RESUMO
Oral endocrine therapies (OET) for breast cancer treatment need to be taken over a long period of time and are associated with considerable side effects. Therefore, adherence to OET is an important issue and of high clinical significance for breast cancer patients' caregivers. We hypothesized that a new bioanalytical strategy based on liquid chromatography and high-resolution mass spectrometry might be suitable for unbiased adherence monitoring (AM) of OET. Four different biomatrices (plasma, urine, finger prick blood by volumetric absorptive microsampling (VAMS), oral fluid (OF)) were evaluated regarding their suitability for AM of the OET abemaciclib, anastrozole, exemestane, letrozole, palbociclib, ribociclib, tamoxifen, and endoxifen. An analytical method was developed and validated according to international recommendations. The analytical procedures were successfully validated in all sample matrices for most analytes, even meeting requirements for therapeutic drug monitoring. Chromatographic separation of analytes was achieved in less than 10 min and limits of quantification ranged from 1 to 1000 ng/mL. The analysis of 25 matching patient samples showed that AM of OET is possible using all four matrices with the exception of, e.g., letrozole and exemestane in OF. We were able to show that unbiased bioanalytical AM of OET was possible using different biomatrices with distinct restrictions. Sample collection of VAMS was difficult in most cases due to circulatory restraints and peripheral neuropathy in fingers and OF sampling was hampered by dry mouth syndrome in some cases. Although parent compounds could be detected in most of the urine samples, metabolites should be included when analyzing urine or OF. Plasma is currently the most suitable matrix due to available reference concentrations.
Assuntos
Antineoplásicos Hormonais , Neoplasias da Mama , Monitoramento de Medicamentos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/urina , Monitoramento de Medicamentos/métodos , Cromatografia Líquida/métodos , Administração Oral , Espectrometria de Massas/métodos , Letrozol/sangue , Adesão à Medicação , Limite de Detecção , Tamoxifeno/uso terapêutico , Tamoxifeno/sangue , Tamoxifeno/análise , Tamoxifeno/urina , Saliva/química , Androstadienos/urina , Androstadienos/análise , Androstadienos/administração & dosagem , Androstadienos/uso terapêutico , Androstadienos/sangue , Anastrozol , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Analytical monitoring of adherence using mass spectrometry (MS) plays an important role in clinical toxicology. Unambiguous detection of drugs (of abuse) and/or their metabolites in body fluids is needed to monitor intake of medication as prescribed or to monitor abstinence as a follow-up to detoxification procedures. This study focused on the advantages and disadvantages of different sample matrices used for MS-based adherence monitoring. METHODS: Relevant articles were identified through a literature search in the PubMed database. English articles published between January 01, 2017, and December 31, 2022, were selected using the keywords "adherence assess*" or "adherence monit*" or "compliance assess*" or "compliance monit*" in combination with "mass spectrom*" in the title or abstract. RESULTS: A total of 51 articles were identified, 37 of which were within the scope of this study. MS-based monitoring was shown to improve patient adherence to prescribed drugs. However, MS analysis may not be able to assess whether treatment was rigorously followed beyond the last few days before the sampling event, except when hair is the sample matrix. For medication adherence monitoring, blood-based analyses may be preferred because reference plasma concentrations are usually available, whereas for abstinence control, urine and hair samples have the advantage of extended detection windows compared with blood. Alternative sample matrices, such as dried blood samples, oral fluid, and exhaled breath, are suitable for at-home sampling; however, little information is available regarding the pharmacokinetics and reference ranges of drug (of abuse) concentrations. CONCLUSIONS: Each sample matrix has strengths and weaknesses, and no single sample matrix can be considered the gold standard for monitoring adherence. It is important to have sufficient information regarding the pharmacokinetics of target substances to select a sample matrix in accordance with the desired purpose.
