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1.
J Forensic Leg Med ; 69: 101890, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32056808

RESUMO

This retrospective study sought to identify a regular pattern of limb bruising which occurs in association with suicidal or accidental hanging. Following exclusion of cases suspicious for homicide, 82 consecutive cases of hanging from a 10-year period were retrospectively reviewed to identify the pattern of traumatic limb injury in each case. Relevant information such as location, toxicology, and type of suspension was also noted. 72% of the reviewed cases had traumatic limb lesions, the majority of which occurred on the posterior upper limb and the anterior lower limb. Although the distribution of limb injury in our study mirrored that found in the literature, the incidence is much higher than in previous studies (7.4-20%). This could either be due to differences in confounding factors such as intoxication and location of hanging or differences in the practice of recording of limb trauma in hanging between centres. Neither type of suspension nor location of hanging were significantly associated with an increased incidence of traumatic limb injury. Positive toxicology was found to increase the likelihood of sustaining limb injury (p = .044084). In conclusion, the presence of this well documented pattern of traumatic limb lesions in cases of hanging should not always raise suspicion of foul play.


Assuntos
Asfixia/patologia , Extremidade Inferior/lesões , Lesões do Pescoço/patologia , Extremidade Superior/lesões , Adulto , Distribuição por Idade , Asfixia/mortalidade , Depressores do Sistema Nervoso Central/sangue , Depressores do Sistema Nervoso Central/urina , Etanol/sangue , Etanol/urina , Feminino , Ciências Forenses , Humanos , Extremidade Inferior/patologia , Masculino , Pessoa de Meia-Idade , Lesões do Pescoço/mortalidade , Preparações Farmacêuticas/sangue , Estudos Retrospectivos , Distribuição por Sexo , Detecção do Abuso de Substâncias , Extremidade Superior/patologia , Adulto Jovem
2.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1126-1127: 121708, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437773

RESUMO

Analysis of acidic pharmaceuticals in complex biological samples is a challenging and formidable task due to the existence of interfering constituents within the sample matrices. Therefore, in order to avoid analytical column clogging and suppression/enhancement of signals of the analyte of interest, herein a simple, cost-effective and quick online ion chromatography based clean-up setup was introduced. This system was further coupled with a cost-effective homemade photochemically induced fluorimetric (PIF) setup for direct online conversion of non-fluorescent acidic pharmaceutical drugs into their respective fluorescent species. This advantageous system was favorably applied for the determination of four non-fluorescent acidic compounds in two complex biological samples (human serum and oral fluid) with minimum labor and organic solvent consumption. At optimized conditions, the developed method has shown good sensitivity, selectivity, satisfactory recoveries (88.68-102.14%) and low limits of detection (0.35-8.10 µg/L) with minimum or zero matrix effect.


Assuntos
Cromatografia por Troca Iônica/métodos , Fluorometria/métodos , Preparações Farmacêuticas/análise , Ácidos/análise , Ácidos/sangue , Ácidos/química , Corantes Fluorescentes/química , Humanos , Limite de Detecção , Modelos Lineares , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/química , Reprodutibilidade dos Testes , Saliva/química
3.
J Chromatogr A ; 1608: 460411, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31405572

RESUMO

In the current study, for the first time, the sugaring-out effect was assessed in a conventional electromembrane extraction (EME) system. Utilizing the sugars in the donor solution as green additives can result in production of a pioneering and influential EME mode. Sugaring-out assisted electromembrane extraction was combined with high-performance liquid chromatography (HPLC) to enhance the extraction of four basic model drugs (pseudoephedrine, lidocaine, propranolol, and ketoconazole). In this mode of EME, not only the transfer of analytes through the supported liquid membrane (SLM) was improved, but also the whole extraction system became more stable than the conventional one in the same voltage. The type and concentration of sugars were optimized in addition to the common experimental parameters influencing the EME, and figures of merit were also studied. Under the optimum conditions, repeatability (RSD%) was obtained in the range of 2.8-6.9% in the water, while RSD value was obtained in the range of 8.2-11.8% (n = 3) for conventional EME with the same state. The linearity range was also in the interval of 5.0-1000.0 ng mL-1 and limits of quantification and detection were in the ranges of 5.0-10.0 ng mL-1 and 1.5-3.0 ng mL-1, respectively, in the introduced EME. Extraction recoveries in the range of 41.2 and 80.8% were obtained resulting in enrichment factors in the range of 96-189. In light of such factor, new suggested EME mode was assessed in the real biological samples including human plasma and urine in order to prove the sugaring-out efficiency in EME systems.


