RESUMEN
"Purple Drank", a soft drink containing promethazine (PMZ) and codeine (COD), has gained global popularity for its hallucinogenic effects. Consuming large amounts of this combination can lead to potentially fatal events. The binding of these drugs to plasma proteins can exacerbate the issue by increasing the risk of drug interactions, side effects, and/or toxicity. Herein, the binding affinity to human serum albumin (HSA) of PMZ and its primary metabolites [N-desmethyl promethazine (DMPMZ) and promethazine sulphoxide (PMZSO)], along with COD, was investigated by high-performance affinity chromatography (HPAC) though zonal approach. PMZ and its metabolites exhibited a notable binding affinity for HSA (%b values higher than 80%), while COD exhibited a %b value of 65%. To discern the specific sites of HSA to which these compounds were bound, displacement experiments were performed using warfarin and (S)-ibuprofen as probes for sites I and II, respectively, which revealed that all analytes were bound to both sites. Molecular docking studies corroborated the experimental results, reinforcing the insights gained from the empirical data. The in silico data also suggested that competition between PMZ and its metabolites with COD can occur in both sites of HSA, but mainly in site II. As the target compounds are chiral, the enantioselectivity for HSA binding was also explored, showing that the binding for these compounds was not enantioselective.
Asunto(s)
Cromatografía de Afinidad , Codeína , Simulación del Acoplamiento Molecular , Prometazina , Unión Proteica , Humanos , Prometazina/metabolismo , Prometazina/química , Codeína/metabolismo , Codeína/química , Cromatografía de Afinidad/métodos , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Sitios de Unión , Cromatografía Líquida de Alta Presión/métodosRESUMEN
A facile electrochemical approach is proposed for the synchronous determination of acetaminophen (ACP), codeine (COD) and caffeine (CAF) utilizing unmodified screen-printed electrodes (SPEs). The determination of ACP, COD and CAF has been explored across different supporting electrolytes including sulfuric acid (H2SO4), hydrochloric acid (HCl), phosphoric acid (H3PO4) and Briton Robinson (B.R) buffer solutions. It was found that a 0.05 mol L-1 sulfuric acid solution is an optimal supporting electrolyte utilized for voltammetric analysis of ACP, COD, and CAF with improved sensitivity, stability, and reproducibility. The electro-analytical sensing of ACP, COD and CAF was investigated using SPEs within linear concentration ranges of 3.0-35.0 µmol L-1, 10-160 µmol L-1 and 10-160 µmol L-1 and revealed competitively low limits of detection (3S/N) of 0.9, 4.8 and 6.3 µmol L-1 for ACP, COD and CAF, respectively. The results indicated the possibility of such a simple and quick electroanalytical protocol for online monitoring of pharmaceutical formulations comprising ACP, COD, and CAF drugs in human fluids with satisfactory recovery.
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Acetaminofén , Cafeína , Codeína , Técnicas Electroquímicas , Electrodos , Grafito , Acetaminofén/análisis , Acetaminofén/química , Codeína/análisis , Codeína/química , Cafeína/análisis , Cafeína/química , Humanos , Grafito/química , Técnicas Electroquímicas/métodos , Límite de Detección , Reproducibilidad de los ResultadosRESUMEN
Codeine is a common analgesic drug that is a pro-drug of morphine. It also has a high risk of abuse as a recreational drug because of its extensive distribution as an OTC drug. Therefore, sensitive and selective screening methods for codeine are crucial in forensic analytical chemistry. To date, a commercial analytical kit has not been developed for dedicated codeine determination, and there is a need for an analytical method to quantify codeine in the field. In the present work, potential modulation was combined with electrochemiluminescence (ECL) for sensitive determination of codeine. The potential modulated technique involved applying a signal to electrodes by superimposing an AC potential on the DC potential. When tris(2,2'-bipyridine)ruthenium(II) ([Ru(bpy)3]2+) was used as an ECL emitter, ECL activity was confirmed for codeine. A detailed investigation of the electrochemical reaction mechanism suggested a characteristic ECL reaction mechanism involving electrochemical oxidation of the opioid framework. Besides the usual ECL reaction derived from the amine framework, selective detection of codeine was possible under the measurement conditions, with clear luminescence observed in an acidic solution. The sensitivity of codeine detection by potential modulated-ECL was one order of magnitude higher than that obtained with the conventional potential sweep method. The proposed method was applied to codeine determination in actual prescription medications and OTC drug samples. Codeine was selectively determined from other compounds in medications and showed good linearity with a low detection limit (150 ng mL-1).
