Organic impurity profiling of fentanyl samples associated with recent clandestine laboratory methods.

Nearly a decade ago, fentanyl reappeared in the United States illicit drug market. In the years since, overdose deaths have continued to rise as well as the amount of fentanyl seized by law enforcement agencies. Research surrounding fentanyl production has been beneficial to regulatory actions and understanding illicit fentanyl production. In 2017, the Drug Enforcement Administration (DEA) began collecting seized fentanyl samples from throughout the United States to track purity, adulteration trends, and synthetic impurity profiles for intelligence purposes. The appearance of a specific organic impurity, phenethyl-4-anilino-N-phenethylpiperidine (phenethyl-4-ANPP) indicates a shift in fentanyl production from the traditional Siegfried and Janssen routes to the Gupta-patent route. Through a collaboration between the DEA and the US Army's Combat Capabilities Development Command Chemical Biological Center (DEVCOM CBC), the synthesis of fentanyl was investigated via six synthetic routes, and the impurity profiles were compared to those of seized samples. The synthetic impurity phenethyl-4-ANPP was reliably observed in the Gupta-patent route published in 2013, and its structure was confirmed through isolation and structure elucidation. Organic impurity profiling results for illicit fentanyl samples seized in late 2021 have indicated yet another change in processing with the appearance of the impurity ethyl-4-anilino-N-phenethylpiperidine (ethyl-4-ANPP). Through altering reagents traditionally used in the Gupta-patent route, the formation of this impurity was determined to occur through a modification of the route as originally described in the Gupta patent.

A Survey of Dentist Anesthesiologists on Preoperative Intramuscular Sedation.

OBJECTIVE: The induction of general anesthesia for children and patients with special needs frequently requires preinduction sedation, especially when anxiety and agitation lead to violent or combative behavior. In these situations, preoperative intramuscular (IM) sedation may facilitate patient transfer, intravenous cannulation, and/or mask induction. This survey aimed to capture data regarding the current preoperative IM sedation practices of dentist anesthesiologists. METHODS: An electronic survey was distributed in 2020 to all members of the American Society of Dentist Anesthesiologists regarding the administration of preoperative IM sedation. It included questions about the demographics of respondents and their patients who require IM sedation, the most common drug regimens used, decision-making criteria regarding ketamine dosing, the intended level of sedation, sequence of anesthetic management following IM sedation, and observed outcomes. RESULTS: A total of 193 responses (43%) were received; of those, 162 reported using preoperative IM sedation. Ketamine was included in 98.7% of reported IM drug regimens. The most common IM sedation regimen was combined ketamine and midazolam (median 2.5 mg/kg and 0.1 mg/kg, respectively). Of the respondents who use preoperative IM sedation, 87% reported using the same drug regimen in at least 80% of cases. CONCLUSION: The most frequently reported drug regimen used by dentist anesthesiologists in North America for preoperative IM sedation was a combination of ketamine and midazolam.

Kawasaki Disease and General Anesthesia for Dental Treatment: A Case Report.

Kawasaki disease (KD) is an acute vasculitis of childhood and is the leading cause of acquired heart disease in children in developed countries. Failure to quickly diagnose and treat patients with KD can result in severe cardiac sequelae, especially coronary artery aneurysms (CAAs). Patients with a prior diagnosis of KD who require general anesthesia (GA) may present unique challenges depending on the severity of any cardiovascular sequelae. This case report describes the perioperative management of a 5-year-old male patient previously diagnosed with incomplete KD approximately 1 year before presenting to Stony Brook University Hospital for full mouth dental rehabilitation under GA. Most uniquely, the patient was at high risk for coronary artery thrombosis due to a giant CAA of his right coronary artery and a small CAA of his left anterior descending artery. The discussion also includes the implications of dental treatment under GA for patients with a history of KD.

Patients with psychiatric disease: implications for anesthesiologists.

PURPOSE OF REVIEW: Psychiatric illness is common in patients presenting for surgery. Overall health and surgical outcomes are adversely affected by the presence of psychiatric comorbidities. RECENT FINDINGS: As new treatment modalities become available, their perioperative implications need to be evaluated. These implications include drug-drug interactions, hemodynamic effects, bleeding risk, and factors affecting perioperative exacerbation of the underlying psychiatric illness. SUMMARY: From our review of the recent literature we continue to support the continuation of psychoactive agents in the perioperative period, taking into consideration the effects these agents have on concomitant drug use in the perioperative period; and the risks of withholding them at a high-stress time.