Assuntos
Análise Química do Sangue/métodos , Preparações Farmacêuticas/isolamento & purificação , Açúcares/química , Urinálise/métodos , Cromatografia Líquida de Alta Pressão , Eletrônica , Humanos , Membranas Artificiais , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/urina
4.
Bioanalysis ; 11(13): 1233-1242, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31298569

RESUMO

Aim: Following the request of a regulatory authority, a rat study was conducted to compare pharmacokinetic parameters from traditional large volume sampling and capillary microsampling. Materials & methods: Rats were dosed with a proprietary compound in three dose groups and blood samples were collected via capillary microsampling (32 µl), immediately followed by traditional large volume sampling (300 µl) up to 24 h postdose. Resulting plasma samples were analyzed for parent drug and two metabolites. AUCs were compared between sampling techniques. Results: There was no statistical difference between AUCs from traditional and microsampling across different doses and analytes. Conclusion: Toxicokinetic parameters generated from plasma collected as a capillary microsample or traditional large volume sample are highly comparable.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Preparações Farmacêuticas/metabolismo , Animais , Área Sob a Curva , Coleta de Amostras Sanguíneas/normas , Capilares , Cromatografia Líquida de Alta Pressão , Teste em Amostras de Sangue Seco , Meia-Vida , Masculino , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/química , Curva ROC , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
5.
J Chromatogr A ; 1602: 117-123, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31229251

RESUMO

The use of miniaturized systems with the possibility for automation has become increasingly popular in the field of bioanalysis. As a new approach to liquid phase microextraction in the 96-well format, parallel artificial liquid membrane extraction (PALME) was introduced in 2013. In the present work, the reliability of the quantitative data obtained with PALME was thoroughly evaluated. Amitriptyline, nortriptyline, quetiapine, venlafaxine, o-desmethylvenlafaxine, and fluoxetine were selected as model analytes. The analytes were extracted under non-exhaustive conditions from human plasma samples and the extracts were analyzed directly by LC-MS/MS. Accuracy was within ±15% and precision was <15% when the QC samples were prepared in both pooled plasma and in plasma from multiple sources. Accuracy and precision was superior when stable isotopically labelled (SIL) internal standards were used, as compared to structural analogue internal standards in the plasma samples from multiple sources. SIL internal standards are therefore recommended as the first choice. Assessment of accuracy and precision was also carried out with four different operators performing the extraction procedure, providing accuracy within ±15% and precision <15%. The extraction recoveries were in the range from 48 to 85 %, and non-exhaustive extraction of the analytes did not affect the accuracy and precision of the method. With the method described, up to 96 samples can be extracted with a total extraction time of 60 min and with a total consumption of organic solvent less than 0.4 mL for the whole wellplate. PALME is therefore a new approach to high-throughput sample preparation, providing accurate quantification, along with simple workflow, low consumption of organic solvent, and extensive sample clean-up.


Assuntos
Microextração em Fase Líquida/métodos , Preparações Farmacêuticas/sangue , Calibragem , Cromatografia Líquida , Humanos , Marcação por Isótopo , Membranas Artificiais , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
6.
Forensic Sci Int ; 300: 125-135, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31103910