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Analgésicos Opioides , Codeína , Aminas , Analgésicos Opioides/análisis , Analgésicos Opioides/química , Codeína/análisis , Codeína/química , Electrodos , Medicamentos sin Prescripción , LuminiscenciaRESUMEN
The adsorption and surface ionization of codeine molecules С18H21O3N (m/z 299) on the surface of oxidized tungsten have been studied by a non-stationary method of voltage modulation under the same experimental conditions with a high-vacuum mass-spectrometric setup using a "black chamber" all walls of which are cooled with liquid nitrogen. For the codeine molecule dissociation with the (C-C1)ß bond breaking and formation of ionizable radicals, the rate constants K+ and K0, the activation energy Ð+ and Ð0 of thermodesorption, and the pre-exponential factors in the continuity equation for the radicals C9H7N+CH3 (m/z 144) have been defined by surface ionization on the surface of oxidized tungsten WxOy. The results of determining the surface ionization coefficient and estimates of the ionization potentials of these radicals have been presented.
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Codeína , Tungsteno , Codeína/química , Espectrometría de Masas , CinéticaRESUMEN
Codeine is derived from morphine, an opioid analgesic, and has weaker analgesic and sedative effects than the parent molecule. This weak opioid is commonly used in combination with other drugs for over-the-counter cough relief medication. Due to the psychoactive properties of opioid drugs, the easily obtained codeine often becomes subject to misuse. Codeine misuse has emerged as a concerning public health issue due to its associated adverse effects such as headache, nausea, vomiting, and hemorrhage. Thus, it is very important to develop reliable analytical techniques to detect codeine for both quality control of pharmaceutical formulations and identifying drug misuse in the community. This review aims to provide critical outlooks on analytical methods applicable to the determination of codeine.
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Técnicas de Química Analítica/métodos , Codeína/análisis , Codeína/química , HumanosRESUMEN
The linkage of molecular components into functional heterogeneous framework materials has revolutionized modern materials chemistry. Here, we use this principle to design polyoxometalate-based frameworks as high affinity adsorbents for drugs of abuse, leading to their application in solid-phase extraction analysis. The frameworks are assembled by the reaction of a Keggin-type polyanion, [SiW12O40]4-, with lanthanoids Dy(III), La(III), Nd(III), and Sm(III) and the multidentate linking ligand 1,10-phenanthroline-2,9-dicarboxylic acid (H2PDA). Their reaction leads to the formation of crystalline 1D coordination polymers. Because of the charge mismatch between the lanthanoids (+3) and the dodecasilicotungstate (-4), we observe incorporation of the PDA2- ligands into crystalline materials, leading to four polyoxometalate-based frameworks where Keggin-type heteropolyanions are linked by cationic {Lnn(PDA)n} groups (Ln = Dy (1), La (2), Nd (3), and Sm (4)). Structural analysis of the polyoxometalate-based frameworks suggested that they might be suitable for surface binding of common drugs of abuse via supramolecular interactions. To this end, they were used for the extraction and quantitative determination of four model drugs of abuse (amphetamine, methamphetamine, codeine, and morphine) by using micro-solid-phase extraction (D-µSPE) and high-performance liquid chromatography (HPLC). The method showed wide linear ranges, low limits of detection (0.1-0.3 ng mL-1), high precision, and satisfactory spiked recoveries. Our results demonstrate that polyoxometalate-based frameworks are suitable sorbents in D-µSPE for molecules containing amine functionalities. The modular design of these networks could in the future be used to expand and tune their substrate binding behavior.