Retrospective Comparison of Intramuscular Admixtures of Ketamine and Dexmedetomidine Versus Ketamine and Midazolam for Preoperative Sedation.

Precooperative children and patients with intellectual disabilities often require intramuscular (IM) sedation prior to the induction of general anesthesia (GA). Ketamine is an effective preinduction sedative but can produce significant adverse side effects. Dexmedetomidine, a sedative with sympatholytic and analgesic properties, may provide advantages when used in combination with ketamine. This retrospective study evaluated the efficacy and safety of IM ketamine with dexmedetomidine for preoperative sedation. We conducted a chart review of all patients (n = 105) treated for dental rehabilitation who received either IM ketamine and dexmedetomidine (study group, n = 74) or IM ketamine and midazolam (control group, n = 31) prior to induction of GA. No significant difference (p = .14) was observed in the time interval from IM administration to operating room entry (median [interquartile range]) between the study and control groups (5 [4-8] vs 5 [2-7] minutes). Patients who received IM dexmedetomidine exhibited significantly lower mean arterial pressures throughout the induction (p = .004) and had lower heart rates (p = .01) throughout the intraoperative period compared with patients who did not receive dexmedetomidine. The combination of dexmedetomidine and ketamine may provide effective and safe IM sedation prior to the induction of GA.

Tracheopulmonary Complications of a Malpositioned Nasogastric Tube.

Tracheopulmonary complications following placement of a nasogastric (NG) feeding tube are uncommon but can cause significant morbidity and mortality. In this case report, an 83-year-old woman of American Society of Anesthesiologists class IV with underlying pulmonary disease required placement of an NG feeding tube after surgical treatment of primary squamous cell carcinoma of the tongue. Malpositioning of the NG feeding tube into the right pleural space was confirmed by computed tomography. Removal of the NG feeding tube resulted in a tension pneumothorax that necessitated chest tube placement. Because of the difficulty of blind NG feeding tube placement in this patient, the subsequently placed NG feeding tube was successfully positioned with the aid of a video laryngoscope. This case report illustrates the risk of NG feeding tube malpositioning in a nasally intubated patient undergoing head and neck surgery and discusses improvements in techniques for proper NG feeding tube placement.

ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens.

ATI-2173 is a novel liver-targeted molecule designed to deliver the 5'-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5'-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5'-phosphoramidate to deliver the 5'-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5'-monophosphate is converted to the active 5'-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5'-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5'-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5'-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.

Analysis of the Potential for N4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function.

N4-Hydroxycytidine (NHC) is an antiviral ribonucleoside analog that acts as a competitive alternative substrate for virally encoded RNA-dependent RNA polymerases. It exhibits measurable levels of cytotoxicity, with 50% cytotoxic concentration values ranging from 7.5 µM in CEM cells and up to >100 µM in other cell lines. The mitochondrial DNA-dependent RNA polymerase (POLRMT) has been shown to incorporate some nucleotide analogs into mitochondrial RNAs, resulting in substantial mitochondrial toxicity. NHC was tested in multiple assays intended to determine its potential to cause mitochondrial toxicity. NHC showed similar cytotoxicity in HepG2 cells incubated in a glucose-free and glucose-containing media, suggesting that NHC does not impair mitochondrial function in this cell line based on the Crabtree effect. We demonstrate that the 5'-triphosphate of NHC can be used by POLRMT for incorporation into nascent RNA chain but does not cause immediate chain termination. In PC-3 cells treated with NHC, the 50% inhibitory concentrations of mitochondrial protein expression inhibition were 2.7-fold lower than those for nuclear-encoded protein expression, but this effect did not result in selective mitochondrial toxicity. A 14-day incubation of HepG2 cells with NHC had no effect on mitochondrial DNA copy number or extracellular lactate levels. In CEM cells treated with NHC at 10 µM, a slight decrease (by ∼20%) in mitochondrial DNA copy number and a corresponding slight increase in extracellular lactate levels were detected, but these effects were not enhanced by an increase in NHC treatment concentration. In summary, the results indicate that mitochondrial impairment by NHC is not the main contributor to the compound's observed cytotoxicity in these cell lines.