RESUMO

Trends in forensic toxicology show the advancement of rapid and sensitive analytical methods for qualitative and quantitative analysis of drugs of abuse. However, forensic toxicologists are continuously faced with the challenges of identifying and quantifying drug blood concentration while simultaneously struggling with manpower shortage. In view of developing a simple and productive toxicological analysis method encompassing total workflow from sample preparation to quantitative analysis, here we describe a simple, robust, and sensitive method for the simultaneous determination and quantification of 63 forensically relevant drugs and pesticides in human whole blood. The method is based on sample preparation by a modified QuEChERS extraction and dispersive solid-phase extraction (dSPE) clean-up followed by gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis. Limits of detection of the target analytes in whole blood ranged in the few ng/mL-order levels. Intra- and inter-day validation result ranges were 0-24% for accuracy (% error) and 0.8-26% for precision (%RSD). Recovery rates ranged from 66% to 84% for barbiturates, 36% to 110% for benzodiazepines, 41% to 86% for tri/tetracyclic antidepressants, 15% to 81% for drugs of abuse, 28% to 44% for phenethylamines, and 25% to 118% for pesticides. The validated results were used to develop a user-friendly, systematic, and quantitative toxicological GC/MS/MS system and software "Quick-DB Forensic".


Assuntos
Toxicologia Forense/métodos , Praguicidas/sangue , Preparações Farmacêuticas/sangue , Fluxo de Trabalho , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Limite de Detecção , Software , Extração em Fase Sólida
7.
Bioconjug Chem ; 30(6): 1711-1723, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31082207

RESUMO

The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking of endogenous albumin opens up an avenue to chaperone small molecules for long-acting therapeutics. Although several FDA-approved fatty acids have shown prolonged residence and therapeutic effect, an easily synthesized, water-soluble, and high-efficiency ABM with versatile drug loading ability is urgently needed to improve the therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperone short-lived molecules, through both computational modeling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery systems.


Assuntos
Azul Evans/análogos & derivados , Azul Evans/metabolismo , Exenatida/análogos & derivados , Exenatida/metabolismo , Albumina Sérica/metabolismo , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Azul Evans/síntese química , Exenatida/sangue , Exenatida/síntese química , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Camundongos , Modelos Moleculares , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Ligação Proteica , Multimerização Proteica , Proteólise , Ratos , Albumina Sérica/química
8.
Biomed Chromatogr ; 33(10): e4602, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31116448

RESUMO

The present work describes novel methods using densitometry and indirect or off-line high performance thin-layer chromatography-mass spectrometry (HPTLC-MS) for the simultaneous detection and quantification of asenapine, propranolol and telmisartan and their phase II glucuronide metabolites. After chromatographic separation of the drugs and their metabolites the analytes were scraped, extracted in methanol and concentrated prior to mass spectrometric analysis. Different combinations of toluene and methanol-ethanol-n-butanol-iso-propanol were tested for analyte separation and the best results were obtained using toluene-methanol-ammonia (6.9:3.0:0.1, v/v/v) as the elution solvent. All of the drug-metabolite pairs were separated with a homologous retardation factor difference of ≥22. The conventional densitometric approach was also studied and the method performances were compared. Both of the approaches were validated following the International Conference on Harmonization guidelines, and applied to spiked human plasma samples. The major advantage of the TLC-MS approach is that it can provide much lower limits of detection (1.98-5.83 pg/band) and limit of quantitation (5.97-17.63 pg/band) with good precision (˂3.0% coefficient of variation) compared with TLC-densitometry. The proposed indirect HPTLC-MS method is simple yet effective and has tremendous potential in the separation and quantitation of drugs and their metabolites from biological samples, especially for clinical studies.


Assuntos
Cromatografia em Camada Delgada/métodos , Densitometria/métodos , Glucuronídeos , Preparações Farmacêuticas , Espectrometria de Massas por Ionização por Electrospray/métodos , Administração Oral , Cromatografia Líquida de Alta Pressão , Glucuronídeos/sangue , Glucuronídeos/isolamento & purificação , Glucuronídeos/metabolismo , Glucuronídeos/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Limite de Detecção , Modelos Lineares , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/isolamento & purificação , Preparações Farmacêuticas/metabolismo , Reprodutibilidade dos Testes
9.
J Mass Spectrom ; 54(7): 600-611, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31066158

RESUMO

A fast and simple approach to overcome challenges in emergency toxicological analysis, using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) has been developed, for the detection of analytes in blood and urine samples from the following drug classes: analgesics, benzodiazepines, antidepressants, anticonvulsants, drugs of abuse, and pesticides. These substances are relevant in the context of emergency toxicology in Brazil. The sample preparation procedure was relatively easy and fast to perform. The method was fully validated giving limits of in the range of 0.5 and 20 ng mL-1 for blood and urine samples. The intraday and interday precision and accuracy were considered adequate for all analytes once the relative standard deviation (RSD) (%) was lower than 20% for quality control (QC) low and lower than 15% for CQ medium and high. The developed method was successfully applied to 320 real samples collected at the Poison Control Center of São Paulo, and 89.1% have shown to be positive for some of the analytes. This confirms its applicability and importance to emergency toxicological analysis, and it could be very useful in both fields of clinical and forensic toxicology.