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Anfetamina/aislamiento & purificación , Codeína/aislamiento & purificación , Cabello/química , Estructuras Metalorgánicas/química , Metanfetamina/aislamiento & purificación , Morfina/aislamiento & purificación , Compuestos de Tungsteno/química , Adsorción , Anfetamina/química , Codeína/química , Voluntarios Sanos , Humanos , Estructuras Metalorgánicas/síntesis química , Metanfetamina/química , Estructura Molecular , Morfina/químicaRESUMEN
Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.
Asunto(s)
Analgésicos Opioides , Codeína/análogos & derivados , Abuso de Medicamentos , Loperamida , Medicamentos sin Prescripción , Analgésicos Opioides/química , Analgésicos Opioides/farmacología , Codeína/química , Codeína/farmacología , Humanos , Loperamida/química , Loperamida/farmacología , Medicamentos sin Prescripción/química , Medicamentos sin Prescripción/farmacologíaRESUMEN
BACKGROUND: Tampering of psychoactive medicines presents challenges to regulation and public health. However, little is currently known about what influences the decisions to treat codeine-containing medicines (CCM) with cold water extraction (CWE) from the perspective of individuals employing these techniques. The article identifies factors influencing utilisation of CWE to separate codeine from compounded analgesics, such as paracetamol and ibuprofen, found in CCM. METHODS: Purposive sampling of 27 participants residing in England who took part in a qualitative interview. Of these, 14 individuals (11 males and 3 females) reported tampering of psychoactive medicines, and the relevant transcripts were included in the analyses for the study. Participants were recruited from one addiction treatment service and from an online survey. The mean age of the participants was 31.5 years (range = 18-42 years). Qualitative data analysis followed the processes of iterative categorization (IC). The codes 'harm reduction', 'information sources' and 'changes on the drug markets' were grouped and summarised. The coding of the data was done in a Microsoft® Word document. RESULTS: Two groups of participants were identified in the data analysis: (i) individuals who used CCM (n = 5), and (ii) individuals who used CCM and heroin (n = 9). Participants in both groups used CWE due to concerns of paracetamol overdose from the use of excessive dosages of CCM. For both of them, information obtained from the internet encouraged the use of CWE. Participants using CCM described how the many steps involved in conducting CWE, including sourcing codeine boxes from pharmacies (over the counter), presented a barrier against using CWE. Participants using CCM and heroin explained how reduced availability in the local heroin supply influenced utilisation of CWE techniques to maintain their use of opioids and avoid withdrawal. Withdrawal symptoms and cravings outweighed the concerns about the quality of the extracted codeine mixtures in this participant group, especially the ability of CWE to remove paracetamol and tablet fillers. CONCLUSIONS: Utilisation of CWE of codeine was influenced by several factors including drug market supply, the availability of detailed information on the internet about CWE and restrictions on codeine sourcing in pharmacies. Risks identified with CWE include consumption of unknown doses of paracetamol if the CWE techniques are not used correctly. Attempts at extracting codeine from CCM should be considered in risk assessments of opioid medicines.
Asunto(s)
Acetaminofén/administración & dosificación , Analgésicos Opioides/administración & dosificación , Codeína/administración & dosificación , Extracción en Fase Sólida/métodos , Acetaminofén/efectos adversos , Acetaminofén/química , Administración Oral , Adolescente , Adulto , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/química , Analgésicos Opioides/uso terapéutico , Codeína/efectos adversos , Codeína/química , Combinación de Medicamentos , Sobredosis de Droga/tratamiento farmacológico , Sobredosis de Droga/prevención & control , Femenino , Humanos , Masculino , Trastornos Relacionados con Opioides/etiología , Solubilidad , Agua/química , Adulto JovenRESUMEN
Atmospheric pressure chemical ionizations (APCIs) of morphine, codeine, and thebaine were studied in a corona discharge ion source using ion mobility spectrometry (IMS) at temperature range of 100°C-200°C. Density functional theory (DFT) at the B3LYP/6-311++G(d,p) and M062X/6-311++G(d,p) levels of theory were used to interpret the experimental data. It was found that in the presence of H3 O+ as reactant ion (RI), ionization of morphine and codeine proceeds via both the protonation and carbocation formation, whereas thebaine participates only in protonation. Carbocation formation (fragmentation) was diminished with decrease in the temperature. At lower temperatures, proton-bound dimers of the compounds were also formed. Ammonia was used as a dopant to produce NH4 + as an alternative RI. In the presence of NH4 + , proton transfer from ammonium ion to morphine, codeine, and thebaine was the dominant mechanism of ionization. However, small amount of ammonium attachment was also observed. The theoretical calculations showed that nitrogen atom of the molecules is the most favorable proton acceptor site while the oxygen atoms participate in ammonium attachment. Furthermore, formation of the carbocations is because of the water elimination from the protonated forms of morphine and codeine.