Assuntos
Monitoramento de Medicamentos , Adesão à Medicação , Espectrometria de Massas em Tandem , Humanos , Líquidos Corporais/química , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
Sewage-based epidemiology using influent wastewater is used to estimate the consumption trends of (illicit) drugs over a short or long period of time in a subpopulation. The current study aimed to develop two separate methods for the quantitative analysis of selected drugs of abuse (DOA) and cognitive enhancers in influent wastewater using reversed-phase (RP) or hydrophilic interaction liquid chromatography (HILIC) coupled to high-resolution tandem mass spectrometry (LC-HRMS/MS). The performance of RP and HILIC column was evaluated. A simple solid phase extraction was used for sample preparation. Short runtimes of 10 and 15 min on the RP and the HILIC column, respectively, allowed sufficient throughput. A six-point calibration was used for quantification with calibration ranges between 10 and 100 ng/L for all analytes except for benzoylecgonine (BZE, 30-300 ng/L). Method validation was performed according to ICH guideline M10. Analytes such as amphetamine (AMPH), BZE, cocaethylene (CE), cocaine (COC), ethyl sulfate, 4-hydroxy-3-methoxymethamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine, methylphenidate (MPH), and ritalinic acid (RA) were included in method development and validation. Two different column types were necessary for sufficient chromatographic resolution. The analytical setup allowed detection of all other analytes at concentration levels between 1 ng/L for methylphenidate to 10 ng/L for amphetamine. A method for the detection and quantification of DOA, cognitive enhancers, and their biomarkers in wastewater was successfully developed and validated. Moreover, six proof-of-concept samples were analyzed in which AMPH, BZE, COC, MDMA, MPH, and RA were identified and further quantified.
RESUMO
OBJECTIVE: Dietary sodium intake represents a risk factor for cardiovascular disease and mortality. The study sought to analyse the sodium content of effervescent dietary supplements and drugs in Germany and the USA. DESIGN: Comparative cross-sectional study. SETTING AND METHODS: The sodium content of 39 dietary supplement effervescent tablets available in Germany was measured in May and June 2022 using optical emission spectrometry with inductively coupled argon plasma. The sodium content of 33 common pharmacy-only effervescent tablets (over-the-counter (OTC) drugs) in Germany was obtained from the summary of product characteristics. We compared the sodium content of the measured German dietary supplement effervescent tablets to that of 51 dietary supplement effervescent tablets available in the USA (data: National Institutes of Health's Dietary Supplement Label Database). RESULTS: The measured sodium content in the German dietary supplements was 283.9±122.6 mg sodium/tablet, equivalent to 14±6% of the maximum recommended daily sodium intake (MRDSI). Vitamin products had the highest (378.3±112.8 mg, 19±6% of MRDSI), and calcium products had the lowest mean sodium content (170.4±113.2 mg, 9±6% of MRDSI). Vitamin products contained significantly more sodium than magnesium (378.3 mg vs 232.7 mg; p=0.004), calcium (378.3 mg vs 170.4 mg; p=0.006) and mineral products (378.3 mg vs 191.6 mg; p=0.048). The sodium content measured in products available in Germany was higher when compared with the declared sodium content on the label of the products sold in the USA (283.9 mg vs 190.0 mg; p<0.001). The median summary of product characteristics-declared sodium content of a single dose of the German OTC drugs was 157.0 mg (IQR: 98.9-417.3 mg); pain/common cold drugs contained the most sodium (median: 452.1 mg; IQR: 351.3-474.0 mg). CONCLUSION: Effervescent tablets of nutritional supplements and OTC drugs contain high amounts of sodium, which often is not disclosed.
Assuntos
Medicamentos sem Prescrição , Sódio , Humanos , Estudos Transversais , Cálcio , Suplementos Nutricionais/análise , Vitaminas , ComprimidosRESUMO
Chloroquine, a drug approved for the treatment of malaria, is frequently used to commit suicide. We report about a suicide attempt by ingesting a high dose of chloroquine in combination with other drugs. Findings of the emergency toxicology screening of blood and urine and those of the follow-up analyses in blood are discussed. Systematic toxicological analysis approaches revealed the presence of chloroquine, butylscopolamine, cafedrine, diazepam, lorazepam, metoclopramide, nordazepam, norephedrine and 11-nor-9-carboxy-∆9-tetrahydroxycannabinol in blood and/or urine of the subject. Suicide due to a combination of chloroquine and benzodiazepines is known as the so-called "Kusch method" in German-speaking countries. The initial chloroquine plasma concentration was determined to be 9.6 mg/L after precipitation and analysis by liquid chromatography-high-resolution tandem mass spectrometry. The analytical procedure was developed ad hoc and validated in accordance with international recommendations. Clinical toxicological follow-up analyses in blood were performed over a period of 3 weeks. The chloroquine concentration remained above the therapeutic range (up to 0.5 mg/L) for 2 weeks and dropped to 0.3 mg/L after 3 weeks. Furthermore, monodesethylchloroquine (MDCQ) and bisdesethylchloroquine (BDCQ) were determined to be the most abundant metabolites in plasma. Within 3 weeks, the area ratios of MDCQ and chloroquine increased 4-fold (from 0.090 to 0.350), and those of BDCQ and chloroquine increased 100-fold (from 0.002 to 0.218). This information may help to estimate the chloroquine excretion progress in the future.