The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection.

The New World alphaviruses Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively) commonly cause a febrile disease that can progress to meningoencephalitis, resulting in significant morbidity and mortality. To address the need for a therapeutic agent for the treatment of Alphavirus infections, we identified and pursued preclinical characterization of a ribonucleoside analog EIDD-1931 (ß-D-N4-hydroxycytidine, NHC), which has shown broad activity against alphaviruses in vitro and has a very high genetic barrier for development of resistance. To be truly effective as a therapeutic agent for VEEV infection a drug must penetrate the blood brain barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly achieved in mice after oral dosing. Once in the plasma EIDD-1931 is efficiently distributed into organs, including brain, where it is rapidly converted to its active 5'-triphosphate. EIDD-1931 showed a good safety profile in mice after 7-day repeated dosing with up to 1000 mg/kg/day doses. In mouse model studies, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal infection when therapeutic treatment was started as late as 24 h post-infection, and partial protection was achieved when treatment was delayed for 48 h post-infection. These results support further preclinical development of EIDD-1931 as a potential anti-alphavirus drug.

Development of a novel progesterone analog in the treatment of traumatic brain injury.

Although systemic progesterone (PROG) treatment has been shown to be neuroprotective by many laboratories and in multiple animal models of brain injury including traumatic brain injury (TBI), PROG's poor aqueous solubility limits its potential for use as a therapeutic agent. The problem of solubility presents challenges for an acute intervention for neural injury, when getting a neuroprotectant to the brain quickly is crucial. Native PROG (nPROG) is hydrophobic and does not readily dissolve in an aqueous-based medium, so this makes it harder to give under emergency field conditions. An agent with properties similar to those of PROG but easier to store, transport, formulate, and administer early in emergency trauma situations could lead to better and more consistent clinical outcomes following TBI. At the same time, the engineering of a new molecule designed to treat a complex systemic injury must anticipate a range of translational issues including solubility and bioavailability. Here we describe the development of EIDD-1723, a novel, highly stable PROG analog with >104-fold higher aqueous solubility than that of nPROG. We think that, with further testing, EIDD-1723 could become an attractive candidate use as a field-ready treatment for TBI patients. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

ß-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome.

Venezuelan equine encephalitis virus (VEEV) is a representative member of the New World alphaviruses. It is transmitted by mosquito vectors and causes highly debilitating disease in humans, equids, and other vertebrate hosts. Despite a continuous public health threat, very few compounds with anti-VEEV activity in cell culture and in mouse models have been identified to date, and rapid development of virus resistance to some of them has been recorded. In this study, we investigated the possibility of using a modified nucleoside analog, ß-d-N4-hydroxycytidine (NHC), as an anti-VEEV agent and defined the mechanism of its anti-VEEV activity. The results demonstrate that NHC is a very potent antiviral agent. It affects both the release of genome RNA-containing VEE virions and their infectivity. Both of these antiviral activities are determined by the NHC-induced accumulation of mutations in virus-specific RNAs. The antiviral effect is most prominent when NHC is applied early in the infectious process, during the amplification of negative- and positive-strand RNAs in infected cells. Most importantly, only a low-level resistance of VEEV to NHC can be developed, and it requires acquisition and cooperative function of more than one mutation in nsP4. These adaptive mutations are closely located in the same segment of nsP4. Our data suggest that NHC is more potent than ribavirin as an anti-VEEV agent and likely can be used to treat other alphavirus infections.IMPORTANCE Venezuelan equine encephalitis virus (VEEV) can cause widespread epidemics among humans and domestic animals. VEEV infections result in severe meningoencephalitis and long-term sequelae. No approved therapeutics exist for treatment of VEEV infections. Our study demonstrates that ß-d-N4-hydroxycytidine (NHC) is a very potent anti-VEEV compound, with the 50% effective concentration being below 1 µM. The mechanism of NHC antiviral activity is based on induction of high mutation rates in the viral genome. Accordingly, NHC treatment affects both the rates of particle release and the particle infectivity. Most importantly, in contrast to most of the anti-alphavirus drugs that are under development, resistance of VEEV to NHC develops very inefficiently. Even low levels of resistance require acquisition of multiple mutations in the gene of the VEEV-specific RNA-dependent RNA polymerase nsP4.

Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats.

The poor aqueous solubility of progesterone (PROG) limits its potential use as a therapeutic agent. We designed and tested EIDD-1723, a novel water-soluble analog of PROG with >100-fold higher solubility than that of native PROG, as candidate for development as a field-ready treatment for traumatic brain injury (TBI). The pharmacokinetic effects of EIDD-1723 on morphological and functional outcomes in rats with bilateral cortical impact injury were evaluated. Following TBI, 10-mg/kg doses of EIDD-1723 or PROG were given intramuscularly (i.m.) at 1, 6 and 24 h post-injury, then daily for the next 6 days, with tapering of the last 2 treatments. Rats were tested pre-injury to establish baseline performance on grip strength and sensory neglect, and then retested at 4, 9 and 21 days post-TBI. Spatial learning was evaluated from days 11-17 post-TBI. At 22 days post-injury, rats were perfused and brains extracted and processed for lesion size. For the edema assay the animals were killed and brains removed at 24 h post-injury. EIDD-1723 significantly reduced cerebral edema and improved recovery from motor, sensory and spatial learning deficits as well as, or better than, native PROG. Pharmacokinetic investigation after a single i.m. injection in rats revealed that EIDD-1723 was rapidly converted to the active metabolite EIDD-036, demonstrating first-order elimination kinetics and ability to cross the blood-brain barrier. Our results suggest that EIDD-1723 represents a substantial advantage over current PROG formulations because it overcomes storage, formulation and delivery limitations of PROG and can thereby reduce the time between injury and treatment.

Water-soluble progesterone analogues are effective, injectable treatments in animal models of traumatic brain injury.

After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries. It is currently being investigated in two, independent phase III clinical trials in hospital settings; however, it presents a formidable solubility challenge that has so far prevented the identification of a formulation that would be suitable for emergency field response use or battlefield situations. Accordingly, we have designed and tested a novel series of water-soluble analogues that address this critical need. We report here the synthesis of C-20 oxime conjugates of progesterone as therapeutic agents for traumatic brain injuries with comparable efficacy in animal models of traumatic brain injury and improved solubility and pharmacokinetic profiles. Pharmacodynamic analysis reveals that a nonprogesterone steroidal analogue may be primarily responsible for the observed activity.

Radical and Heck cyclizations of diastereomeric o-haloanilide atropisomers.

The outcomes of radical cyclizations and Heck reactions of N-(cyclohex-2-enyl)-N-(2-iodophenyl)acetamides depend critically on the configurations of the chiral axis and the stereocenter. In substrates without an ortho-methyl group, the diastereomeric precursors interconvert slowly at ambient temperatures. Cyclization of enriched mixtures of diastereomers provided similar yields of acetyl tetrahydrocarbazoles or dihydrocarbazoles, suggesting that interconversion of the radical or organometallic intermediates also occurs. Diastereomers of N-(cyclohex-2-enyl)-N-(2-iodo-4,6-dimethylphenyl)acetamides with an additional ortho-methyl group did not interconvert at ambient temperatures and were readily resolved. In radical cyclizations, syn diastereomers were prone to cyclize, while anti isomers were not. Strikingly, Heck reactions gave the opposite result; anti isomers were prone to cyclization and syn isomers were not. Heck reactions of allylic acetates occur with ß-hydride elimination when acetate is trans to palladium and with ß-acetoxy elimination when acetate is cis. This is surprising because prior studies have suggested that a trans relationship of palladium and acetoxy is essential for acetate elimination. Analyses of the results provide insights into mechanisms for radical cyclization and for insertion and elimination in the Heck reaction.

Memory of axial chirality in aryl radical phosphanylations.