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Codeína/química , Espectrometría de Movilidad Iónica/métodos , Morfina/química , Narcóticos/química , Tebaína/química , Compuestos de Amonio/química , Presión Atmosférica , Modelos Moleculares , ProtonesRESUMEN
The solubility profile of codeine phosphate in the carbitol and 2-propanol mixtures at 293.2-313.2 K are determined and correlated with some developed cosolvency models. Moreover, the density values of codeine phosphate saturated solutions are also determined and fitted with the Jouyban-Acree model. The model accuracy is investigated by calculating the mean relative deviations (MRDs%). The thermodynamic parameters of codeine phosphate dissolution in the non-aqueous mixtures of carbitol and 2-propanol are also computed by using van't Hoff and Gibbs equations.
Asunto(s)
1-Propanol , 2-Propanol , Codeína/química , Glicoles de Etileno/química , Solubilidad , Solventes , Temperatura , TermodinámicaRESUMEN
The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund's Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.
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Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Codeína/síntesis química , Codeína/farmacología , Analgésicos Opioides/química , Analgésicos Opioides/uso terapéutico , Animales , Unión Competitiva , Codeína/química , Codeína/uso terapéutico , Adyuvante de Freund , Tránsito Gastrointestinal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inyecciones Intraventriculares , Masculino , Ratones , Naloxona/farmacología , Naloxona/uso terapéutico , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Ratas Wistar , Receptores Opioides mu/metabolismoRESUMEN
In this work, a new mode of gel-electromembrane extraction (G-EME), called "inside" gel-EME (IG-EME) is proposed for the extraction of morphine and codeine as model basic drugs from complex biological samples. Here, an aqueous media that was captured inside the agarose gel membrane, acted as both gel membrane and the acceptor phase (AP) at the same time. In this regard, the membrane served as the separation filter (membrane) and supported liquid acceptor phase (SLAP) as well. With this new development, unwanted changes of the AP volume during the extraction, which is a common issue in the G-EME (due to electroendosmosis (EEO) phenomenon), was addressed properly. Briefly, the setup involved insertion of negative electrode inside the gel membrane and positive electrode into the donor phase (DP). Following that, the IG-EME was easily performed using optimal conditions (pH of the DP: 6.0; membrane composition (agarose concentration: 1% (w/v) in aqueous media with pH 3.0, and 15 mm thickness); voltage: 25 V; and extraction time: 30 min). After extraction, the agarose gel was withdrawn and centrifuged for 5 min with 12000 rpm, to disrupt its framework to release the "trapped aqueous AP" apart from the gel structure. The separated AP was finally injected into the HPLC-UV for the analysis. The limits of detection (LODs) and recoveries in this proposed method were obtained 1.5 ng mL-1 and 67.7 %-73.8 %, respectively. The system feasibility was examined by the quantification of model drugs in the real plasma and urine samples.