Assuntos
/sangue , Praguicidas/sangue , Praguicidas/urina , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/urina , Analgésicos/sangue , Analgésicos/urina , Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Antidepressivos/sangue , Antidepressivos/urina , Benzodiazepinas/sangue , Benzodiazepinas/urina , Brasil , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Espectrometria de Massas em Tandem
10.
Eur J Pharm Sci ; 134: 194-204, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047967

RESUMO

Several reports demonstrated that rifampicin affected pharmacokinetics of victim drugs following oral more than intravenous administration. We aimed to establish a semi-physiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and transporter turnover to simultaneously predict pharmacokinetic interaction of rifampicin with oral versus intravenous substrates of cytochrome P450 (CYP) 3A4/P­glycoprotein (P-GP) in human. Rifampicin was chosen as the CYP3A /P-GP inducer. Thirteen victim drugs including P-GP substrates (digoxin and talinolol), CYP3A substrates (alfentanil, midazolam, nifedipine, ondansetron and oxycodone), dual substrates of CYP3A/P-GP (quinidine, cyclosporine A, tacrolimus and verapamil) and complex substrates (S-ketamine and tramadol) were chosen to investigate drug-drug interactions (DDIs) with rifampicin. Corresponding parameters were cited from literatures. Before and after multi-dose of oral rifampicin, the pharmacokinetic profiles of victim drugs for oral or intravenous administration to human were predicted using the semi-PBPK model and compared with the observed values. Contribution of both CYP3A and P-GP induction in intestine and liver by rifampicin to pharmacokinetic profiles of victim drugs was investigated. The predicted pharmacokinetic profiles of drugs before and after rifampicin administration accorded with the observations. The predicted pharmacokinetic parameters and DDIs were successful, whose fold-errors were within 2. It was consistent with observations that the DDIs of rifampicin with oral victim drugs were larger than those with intravenous victim drugs. DDIs of rifampicin with CYP3A or P-GP substrates following oral versus intravenous administration to human were successfully predicted using the developed semi-PBPK model.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/agonistas , Indutores do Citocromo P-450 CYP3A/farmacocinética , Preparações Farmacêuticas/metabolismo , Rifampina/farmacocinética , Administração Intravenosa , Administração Oral , Simulação por Computador , Citocromo P-450 CYP3A , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Interações de Medicamentos , Humanos , Modelos Biológicos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/sangue , Farmacocinética , Rifampina/administração & dosagem
11.
Bioanalysis ; 11(7): 619-628, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30973016

RESUMO

There is continuing interest in the development and application of various microsampling technologies for drug development. The AAPS bioanalytical community microsampling subgroup and the European Bioanalysis Forum conducted a survey of their members (39 individual organizations). This gives a snapshot of current practices and demonstrates that implementation of microsampling approaches is becoming increasingly commonplace, but not universal. Greater adoption was observed for nonclinical studies, particularly nonregulatory. A number of respondents reported that they have included microsampling data in regulatory submissions. Another important observation was that where microsampling is employed for clinical studies, dried blood approaches predominate, reflecting the interest in their use where they enable sample collection which is not feasible with standard approaches or to derive richer data sets.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Preparações Farmacêuticas/análise , Sociedades Científicas , Animais , Teste em Amostras de Sangue Seco , Avaliação Pré-Clínica de Medicamentos , Humanos , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/metabolismo , Inquéritos e Questionários
12.
Bioanalysis ; 11(6): 525-532, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30973017

RESUMO

Following the completion of a detailed experimental protocol into the potential inhomogeneity of capillary liquid microsamples, which was performed at seven European Bioanalysis Forum member companies, the summary and conclusion on the data are reported here. It has been demonstrated that it is possible to generate homogeneous samples using these microsampling techniques; that the resultant microsamples can be accurate and precise and that capillary liquid microsampling data can be consistent with conventional larger volume plasma samples. However, the data contain some variability which is contributed to by the different range of experiences that each investigating site had with these techniques. Therefore, knowledge of the compounds, well-designed experiments and experience with these techniques are essential for the delivery of high quality data.