Assuntos
Cloroquina , Tentativa de Suicídio , Humanos , Seguimentos , Cloroquina/urina , Diazepam , NordazepamRESUMO
Volumetric absorptive microsampling (VAMS), an emerging microsampling technique, is a promising tool for adherence monitoring. This study focused on development of an analytical methodology to improve VAMS-based strategies for adherence assessment by analyzing angiotensin-converting-enzyme (ACE) inhibitors, loop diuretics, a potassium-sparing diuretic, and a thiazide diuretic. Development included sample preparation, chromatographic conditions, mass spectrometry settings, validation, and demonstrating proof of concept. Quantification of analytes, by name furosemide, hydrochlorothiazide, lisinopril, torasemide, and the active metabolites, canrenone, enalaprilat, and ramiprilat in finger prick blood (FPB), was validated based on international guidelines. Selectivity, carryover, and within/between-run accuracy and precision were in accordance with the recommendations. The matrix effect was evaluated at three different hematocrit levels (HT: 20%, 40%, 60%) and the coefficients of variation did not exceed 15%. Dilution integrity (1:10 and 1:20) was given for all analytes except lisinopril, yet for lisinopril, the therapeutic range was already covered by the calibration range. Long-term stability in VAMS tips was tested for 2 weeks at 24 °C in the dark and revealed no degradation of analytes. The proof of concept was performed by analyzing 35 intakes of ACE-inhibitors and diuretics in 18 VAMS and matched plasma samples. Hereby, determined concentration in FPB and plasma cannot be used interchangeably, and thus specific reference ranges for whole blood must be established. Nevertheless, the VAMS-based strategy was shown to be suitable for assessing adherence of all classes of antihypertensive drugs used in the guidelines to manage hypertension.
Assuntos
Anti-Hipertensivos , Lisinopril , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Coleta de Amostras Sanguíneas/métodos , Inibidores da Enzima Conversora de Angiotensina , Adesão à Medicação , Teste em Amostras de Sangue Seco/métodosRESUMO
The active, poisonous constituents in Taxus baccata, the yew plants, are taxine alkaloids whose main action is suggested to be a block of calcium and sodium channels. The main alkaloids are taxine B (30%) and taxine A (1.3%). Symptoms can include bradycardia, bradypnea, diastolic, and cardiac standstill. The current investigation reports the analytical toxicology of human blood and urine to confirm a suspected ingestion of yew needles. This includes the qualitative detection of several yew ingredients, including the main alkaloids, the validated quantification of 3,5-dimethoxyphenol, and the discussion of suitable analytical targets. After analyzing human specimens and yew needle extracts using the developed procedures, the five alkaloids 1-deotaxine B, taxicatin, taxine A, taxine B, and taxine I could be detected and tentatively identified. Finally, taxine A and B can be recommended as analytical targets besides 3,5-dimethoxyphenol.