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Líquidos Corporales/química , Codeína/química , Técnicas Electroquímicas/métodos , Geles/química , Morfina/química , Humanos , Límite de Detección , Membranas Artificiales , Agua/químicaRESUMEN
Introduction: Tampering with opioid containing medications for use other than their prescribed indication is well documented; however, the published literature has concentrated on stronger, prescription opioids. Less potent opioids, such as codeine, are available without prescription in many European countries in the form of combination analgesic products and these can also be altered, with reports in particular of "cold-water extraction" being a tampering method achievable using household kitchen equipment.Methods: We searched a database of patients attending two South London emergency departments for cases of self-reported ingestion of the products of cold-water extraction, with subsequent review of their case notes. We searched the scientific and grey literature to identify current knowledge of this technique.Results: We identified seven presentations in six patients, none of whom developed paracetamol toxicity or had concentrations suggesting ingestion of a significant dose of paracetamol. A review of the scientific literature on the method also demonstrated that the technique reduces recovered paracetamol in experimental laboratory settings. Additionally, the established literature characterizes the use of codeine in a recreational setting and reports one fatality associated with the method. Review of grey literature user-forums further describes recreational codeine use in relation to the method and frequent adverse events including hospital admission for paracetamol toxicity.Discussion: Whilst the method appears capable of providing a recreational dose of codeine with reduction in the recovered paracetamol, it cannot be considered safe. Pharmaceutical production methods have been successfully developed to prevent tampering through other means but none thus far have been directed at the cold water extraction technique.Conclusions: Clinicians should be aware of the potential toxicity from tampered nonprescription analgesics. There is also the need for public health education regarding the potential risks associated with these methods.
Asunto(s)
Acetaminofén/administración & dosificación , Analgésicos Opioides/administración & dosificación , Codeína/administración & dosificación , Trastornos Relacionados con Opioides , Extracción en Fase Sólida/métodos , Acetaminofén/efectos adversos , Acetaminofén/química , Administración Oral , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/química , Química Farmacéutica , Codeína/efectos adversos , Codeína/química , Combinación de Medicamentos , Humanos , Inyecciones Intravenosas , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/etiología , Solubilidad , Agua/químicaRESUMEN
Krokodil is a cheap and effective home-made substitute for heroin. It is widely used over the territory of the former USSR (Russia, Ukraine, Armenia and others). Krokodil drug-related midface ON often occurs as a complication of maxillary ON. Treatment of Krokodil drug-related ON of the midface is challenging. It is difficult to determine the ON zone preoperatively and intraoperatively, due to the complex anatomy of the midface and the different periods of the disease onset in different areas. The aim of this study is to show variations of the clinical course and treatment options of Krokodil drug-related ON of the midface. In this study, 3 cases of Krokodil drug-related midface ON are reported. The main clinical feature of midface ON is extraoral fistula in the midfacial zone with purulent discharge or extraoral exposure of zygomatic bone. Surgery is the main treatment method for Krokodil drug-related midface osteonecrosis. Surgery includes necrotic bone removal and defect closure. Usually an extraoral approach is used to expose necrotic bone. Intraoral maxillary sinus floor defect is closed with the use of a buccal fat pad to prevent formation of oroantral communication. Drug withdrawal, radical necrectomy, and proper closure of formed defects are the main factors that lead to successful treatment of Krokodil drug-related midface ON patients.
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Codeína/análogos & derivados , Drogas Ilícitas/efectos adversos , Drogas Ilícitas/química , Necrosis/inducido químicamente , Osteonecrosis/inducido químicamente , Elevación del Piso del Seno Maxilar , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Codeína/efectos adversos , Codeína/química , Humanos , Masculino , Maxilar , Persona de Mediana Edad , Necrosis/cirugía , Osteonecrosis/cirugía , Resultado del TratamientoRESUMEN
Desomorphine, the principal opioid in Krokodil, has an analgesic potency approximately ten-times that of morphine. Similar to other opioids, during phase II metabolism it undergoes conjugation with glucuronic acid to form desomorphine-glucuronide. Although hydrolysis of conjugated species is sometimes required prior to analysis, desomorphine-glucuronide has not been fully investigated. In this study, six hydrolysis procedures were optimized and evaluated. Deconjugation efficiencies using chemical and enzymatic hydrolysis were evaluated and stability in aqueous solution was assessed. Acid hydrolysis was compared with five ß-glucuronidase sources (BGTurbo™, IMCSzyme™, Escherichia coli, Helix pomatia and Patella vulgata). At optimal conditions, each hydrolysis method produced complete hydrolysis (≥96%). However, under simulated challenging conditions, P. vulgata was the most efficient ß-glucuronidase for the hydrolysis of desomorphine-glucuronide. Both BGTurbo™ and IMCSzyme™ offered fast hydrolysis with no need for sample cleanup prior to liquid chromatography-quadrupole/time of flight-mass spectrometry (LC-Q/TOF-MS) analysis. Hydrolysates using E. coli, H. pomatia and P. vulgata underwent additional sample treatment using ß-Gone™ cartridges. Additionally, the stability of free and conjugated drug was evaluated at elevated temperature (60°C) in aqueous solutions between pH 4 and 10. No degradation was observed for either desomorphine or desomorphine-glucuronide under any of the conditions tested.
