Analysis of unknown (unlabeled/mislabeled) drug products for active pharmaceutical ingredients and related substances by an international mail facility satellite laboratory equipped with rapid screening devices.

Two chemists employed a three-device rapid screening "toolkit" consisting of a handheld Raman spectrometer, transportable mass spectrometer, and portable Fourier transform infrared (FT-IR) spectrometer at an international mail facility (IMF) satellite laboratory to examine unknown (unlabeled/mislabeled) products for the presence of active pharmaceutical ingredients (APIs). Phase I of this project previously demonstrated that this toolkit was the most effective collection of instruments for identifying APIs in product types collected at IMFs during a nationwide mail blitz and Phase II of this project previously demonstrated that results generated using the toolkit during a satellite laboratory pilot program were as reliable as those generated by a full-service library when two or more of these instruments identify an API. This study (Phase III) described the results of the satellite laboratory toolkit during production mode and encompassed the period ranging from June 2021 through December 2022. During this study, a total of 858 products were examined on-site at the IMF. The satellite laboratory yielded conclusive results for 726 (84.6%) products, which were used to support regulatory action, and identified 132 (15.4%) products that required additional full-service laboratory analyses due to inconclusive results. The satellite and full-service laboratory verified/confirmed at least one API/related substance in 617 (71.9%) products. A total of 709 APIs/related substances were found in the 617 products, and 202 of these 709 compounds were unique/different. Overall, during Phases I through III of this program, 350 different substances have been identified in products collected at IMFs.

Rapid screening of 2-benzylbenzimidazole nitazene analogs in suspect counterfeit tablets using Raman, SERS, DART-TD-MS, and FT-IR.

Developing methods to rapidly screen for novel synthetic 2-benzylbenzimidazole opioids, also known as nitazenes, has become increasingly important due to their high potency. These compounds have potency comparable or exceeding that of fentanyl by up to 10 times and have been implicated in approximately 5% of all drug overdose deaths in the United States in 2021. This paper details the authenticity determination of suspect tablets and the identification of three nitazene analogs (N-pyrrolidino etonitazene, isotonitazene, and etodesnitazene) in suspect tablets seized at a mail facility using Raman and surface-enhanced Raman scattering (SERS) with handheld devices, portable Fourier transform infrared spectrometer (FT-IR), and a direct analysis in real-time ambient ionization coupled to a thermal desorption unit and a mass spectrometer (DART-TD-MS). These methods are rapid and excellent for screening opioids in suspect tablets but could not fully determine the exact structure of some of the nitazene analogs present due to spectral similarities or similar fragmentation patterns. Liquid chromatography-mass spectrometry (LC-MS) confirmed the presence of these nitazene compounds in addition to other opioids/drugs that were in trace quantities. The quantitative high-performance liquid chromatography coupled with ultraviolet (HPLC-UV) detection experiments determined that the suspect tablets contained an average of 0.817 mg of N-pyrrolidino etonitazene per tablet. The results obtained reveal that the simultaneous deployment of these complementary and orthogonal portable analytical techniques as part of a workflow allows suspect tablets to be screened and nitazene-type drugs to be identified in suspect counterfeit tablets at remote sampling sites.

Rapid detection of active pharmaceutical ingredients in drug products collected at an international mail facility by a satellite laboratory using a "toolkit" consisting of a handheld Raman spectrometer, portable mass spectrometer and portable FT-IR spectrometer.