Assuntos
Análise Química do Sangue/métodos , Coleta de Amostras Sanguíneas/métodos , Análise Química do Sangue/normas , Coleta de Amostras Sanguíneas/instrumentação , Coleta de Amostras Sanguíneas/normas , Europa (Continente) , Humanos , Preparações Farmacêuticas/sangue , Reprodutibilidade dos Testes
13.
Bioanalysis ; 11(6): 533-542, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30973018

RESUMO

Aim: Microsampling in preclinical pharmacokinetics (PK) studies is currently widely adopted across the pharmaceutical industry. Materials & methods: The European Bioanalysis Forum liquid microsampling consortium member companies assessed the accuracy and precision of handheld pipettes and microcapillaries at volumes of less than 10 µl. The following key factors on pipetting performance were also evaluated: Pipette type (positive displacement, air displacement and microcapillary), experience of user and the liquid type. Water was selected as a best-case scenario for accuracy and precision determination and blood plasma as a 'real world' bioanalysis sample type. Conclusion: Accuracy and precision on the pipetted volume decreased at lower volumes and experienced laboratory technicians performed better compared with the infrequent users. With respect to the pipetting devices used, microcapillaries showed better or equivalent accuracy and precision compared with handheld pipettes across the volume range 1-8 µl independent of the matrix used.


Assuntos
Análise Química do Sangue/métodos , Coleta de Amostras Sanguíneas/instrumentação , Análise Química do Sangue/normas , Coleta de Amostras Sanguíneas/normas , Europa (Continente) , Humanos , Preparações Farmacêuticas/sangue , Reprodutibilidade dos Testes
14.
Biol Pharm Bull ; 42(3): 327-336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828063

RESUMO

Predicting human pharmacokinetics (PK) such as clearance (CL) and volume of distribution (Vd) is a critical component of drug discovery. These predictions are mainly performed by in vitro-in vivo extrapolation (IVIVE) using human biological samples, such as hepatic microsomes and hepatocytes. However, some issues with this process have arisen, such as inconsistencies between in vitro and in vivo findings; the integration of predicted CYP, non-CYP and transporter-mediated human PK; and the difficulty of evaluating very metabolically stable compounds. Various approaches to solving these issues have been reported. Allometric scaling using experimental animals has also often been used. However, this method has also shown many problems due to interspecies differences, albeit that various correction methods have been proposed. Another approach involves the production of chimeric mice with humanized liver via the transplantation of human hepatocytes into mice. The livers of these mice are repopulated mostly with human hepatocytes and express human drug-metabolizing enzymes and drug transporters, suggesting that these mice are useful for solving the issues of IVIVE and allometric scaling, and more reliably predicting human PK. In this review, we summarize human PK prediction methods using IVIVE, allometric scaling and chimeric mice with humanized liver, and discuss the utility of predicting human PK in drug discovery by comparing these chimeric mice with IVIVE and allometric scaling.


Assuntos
Descoberta de Drogas/métodos , Fígado/metabolismo , Animais , Humanos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos , Preparações Farmacêuticas/sangue , Farmacocinética
15.
J Forensic Leg Med ; 62: 92-96, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30708197