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Codeína/análogos & derivados , Glucuronidasa/química , Glucurónidos/química , Glucuronosiltransferasa/química , Animales , Codeína/química , Estabilidad de Medicamentos , Escherichia coli/enzimología , Gastrópodos/enzimología , Humanos , Hidrólisis , Estructura Molecular , Proteínas Recombinantes/químicaRESUMEN
Opium poppy has important medical, socioeconomic, forensic and political implications. More than 80 benzylisoquinoline alkaloids have been described, many of them with relevant therapeutic properties such as morphine, codeine, papaverine and noscapine. Heroin, a semi-synthetic drug produced from morphine is a worldwide serious cause of morbidity and mortality. Heroin dependence is complex phenomenon with environmental and genetic influence, and several biomarkers of exposure have been proposed. This work aims to review the metabolism and metabolomics of opiates with particular interest on their relevance as potential clinical and forensic antemortem and postmortem biomarkers. It is known that the heroin is mainly a prodrug that is rapidly deacetylated in blood to its active metabolite, 6-acetylmorphine, which is then subsequently slowly deacetylated to morphine. Therefore, 6-acetylmorphine has been used as the main target metabolite to prove heroin abuse in clinical, but mostly in forensic routine. Nevertheless, its applicability is limited due to the reduced detection window. Therefore, morphine (and its metabolites morphine-3-glucuronide and morphine-6-glucuronide), codeine, codeine-6-glucuronide, 6-acetylcodeine, noscapine (and its metabolites meconine, desmethylmeconine, and cotarnine), papaverine (and its metabolites 6-desmethylpapaverine, hydroxypapaverine, dihydroxypapaverine, 6-desmethylpapaverine-glucuronide) and thebaine (and acetylthebaol and the non-acetylated analog thebaol) have been additionally recommended to obtain the most reliable results possible. More recently, the identification by metabolomics analysis of several endogenous compounds offered an alternative approach of significant importance to uncover toxic effects. Profound alterations in the neurotransmitters levels and energy and amino acid metabolism have been reported with l-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetate being suggested as potential non-specific biomarkers of long-term heroin addiction. These endogenous metabolic profiles and exogenous components that together comprise the exposome will certainly help to uncover metabolic disturbances and patterns that may be associate to addiction with relevant clinical and forensic implications.
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Analgésicos Opioides/farmacocinética , Metabolómica , Alcaloides Opiáceos/farmacocinética , Analgésicos Opioides/química , Biomarcadores , Codeína/química , Codeína/farmacocinética , Toxicología Forense , Heroína/química , Heroína/farmacocinética , Humanos , Estructura Molecular , Morfina/química , Morfina/farmacocinética , Trastornos Relacionados con OpioidesRESUMEN
A novel tripodal codeine scaffold (CC3) was rationally designed using computational methods as a DNA condensing alkaloid. Separation of the piperidine nitrogen atoms in CC3 is considerably larger at 14.36â Å than previously reported tripodal opioids allowing for enhanced aggregation of larger DNA plasmids (>4,000â bp). The scaffold undergoes protonation at physiological pH that allows for controlled compaction and release of nucleic acids. Condensation is inhibited under basic conditions and nucleic acid release can be achieved by modulating the ionic strength. Zeta potential experiments indicate stabilised DNA particles at low alkaloid loading with AFM measurements showing particles sizes with a height of 103â nm and diameter of 350â nm. Since condensation is a prerequisite for the cellular uptake of DNA, this new class of alkaloid represents a novel nucleic acid condensation agent with potential gene therapy applications.