A satellite laboratory "toolkit" consisting of a handheld Raman spectrometer, portable direct analysis in real-time mass spectrometer (DART-MS) and portable Fourier transform infrared (FT-IR) spectrometer was employed to examine 926 pharmaceutical, unknown and dietary supplement products collected at an international mail facility (IMF) for the presence of declared and undeclared active pharmaceutical ingredients (APIs) over the course of 68 working days. The toolkit successfully identified over 650 APIs, including over 200 unique APIs, using two or more devices. The performance of each individual device, and toolkit as a whole, were evaluated on all products and a subset of the products was forwarded to full-service laboratories for confirmatory analysis to determine false positive and false negative rates of the toolkit. The subset consisted of seven negative items (those not found to contain APIs using the toolkit) and 124 positive items (those found to contain at least one API using the toolkit). Overall, no false positives were detected in the negative items and only four false negatives and five false positives were detected in the positive items. Regarding the positive items, 119 of the 124 items were found to contain at least one API using at least two toolkit devices; each of these APIs were confirmed by a full-service laboratory. Furthermore, 90.2% of the APIs found by confirmatory laboratory analysis were detected by at least two toolkit devices. Based on these metrics and the fact that no false positives were detected by more than one device, it was concluded that when the toolkit detects and subsequently verifies/confirms an API using two or more devices, the results are as reliable as those generated by a full-service laboratory.

Opportunity costs of attending surgical clinic appointments and experiences with telemedicine for follow-up care.

OBJECTIVES: Telemedicine has been rapidly implemented in orthopedics during the coronavirus (COVID-19) pandemic. The purpose of this study was to quantify opportunity costs for patients attending typical in-person appointments and understand their perceptions of telemedicine for follow-up care. METHODS: A cross-sectional study was performed by surveying patients who had elective orthopedic surgery and attended at least one in-person and one phone call appointment. The survey assessed opportunity costs associated with in-person appointments, experience with telemedicine, and preferred type of future appointment. RESULTS: Of the 49 eligible patients, 41 (83.7%) completed the survey. The median travel distance to the clinic was 108 km, and the time spent in the clinic was 60 min. Participants responded "yes" to various forms of opportunity costs associated with attending in-person appointments, including missed work (46.3%), lost income (34.1%), recreational activities (26.8%), home or yard care (14.6%), socializing with friends or family (12.2%), school (2.4%), and childcare (2.4%). In addition, elements of the telemedicine appointment were rated from 1 (least favorable) to 10 (most favorable), and averages were calculated for ease of use (9.2), convenience (8.4), confidence in the doctor's diagnostic ability (8.2), likelihood of using the service again (6.4), and overall satisfaction (8.2). Preferred future appointment types included having the first visit in-person and subsequent visits via telephone (61.0%), in-person only (36.6%), and unsure (2.4%). CONCLUSION: This study identifies various opportunity costs associated with in-person orthopedic appointments and a favorable view toward telemedicine for follow-up care.

Evaluation of "Toolkit" consisting of handheld and portable analytical devices for detecting active pharmaceutical ingredients in drug products collected during a simultaneous nation-wide mail blitz.

A "toolkit" consisting of a handheld Raman spectrometer equipped with a 1064 nm laser, a portable Fourier transform infrared (FT-IR) spectrometer and a portable direct analysis in real-time mass spectrometer (DART-MS) was employed in a laboratory setting to examine 82 representative products collected during a nationwide mail blitz for the presence of APIs. These results were compared to those obtained using laboratory-based methods; 8 of the products were not found to contain APIs and 74 of the products were found to contain a total of 88 APIs (65 of the 88 APIs were unique). The individual performance of each device and combined performance of the three-device toolkit were evaluated with regard to true positives, true negatives, false positives and false negatives. Using this toolkit, 81 (92.0 %) of the APIs were detected by at least one technique and 47 (64.8 %) of the APIs were detected by at least two techniques. Seven false negatives (8.0 %) were encountered and while the toolkit yielded 12 false positives, no false positives were detected by more than one technique. Overall, this study demonstrated that when the toolkit detects an API using two or more devices, the results are as reliable as those generated by a full-service laboratory.

Evaluation of four field portable devices for the rapid detection of mitragynine in suspected kratom products.