RESUMO

The aim of this study was to collect all available data from 2009 to 2016 focusing on the epidemiological, clinical and pharmacological issues only related to acute intoxication fatalities in the Unit of Legal Medicine of the Department of Medicine and Surgery at the University of Parma. All death certificates and autopsy reports were retrieved from the archives and evaluated to identify cases in which only acute intoxication from xenobiotics could be defined as the cause of death, however statistical and descriptive analyses were applied to all the data. A more comprehensive analysis on all causes of death showed that out of 1005 total cases the most common is haemorrhagic shock/traumatic shock (36.5%), followed by cardiogenic shock with 27.4%; asphyxia ranks as the third cause of death (11.8%); concerning encephalic injuries, our data show 10.9% of cases, while acute intoxication by xenobiotics accounts for 5.7%. Data show that the majority of subjects are poly-abuser (75.4%); people not enrolled within a preventive treatment (59.4%) were more likely to commit suicide (28.1%), whereas only 6.2% in the sub-population in treatment (40.6%) committed suicide: therefore, data strongly suggest the evidence that joining a preventive programme can decrease the probability of extreme action. Access to a full case history may indeed save considerable time and expense in carrying out tests, but also valuable targeted samplings. The investigating officer should, therefore, submit as much information as possible about the case, as this may influence the type and extent of analysis undertaken, as well as the interpretation of analytical results.


Assuntos
Causas de Morte , Preparações Farmacêuticas/sangue , Envenenamento/mortalidade , Acidentes/mortalidade , Adulto , Distribuição por Idade , Idoso , Asfixia/mortalidade , Lesões Encefálicas/mortalidade , Depressores do Sistema Nervoso Central/sangue , Afogamento/mortalidade , Etanol/sangue , Feminino , Medicina Legal , Homicídio/estatística & dados numéricos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Distribuição por Sexo , Choque/mortalidade , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Suicídio/estatística & dados numéricos , Adulto Jovem
16.
J Pharm Biomed Anal ; 167: 21-29, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738240

RESUMO

A new methodology based on Nuclear Magnetic Resonance (NMR) was developed to determine plasma protein binding (PPB) of drug candidates in drug discovery programs. A strong correlation was found between the attenuation of NMR signals of diverse drugs in the presence of different plasma concentrations and their fraction bound (fb) reported in the literature. Based on these results, a protocol for a rapid calculation of fb of small molecules was established. The advantage of using plasma instead of purified recombinant proteins and the possibility of pool analysis to increase throughput were also evaluated. This novel methodology proved to be very versatile, cost-effective, fast and suitable for automation. As a plus, it contemporarily provides a quality check and solubility of the compound.


Assuntos
Proteínas Sanguíneas/química , Descoberta de Drogas/métodos , Ressonância Magnética Nuclear Biomolecular , Preparações Farmacêuticas/sangue , Descoberta de Drogas/instrumentação , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Preparações Farmacêuticas/química , Ligação Proteica , Proteínas Recombinantes/química , Albumina Sérica Humana/química , Bibliotecas de Moléculas Pequenas/química
17.
J Chromatogr A ; 1587: 209-226, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30595433

RESUMO

The screening analysis for drugs and poisons always symbolizes the capabilities of a forensic laboratory. Due to the rapid emergence of new compounds in clinical and forensic intoxication cases, sensitive and specific methods are necessary for the screening of wide range of target compounds. A novel high-throughput screening method has been developed for the toxicological analysis of 288 drugs and poisons in human blood using Orbitrap technology with gas chromatography-high resolution mass spectrometry (GC-HRMS). This method allows for the fast detection and identification of high-throughput forensically important drugs and poisons, e.g., drugs of abuse (cocaine, amphetamines, synthetic cannabinoids, opiates, hallucinogen), sedative-hypnotics, antidepressants, non-steroidal anti-inflammatory drugs, pesticides (acaricides, fungicides, insecticides, nematicides), and cardiovascular agents in one single GC-Q Exactive run. After a simple extraction with ethyl ether and buffer, following centrifugation, the supernatant was injected into the system. For detection, spiked blood samples were analyzed by Orbitrap-GC-HRMS using an electrospray ionization in full scan mode with a scan range from 40 to 650 (m/z). The identification of drugs and poisons in the samples was carried out by searching the accurate molecular mass of characteristic fragment ions, ion rations and retention time (RT) against the in-house library that we developed with 70 ev electron energy. The limit of detection (LOD) for most compounds (249 in a total of 288 compounds) was below 100 ng/mL. For selectivity, no substances have been identified in drug-free blood samples from six different sources, and the method was suitable for the recovery and the carryover. The coefficient of variation (CV) of the RTs was below 0.99% in all reproducibility experiments. Mass accuracy was always better than 3 ppm, corresponding to a maximum mass error of 1.04 millimass units (mmu). The developed method was applied to 136 real samples from forensic cases, demonstrating its suitability for the sensitive and fast screening of high-throughput drugs in human blood samples.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Ensaios de Triagem em Larga Escala/métodos , Preparações Farmacêuticas/sangue , Venenos/sangue , Análise de Dados , Humanos , Limite de Detecção , Reprodutibilidade dos Testes
18.
Pharm Res ; 36(2): 32, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604282