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Codeína/química , Plásmidos/química , Concentración de Iones de Hidrógeno , Microscopía de Fuerza Atómica , Conformación Molecular , Concentración Osmolar , Tamaño de la Partícula , Plásmidos/metabolismo , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
Drug functionalization through the formation of hydrophilic groups is the norm in the phase I metabolism of drugs for the modification of drug action. The reactions involved are mainly oxidative, catalyzed mostly by cytochrome P450 (CYP) isoenzymes. The benzene ring, whether phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand, the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e., the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e., the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retention, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues are presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design, and drug development.
Asunto(s)
Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Analgésicos Opioides/química , Codeína/química , Isoenzimas/química , Isoenzimas/metabolismo , Oxidación-ReducciónRESUMEN
Thiol-ene click reaction of N-acetyl-L-cysteine methyl ester to codeine, followed by reaction with allyl isocyanate and hydrolysis to the corresponding zwitterionic chiral selector and its subsequent bonding to the surface of a methacrylate monolith provided a new chiral capillary column for enantiomer separation of chiral acids and chiral bases. First, the epoxy groups of a poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith were converted into amine residues, followed by reaction with allylglycidyl ether. In this way, a spacer arm was bonded to the surface before coating and cross-linking poly(3-mercaptopropyl methylsiloxane) (PMPMS) via radical addition (thiol-ene click reaction) to the surface. In order to improve the performance of the monolithic chiral stationary phase, thio ether and residual thiol groups were oxidized to sulfonyl and sulphonate groups, respectively. This novel chiral stationary phase (CSP) was evaluated by capillary electrochromatography (CEC) using two chiral model compounds, namely N-3,5-dinitrobenzoyl-R,S-leucine (retained by anion-exchange mechanism) and mefloquine (by cation-exchange process). The ion-exchange retention mechanism on the CSP was characterized for these two counterionic model solutes by varying the mobile phase composition, including the nature of solvents, the concentration of counter-ions and co-ions, and the acid-to-base ratio. A series of chiral ß-blockers and amino acid derivatives was used to further check the performance of the modified monolith under the optimal conditions. Several enantiomers were baseline resolved with reasonable peak efficiencies (up to 60,000 theoretical plates per meter for the second eluted enantiomer).
Asunto(s)
Electrocromatografía Capilar/métodos , Codeína/química , Metacrilatos/química , Concentración de Iones de Hidrógeno , Leucina/análogos & derivados , Leucina/química , Leucina/aislamiento & purificación , Mefloquina/química , Mefloquina/aislamiento & purificación , Modelos Químicos , Siloxanos/química , EstereoisomerismoRESUMEN
Two binary mixtures containing codeine (COD) with either ibuprofen (IBU), mixture 1, or with phenylephrine hydrochloride (PE), mixture 2, were analyzed using three simple eco-friendly spectrofluorimetric methods without the need to a prior separation step. The first method is derivative emission spectrofluorimetry using λexâ¯=â¯236â¯nm and 275â¯nm for mixtures 1 and 2, respectively. The second method is constant-wavelength synchronous spectrofluorimetry using ∆λâ¯=â¯100â¯nm and 60â¯nm for mixtures 1 and 2, respectively. The last method is constant-energy synchronous spectrofluorimetry where a wave number interval of -7000â¯cm-1 was used for the analysis of the two binary mixtures. All measurements were performed in acetate buffer pHâ¯5 and thus no toxic volatile solvents were used increasing method greenness. High sensitivity was attained for the three studied drugs where the lower limits of quantitation of COD, IBU and PE reached 0.064, 0.512 and 0.087⯵g/mL, respectively. Analysis of the two binary mixtures in their tablet and liquid dosage forms was performed with good accuracy and precision using the developed methods. The results of the proposed and reported methods were statistically evaluated using one-way ANOVA test and no significant difference among them was obtained. In addition, all aspects of ICH guidelines on analytical method validation were conducted.