Assuntos
Alcaloides , Taxus , Humanos , Extratos Vegetais/química , Espectrometria de Massas em Tandem/métodos , Alcaloides/análise , Cromatografia Líquida/métodos , Taxus/químicaRESUMO
BACKGROUND: Every year, more new psychoactive substances (NPSs) emerge in the market of the drugs of abuse. NPSs belong to various chemical classes, such as synthetic cannabinoids, phenethylamines, opioids, and benzodiazepines. The detection of NPSs intake using different types of biological matrices is challenging for clinical toxicologists because of their structural diversity and the lack of information on their toxicokinetics, including their metabolic fate. METHODS: PubMed-listed articles reporting mass spectrometry-based bioanalytical approaches for NPSs detection published during the past 5 years were identified and discussed. Furthermore, the pros and cons of using common biological matrices in clinical toxicology (CT) settings to screen for NPSs are highlighted in this review article. RESULTS: Twenty-six articles presenting multianalyte screening methods for use in the field of CT were considered. The advantages and disadvantages of different biological matrices are discussed with a particular view of the different analytical tasks in CT, especially emergency toxicology. Finally, an outlook introduces the emerging trends in biosamples used in CT, such as the exhaled breath. CONCLUSIONS: Blood and urine represent the most common biological matrices used in a CT setting; however, reports concerning NPSs detection in alternative matrices are also available. Noteworthy, the selection of the biological matrix must depend on the clinician's enquiry because the individual advantages and disadvantages must be considered.
Assuntos
Benzodiazepinas , Psicotrópicos , Analgésicos Opioides , Benzodiazepinas/toxicidade , Humanos , Espectrometria de Massas , Fenetilaminas , Detecção do Abuso de Substâncias/métodosRESUMO
Volumetric absorptive microsampling (VAMS), an emerging microsampling technique, is expected to overcome some disadvantages of dried blood spots. This study aimed to develop and evaluate a VAMS-based strategy for quantifying ten frequently prescribed antihypertensive drugs (AHD) (amlodipine, bisoprolol, candesartan, carvedilol, lercanidipine, losartan carboxylic acid, metoprolol, nebivolol, telmisartan, valsartan) in finger prick blood (FPB) within the scope of adherence monitoring. The straightforward workflow consisted of VAMS tip hydration and subsequent precipitation. Samples were analyzed by using reversed phase ultra-high performance liquid chromatography coupled to orbitrap mass spectrometry operating in parallel reaction monitoring mode. The analytical procedure was successfully validated based on international recommendations for most of the analytes. Selectivity and within/between-run accuracy and precision were in accordance with the recommendations. Internal standard normalized matrix factor met recommended criteria for all analytes at HT 20%, 40%, and 60% except for amlodipine were the CV exceeded 15% at HT 20% (CV 18%). Dilution integrity was given for all substances, covering the quantification in the upper part of the therapeutic range of selected AHD. Long-term stability in VAMS tips was tested and revealed degradation of lercanidipine after one week of storage at 24 °C. A proof of concept of the analytical applicability was done by quantification of selected AHD in VAMS tips and matched plasma samples. Results revealed that determined concentration in FPB by VAMS and plasma cannot be used interchangeably, and thus that specific reference ranges have to be established. However, a novel VAMS application was implemented in the context of adherence monitoring for at least the investigated AHD.
Assuntos
Anti-Hipertensivos , Espectrometria de Massas em Tandem , Coleta de Amostras Sanguíneas , Cromatografia Líquida , Teste em Amostras de Sangue Seco , Adesão à MedicaçãoRESUMO
Volumetric absorptive microsampling (VAMS), an emerging microsampling technique, is expected to overcome some disadvantages of dried blood spots such as volume inaccuracy and influence of hematocrit (HT). This study aimed to develop and evaluate a VAMS-based strategy for quantification of 13 frequently prescribed antipsychotics in finger prick blood within the scope of adherence monitoring to complement already-established qualitative urine analysis. The final workflow consisted of VAMS tip hydration and subsequent precipitation. Samples were analyzed by using reversed-phase ultra-high-performance liquid chromatography and Orbitrap mass spectrometry operated in parallel reaction monitoring mode. The analytical procedure was successfully validated based on international recommendations at three different HT values (20%, 40%, 60%) for most of the analytes. Selectivity and within/between-run accuracy and precision were in accordance with the recommendations in most cases. Internal standard-normalized matrix factor met recommended criteria for all analytes at HT 40%. For the HT values of 20% and 60%, only four substances did not meet the criteria. Dilution integrity was given for all substances, except for olanzapine, allowing a quantification over the whole therapeutic range of selected antipsychotics. Long-term stability in VAMS tips was tested and revealed degradation of five antipsychotic drugs after 1 week of storage at 24 °C. A proof of concept of the applicability of the method was obtained by quantification of a selection of the 13 antipsychotic drugs in VAMS tips and matched plasma samples. Results were coherent between matrices. Thus, VAMS was shown to be a promising alternative for adherence monitoring of at least the investigated antipsychotics.