RESUMO

PURPOSE: Various blood collection methods were developed and used in the pharmacokinetic evaluation of drugs. However, the influence of different blood sampling methods on plasma drug concentrations has not been clarified. In the present study, we aimed to determine whether the plasma concentration of a target drug changes based on the collection site and elucidate the mechanism responsible for this change. METHODS: We compared three blood sampling methods commonly used in small animals. Eight clinical drugs were selected and administered to rats simultaneously via intracardiac injection or oral gavage. Blood samples were collected from different sites at the same individual, and pharmacokinetic properties of the drugs were then evaluated. RESULTS: Study results showed that the maximum plasma concentration or area under the curve of three study drugs was significantly higher in rats when blood was sampled from the carotid artery than when it was sampled from the caudal vein or by tail snip. CONCLUSIONS: Pharmacokinetics of certain drugs may differ based on the blood sampling site. The acid-base properties of drugs may influence pharmacokinetic evaluation. The rate and extent of drug distribution may also cause such differences and have significant effects on plasma drug levels.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Preparações Farmacêuticas/sangue , Animais , Área Sob a Curva , Cromatografia Líquida/métodos , Limite de Detecção , Modelos Lineares , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
19.
Reprod Toxicol ; 84: 93-97, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30615926

RESUMO

OBJECTIVE: To compare assessment of early pregnancy medication exposure using three methods of data collection. METHODS: Serum samples were obtained from 752 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study before gestational week 17. For 52 women using medication at the date of blood sampling according to Web-based questionnaires or pharmacy records, we analysed serum samples using untargeted liquid chromatography time-of-flight spectrometry. RESULTS: Medication was detected in 18 serum samples (35%). Medications taken orally for chronic conditions reported in the questionnaire were detected in serum and vice versa. Pharmacy records did not identify additional exposed women, but missed exposure in 5 women mainly due to unavailability. We observed substantial discordance between the three methods for inhaled medication, dermatological preparations, and medications for short-term use, which went often undetected in serum. CONCLUSIONS: It remains challenging to assess medication use in large-scale studies as no 'gold standard' is currently available.


Assuntos
Uso de Medicamentos , Preparações Farmacêuticas/sangue , Gravidez/sangue , Adulto , Monitoramento de Medicamentos , Feminino , Humanos , Internet , Registros Médicos , Farmácias , Autorrelato , Inquéritos e Questionários
20.
Drug Metab Pharmacokinet ; 34(1): 78-86, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528195

RESUMO

This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2.2, 1.7 and 1.58-times greater than the corresponding values in OATP1B1 *1b/*1b, respectively, whereas that of fluvastatin was identical to those in other OATP1B1 genotypes. OATP1B1 *15/*15 also showed higher mean plasma concentrations of OATP1B1 endogenous substrates compared with the other OATP1B1 genotypes, such as coproporphyrin I, glycochenodeoxycholate sulfate (GCDCA-S), lithocholate sulfate (LCA-S), glycolithocholate sulfate (GLCA-S) and taurolithocholate sulfate (TLCA-S), but not total or direct bilirubin, chenodeoxycholate-24-glucuronide, or ω-dicarboxylic long-chain fatty acids. Area under the plasma concentration-time curves of plasma coproporphyrin I and GLCA-S discriminated OATP1B1 genotype *15/*15 from the other genotypes. In combination with previously published clinical studies, these results support the notion that coproporphyrin I, and GLCA-S and GCDCA-S could be a surrogate probe for assessing human in vivo OATP1B1 activities.


Assuntos
Genótipo , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Adulto , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/sangue , Especificidade por Substrato/fisiologia , Adulto Jovem
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