Many over the counter available cough and cold medications contain combination of a decongestant, cough suppressant, antihistamine, expectorant, or antipyretic, which are irrational. Parents administer these medications to children for giving temporary relief from the discomfort caused by the of upper respiratory infections such as runny nose, congestion, cough, and fever. As per the recommendation of US Food and Drug Administration, children under the age of two should never be given these preparations. Most of the labels of products mention that cough and cold preparations should not be given to children under the age of four. Yet the practice continues.

Interventional Study of Dextromethorphan Abuse Within the U.S. Military Community in Okinawa, Japan

Dextromethorphan, a common over-the-counter cough suppressant, has potential for abuse. In the present commentary, we summarize findings to suggest extensive dextromethorphan overuse/abuse within the U.S. military community residing in Okinawa, Japan. We first compared sales of dextromethorphan-containing medications within the U.S. military community of Okinawa, Japan with sales within the U.S military community from the other nearby locations in the Pacific region. Our report revealed that dextromethorphan use is far more prevalent within the military community in Okinawa. To further substantiate the claim that dextromethorphan abuse is widespread in Okinawa’s U.S. military community, a survey of medical records showed high rates of treatment provided for dextromethorphan intoxication. These findings motivated interventions established throughout the military community in Okinawa to combat dextromethorphan overuse. These stricter policy changes resulted in decreases in sales of dextromethorphan-containing medications as well as a substantial drop in hospital visits from dextromethorphan intoxication, suggesting that the interventions were largely effective and should be maintained.