Assuntos
Antipsicóticos/análise , Antipsicóticos/sangue , Coleta de Amostras Sanguíneas/métodos , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Hematócrito , Espectrometria de Massas em Tandem/métodos , Calibragem , Cromatografia Líquida de Alta Pressão , Teste em Amostras de Sangue Seco , Humanos , Limite de Detecção , Adesão à Medicação , Controle de Qualidade , Reprodutibilidade dos Testes , TemperaturaRESUMO
Background It is currently unknown if antihypertensive drugs can be monitored in oral fluid (OF) using liquid chromatography coupled to high-resolution mass spectrometry. Methods and Results We assessed adherence using liquid chromatography coupled to high-resolution mass spectrometry in OF, plasma, and urine of 56 consecutive patients with hypertension referred to a tertiary hypertension unit. Of these patients, 59% were completely adherent (all drugs detectable in urine), whereas 29% and 13% were partially adherent (1 drug not detectable in urine) or nonadherent (>1 drug not detectable in urine), respectively. Adherent patients were on fewer antihypertensive drugs (P=0.001), had fewer daily drug doses (P=0.012), and had lower 24-hour ambulatory systolic (P=0.012) and diastolic (P=0.009) blood pressures than nonadherent or partially adherent patients. Most drugs were detected in urine compared with plasma and OF (181 versus 119 versus 88; P=0.001). Compared with urine and plasma, detection rates of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics were lower in OF. There was no difference in the frequency of detecting ß blockers (P=1.0) and calcium channel blockers (P=0.063) when comparing OF with urine. There was no difference in the number of calcium channel blockers (P=0.727), ß blockers (P=1.000), thiazide diuretics (P=0.125), and α-2 agonists (P=0.125) identified between OF and plasma. Conclusions This study shows the feasibility of drug adherence testing for several antihypertensive drugs, especially those without acidic components, in OF, with a similar recovery compared with plasma. Therefore, drug adherence testing in OF should be further explored as a noninvasive approach, which can easily be performed in an "out-of-office" setting.
Assuntos
Anti-Hipertensivos/análise , Adesão à Medicação , Adulto , Idoso , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-IdadeRESUMO
Nonadherence to antihypertensive drugs therapy is known to be a serious issue in hypertension treatment. Liquid chromatography (LC) coupled to mass spectrometry (MS) was shown to allow the assessment of such nonadherence in blood and urine sample. However, their sampling may represent a logistical challenge and are often not favored by the patients. We questioned whether oral fluid (OF) might be an easier accessible alternative matrix for adherence monitoring of cardiovascular drugs (CD). A qualitative method for adherence monitoring of 78 commonly prescribed cardiovascular drugs in OF using LC high-resolution MS (LC-HRMS/MS) was therefore developed, validated, and used to study the presence of antihypertensive medication in OF. Selectivity, ion suppression and enhancement due coeluting analytes, carry over, limits of detection (LOD), limits of identification (LOI), recovery (RE), matrix effects (ME), and process efficiency (PE) were investigated. For demonstrating applicability, over 50 OF samples were investigated and data were compared to findings in blood and urine. Selectivity in OF was given for all compounds via their MS2 spectra and no total suppression of signals could be observed. Determined LOI in OF for ten analytes was higher than the given therapeutic plasma concentration. Furthermore, RE, ME, and PE were in acceptable ranges for more than 65% of the compounds. In total, 208 prescriptions of CD to 57 patients were analyzed and demonstrated the suitability of for adherence monitoring in principle. OF was comparable to plasma regarding the drug categories and the frequencies of hits, except for acidic compounds but more hits could be found in urine samples. A analytical method using OF as analytical matrix was successfully developed. Application showed that it might be a suitable alternative for adherence monitoring of selected drugs in the future, particularly those having no acidic function.