The rate constant for phosphanylation of an aryl radical with trimethylstannyl diphenylphosphane (Me(3)SnPPh(2)) has been measured as k(phos) approximately 9 x 10(8) M(-1) s(-1). Aryl radicals derived from several axially chiral o-haloanilides are trapped by Me(3)SnPPh(2) with complete retention of axial chirality as shown by oxidation of the phosphanes to give stable, easily analyzed phosphane oxides or sulfides. Double phosphanylations of o,o'-dihaloanilides followed by treatment with H(2)O(2) or S(8) in either order give enantiomers of a mixed diphosphane oxide sulfide. Chemodivergent trapping of diastereomers of an N-(cyclohex-2-enyl)anilide anilide is observed. For one isomer, the cyclization precedes the Me(3)SnPPh(2) trapping, while for the other isomer direct trapping with Me(3)SnPPh(2) supersedes the cyclization. The products are chiral triaryl phosphanes, oxides, and sulfides that are potentially interesting ligands in asymmetric catalysis.

Synthesis of highly enantioenriched 3,4-dihydroquinolin-2-ones by 6-exo-trig radical cyclizations of axially chiral alpha-halo-ortho-alkenyl anilides.

Radical cyclizations (Bu(3)SnH, Et(3)B/air, rt) of racemic alpha-halo-ortho-alkenyl anilides provide 3,4-dihydroquinolin-2-ones in high yield. Cyclizations of enantioenriched precursors occur in similarly high yields and with transfer of axial chirality to the new stereocenter of the products with exceptionally high fidelity (often >95%). Single and tandem cyclizations of alpha-halo-ortho-alkenyl anilides bearing an additional substituent on the alpha-carbon occur with high chirality transfer and high diastereoselectivity. Straightforward models are proposed to interpret both the chirality transfer and diastereoselectivity aspects. These first examples of an approach for axial chiral transfer from a reactive species in the amide to an acceptor suggest broad potential for extension both within and beyond radical reactions.

Bond rotation dynamics of N-cycloalkenyl-N-benzyl alpha-haloacetamide derivatives.

Barriers to rotation of the N-alkenyl bond in a series of N-cycloalkenyl-N-benzyl alpha-haloacetamide derivatives have been measured by variable-temperature NMR experiments. The barriers range from 10 to 18 kcal/mol, depending on ring size and on substituents on the cycloalkene and the amide. The observed trends aid in the design of substituent combinations that provide resolvable enantiomers or diastereomers at ambient temperature. The compounds undergo 4-exo and 5-endo radical cyclizations at rates that may be faster or slower than the estimated rate of N-alkenyl bond rotation in the derived radicals, depending on the substituents.

Asymmetric radical and anionic cyclizations of axially chiral carbamates.

Standard Boc, Alloc, and Cbz derivatives of N-2,4-dimethyl-6-iodophenyl-N-allyl anilines are axially chiral and can be readily resolved into atropisomers whose racemization barriers exceed 30 kcal/mol. The resolved axially chiral carbamates undergo radical and anionic cyclizations with high levels of chirality transfer from the N-Ar axis to the new stereocenter in the substituted dihydroindole products. The carbamate groups of the products are readily removed.

How do analogous alpha-chloroenamides and alpha-iodoenamides give different product distributions in 5-endo radical cyclizations?

5-Endo cyclizations of N-alkenyl carbamoylmethyl radicals provide gamma-lactam radicals, which in turn evolve to reduced or non-reduced (alkene) products depending on reagents and reaction conditions. Several groups have made surprising observations that chlorides are better radical precursors than iodides in such cyclizations. Here is described a detailed study of tin and silicon hydride-mediated radical cyclizations of N-benzyl-2-halo-N-cyclohex-1-enylacetamides. The ratios of directly reduced, cyclized/reduced, and cyclized/non-reduced products depend not only on the reaction conditions and reducing reagent but also on the precursor. Prior explanations for the precursor-dependent product ratios based on amide rotamer effects are ruled out. The precursor-dependent behavior is further dissected into two different effects: (1) the ratio of cyclized/reduced products to cyclized/non-reduced products depends on the ability of the radical precursor to react with the product gamma-lactam radical in competition with tin hydride (iodides can compete, chlorides cannot), and (2) the occurrence of large amounts of directly reduced (noncyclized) products in the case of iodides is attributed to a competing ionic chain reaction by which the precursor is reductively deiodinated with HI. This side reaction is not available to chlorides, thereby explaining why the chlorides are better precursors in such reactions. The ability of the iodides to provide cyclized products can be largely restored by adding base. The chlorides and iodides then become complementary precursors, with chlorides giving largely cyclized/reduced products and iodides giving largely cyclized/non-reduced products.