The development of a method for the rapid screening of food and drug products for constituents such as mitragynine, the most abundant alkaloid found in Mitragyna speciosa (kratom) plant leaves, has become increasingly important. The use of kratom is said to produce stimulant or narcotic effects and poses risks of addiction, abuse, and dependence, much like other opioids. Direct Analysis in Real Time with thermal desorption mass spectrometry (DART-TD-MS), hand-held mass spectrometry, portable ion mobility spectrometry (IMS), and portable Fourier-transform infrared spectroscopy (FT-IR) were each evaluated as field-deployable screening techniques for the detection of mitragynine in food and drug products. These devices offer the potential for rapid, early detection of mitragynine in suspect products entering the United States through international mail facilities and other ports of entry. Ninety-six kratom products, including capsules, bulk powder, and bulk plant material, were analyzed by either direct sampling of the solid material or by solvent extraction. True and false positive and negative results are reported, based on comparison to results from qualitative screening using gas chromatography with mass spectral detection (GC-MS), liquid chromatography with mass spectral detection (LC-MS), and/or quantitative screening using high-performance liquid chromatography with ultraviolet detection (HPLC-UV), with a discussion of the assessment of each technique for use in the field. Each device demonstrated attributes that would be favorable for use in screening of suspected mitragynine-containing products at places like ports of entry, and simultaneous deployment of two or more of these devices as part of a workflow would be the most effective for rapid screening of these products. This combination of rapid screening orthogonal techniques suited to a non-laboratory environment will allow onsite destruction of products found to contain mitragynine.

Detection of Mitragynine in Mitragyna Speciosa (Kratom) Using Surface-Enhanced Raman Spectroscopy with Handheld Devices.

A simple, quick, selective, sensitive, and effective field-friendly method capable of being used by nonexperts has been developed for detecting mitragynine in Mitragyna speciosa (kratom) using surface-enhanced Raman spectroscopy (SERS). Over 100 samples and blanks (known to be either positive or negative for the presence of mitragynine) were examined in duplicate using five identical handheld Raman spectrometers, which provided a data set of over 1,000 examinations. Based on the results of these analyses, the method yielded a true-positive rate of 99.3%, a true-negative rate of 97.9%, a false-positive rate of 2.1%, and a false-negative rate of 0.7%. The average minimum detectable concentration (Cm ) of mitragynine that reproducibly yielded a match for one of the library spectra on all five instruments was determined to be 342 ng/mL (ppb). This Cm value is a conservative estimate considering that the extraction process was not fully optimized by this study, which was not necessary since the Cm value achieved was well below typical mitragynine concentrations in kratom (1.3-2.3%). The method is ideal (i) for prioritizing samples for additional testing using other more time-consuming laboratory-based techniques needed to detect and quantify mitragynine and (ii) for field use at international mail facility (IMF) satellite laboratories to help interdict kratom and prevent this dangerous product from reaching the U.S. supply chain.

Evaluation of Suspected Counterfeit Pharmaceutical Tablets Declared to Contain Controlled Substances Using Handheld Raman Spectrometers.

This study describes the performance of handheld Raman devices for determining whether suspect pharmaceutical tablets declared to contain controlled substances were consistent with authentic (CWA) or not consistent with authentic (NCWA) tablets using a simple, rapid, field-friendly method capable of being used by nonexperts. Twenty-five authentic products and 84 known NCWA tablets were examined using three "parent" devices for a total of 327 analyses. On average, the parent devices yielded a true pass rate of 100%, a true fail rate of 98.4%, a false pass rate of 1.6%, and a false fail rate of 0%. The methods/libraries were then transferred to 13 identical "daughter" devices, which were used to examine 10 suspect finished dosage forms in duplicate (six known NCWA tablets and four authentic tablets) for a total of 260 measurements. On average, the daughter devices had a true pass rate of 100%, a true fail rate of 95.5%, a false pass rate of 4.5%, and a false fail rate of 0.0%. These data demonstrate that the parent-daughter electronic transfer method was successful, which permits the ability to develop methods in the laboratory that can be seamlessly pushed out to field devices. The methods can then be used to (i) prioritize samples for additional testing using other more time-consuming laboratory-based techniques needed to detect and quantify active ingredients and (ii) help support the interdiction of dangerous tablets at ports of entry, thereby preventing them from reaching the supply chain.

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 1: IV options).

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a predominant pathogen resulting in significant morbidity and mortality. Optimal dosing of anti-MRSA agents is needed to help prevent the development of antimicrobial resistance and to increase the likelihood of a favorable clinical outcome. Areas covered: This review summarizes the available data for antimicrobials routinely used for MRSA infections that are not administered orally or topically. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 - Present) search was performed to identify relevant literature for this review. Expert commentary: Improvements in MIC determination and therapeutic drug monitoring are needed to fully implement individualized dosing that optimizes antimicrobial pharmacodynamics.Additional data will become available for these agents in regards to effectiveness for severe MRSA infections and pharmacokinetic data for special patient populations.

Measurement of glucose in blood with a phenylboronic acid optical sensor.

BACKGROUND: Current methods of glucose monitoring rely predominantly on enzymes such as glucose oxidase for detection. Phenylboronic acid receptors have been proposed as alternative glucose binders. A unique property of these molecules is their ability to bind glucose in a fully reversible covalent manner that facilitates direct continuous measurements. We examined (1) the ability of a phenylboronic-based sensor to measure glucose in blood and blood plasma and (2) the effect on measurement accuracy of a range of potential interferents. We also showed that the sensor is able to track glucose fluctuations occurring at rates mimicking those experienced in vivo. METHOD: In vitro static measurements of glucose in blood and blood plasma were conducted using holographic sensors containing acrylamide, N,N'-methylenebisacrylamide, 3-acrylamidophenylboronic acid, and (3-acrylamidopropyl) trimethylammonium chloride. The same sensors were also used for in vitro measurements performed under flow conditions. RESULTS: The opacity of the liquid had no affect on the ability of the optical sensor to measure glucose in blood or blood plasma. The presence of common antibiotics, diabetic drugs, pain killers, and endogenous substances did not affect the measurement accuracy, as shown by error grid analysis. Ex vivo flow experiments showed that the sensor is able to track changes accurately in concentration occurring in real time without lag or evidence of hysteresis. CONCLUSIONS: The ability of phenylboronic acid sensors to measure glucose in whole blood was demonstrated for the first time. Holographic sensors are ideally suited to continuous blood glucose measurements, being physically and chemically robust and potentially calibration free.

Continuous blood glucose monitoring with a thin-film optical sensor.

BACKGROUND: We recently described a holographic optical sensor with improved selectivity for glucose over fructose that was based on a thin-film polymer hydrogel containing phenylboronic acid receptors. The aim of the present work was to measure glucose in human blood plasma as opposed to simple buffers and track changes in concentration at a rate mimicking glucose changes in vivo. METHODS: We used holographic sensors containing acrylamide, N,N'-methylenebisacrylamide, 3-acrylamidophenylboronic acid, and (3-acrylamidopropyl)trimethylammonium chloride to measure 7 human blood plasma samples at different glucose concentrations (3-33 mmol/L) in static mode. Separately, using a flow cell, the glucose concentration was varied at approximately 0.17-0.28 mmol(-1) x L(-1) x min(-1), and the sensor's ability to continuously monitor glucose was investigated over an extended period. RESULTS: We subjected the results of the ex vivo static measurements to error grid analysis. Of 46 measurements, 42 (91.3%) fell in zone A of a Clarke error grid, and the remainder (8.7%) fell in zone B. The ex vivo flow experiments showed that the sensor is able to accurately track changes in concentration occurring in real time without lag or evidence of hysteresis. CONCLUSIONS: We demonstrate the ability of a phenylboronic acid-based sensor to measure glucose in human blood plasma for the 1st time in vitro. Holographic glucose sensors can be used without recourse to recalibration. Their robust nature, coupled with their format flexibility, makes them an attractive alternative to conventional electrochemical enzyme-based methods of glucose monitoring for people with diabetes.