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Codeine and morphine are among the few natural products that are used directly as drugs for medical treatment. However, the availability of these is widely dependent on natural resources. Herein, we report an efficient enantioselective seven-step synthesis of (-)-codeine starting from simpler starting materials. The key steps involve microwave-assisted intramolecular cascade double heck cyclization to access the ABCE ring of opium alkaloids with the required stereocenters in one pot. A photoinduced intramolecular hydroamination of carboxamide forms the D ring and completes the pentacyclic core of the morphinans. Following that, an oxidation followed by global reduction leads to the formation of (-)-codeine. Our synthesis relies on simple and classical reactions to address the opium alkaloids and will serve as an efficient route to access the other morphinans.

"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., (© 2024. The Author(s).)

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 (H 2 SO 4 ), hydrochloric acid (HCl), phosphoric acid (H 3 PO 4 ) 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.

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 ).

The adsorption and surface ionization of codeine molecules С 18 H 21 O 3 N ( 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 - C 1 ) β bond breaking and formation of ionizable radicals, the rate constants K + and K 0 , the activation energy Е + and Е 0 of thermodesorption, and the pre-exponential factors in the continuity equation for the radicals C 9 H 7 N + CH 3 ( m/z 144) have been defined by surface ionization on the surface of oxidized tungsten W x O y . The results of determining the surface ionization coefficient and estimates of the ionization potentials of these radicals have been presented.

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.

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, [SiW 12 O 40 ] 4- , with lanthanoids Dy(III), La(III), Nd(III), and Sm(III) and the multidentate linking ligand 1,10-phenanthroline-2,9-dicarboxylic acid (H 2 PDA). 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 PDA 2- ligands into crystalline materials, leading to four polyoxometalate-based frameworks where Keggin-type heteropolyanions are linked by cationic {Ln n (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.

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 H 3 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 NH 4 + as an alternative RI. In the presence of NH 4 + , 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., (© 2020 John Wiley & Sons, Ltd.)

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.

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.

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.

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., Competing Interests: Declaration of Competing Interest There are no financial or commercial conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 [ 35 S]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.

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.

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., (Copyright © 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

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 β-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 β-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 β-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., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

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 14.36 Å than previously reported tripodal opioids allowing for enhanced aggregation of larger DNA plasmids (>4,000 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 103 nm and diameter of 350 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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 λ ex  = 236 nm and 275 nm for mixtures 1 and 2, respectively. The second method is constant-wavelength synchronous spectrofluorimetry using ∆λ = 100 nm and 60 nm for mixtures 1 and 2, respectively. The last method is constant-energy synchronous spectrofluorimetry where a wave number interval of -7000 cm -1 was used for the analysis of the two binary mixtures. All measurements were performed in acetate buffer pH 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 μg/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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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 β-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)., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

Opioid analgesics devoid of central side effects are unmet medical need in the treatment of acute pain (e.g. post-operative pain). Recently, we have reported on 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), a novel opioid agonist of high efficacy producing peripheral antinociception in subchronic inflammatory pain in certain doses. The present study focused on the antinociceptive effect of 14-O-MeM6SU compared to morphine in formalin test of an early/acute (Phase I) and late/tonic (Phase II) pain phases. Subcutaneous 14-O-MeM6SU (253-1012 nmol/kg) and morphine (3884-31075 nmol/kg) dose dependently reduced the pain behaviors of both phases. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid antagonist, abolished the antinociceptive effect of 506 nmol/kg 14-O-MeM6SU. On the other hand, the effects of 14-O-MeM6SU (1012 nmol/kg) and morphine (15538 nmol/kg) were only partially affected by NAL-M, indicating the contribution of CNS to antinociception. Locally injected test compounds into formalin treated paws caused antinociception in both phases. Locally effective doses of test compounds were also injected into contralateral paws. Morphine showed effects in both phases, 14-O-MeM6SU in certain doses failed to produce antinociception in either phase. A NAL-M reversible systemic dose of 14-O-MeM6SU and the lowest systemic effective dose of morphine were evaluated for their sedative effects following isoflurane-induced sleeping (righting reflex). In contrast to morphine, 14-O-MeM6SU in certain antinociceptive doses showed no impact on sleeping time. These data highlight that high efficacy opioids of limited CNS penetration in certain doses mitigate somatic and inflammatory pain by targeting MOR at the periphery.

Drug tampering practices, with the aim to increase availability of drug delivery and/or enhance drug effects, are accessible on Internet and are practiced by some portion of recreational drug users. Not rarely, recreational misuse may result in toxic and even fatal results. The aim of the present study was to assess the tampering risk of medicaments containing different formulations of an opioid in combination with paracetamol or dexketoprofen, following the procedures reported in dedicated forums on the web. Tablets and suppositories containing codeine, tramadol and oxycodone were extracted following the reported "Cold water extraction"; dextromethorphan was extracted from cough syrup following the procedure reported as "Acid/base extraction" and fentanyl was extracted from transdermal patches according the procedure reported in Internet. The tampered products and opportunely prepared calibrators in water were analysed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The separation of the analytes was carried on Agilent ZORBAX Eclipse Plus C18 (RRHT 2.1 mm × 50 mm, 1.8 μm) by the gradient elution of 0.01% formic acid in water and 0.01% formic acid in methanol. Acquisition was by MRM mode considering at least two transitions for compound. Declared recoveries for these home-made extractions claimed to exceed 99% for the opioid and to complete remove paracetamol, often associated to liver toxicity and thus to obtain a "safer" preparation. In this study, the authors demonstrated that rarely the recoveries for the opioid reached 90% and that up to 60% of the paracetamol amount remained in solution. Thus, high risks for health remained both for the potential lethality of the opioid content, but also for the sub-lethal chronic use of these mixtures, which contained still uncontrolled, ignored, but often important amounts of paracetamol., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dual-template magnetic molecularly imprinted polymer nanoparticles were synthesized and used for the solid-phase extraction of acetaminophen and codeine before simultaneous determination by corona discharge ion mobility spectrometry. The magnetic molecularly imprinted polymer nanoparticles were prepared using silica-coated magnetic nanoparticles as supporters, acetaminophen and codeine as template molecules, 3-aminopropyltriethoxysilane and phenyltriethoxysilane as functional monomers, and tetraethoxysilane as a cross-linker. The obtained molecularly imprinted polymer was characterized by transmission electron microscopy, x-ray diffraction and Fourier-transform infrared spectroscopy. The adsorption performance of the imprinted polymers was studied by a series of experiments, indicating a satisfactory recognition ability of products for acetaminophen and codeine. The detection limits of 0.05 and 0.12 μg mL -1 , and the dynamic range of 0.20 - 2.0 and 0.40 - 3.0 μg mL -1 were achieved for acetaminophen and codeine, respectively. The proposed method was used for simultaneous determinations of acetaminophen and codeine in urine samples, and the corresponding recoveries were calculated in the range of 87 - 94%. These satisfactory results revealed the ability of the method for a routine analysis of acetaminophen and codeine, simultaneously.

Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug-excipient interactions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredients (APIs) under study are carvedilol (CAR) and codeine phosphate (COP), which are known to undergo esterification with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addition, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano-activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of moisture. We further studied drug-excipient interactions under mechano-activation (comilling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.

To which extent illicit drugs are transformed during in-sewer transport, depends on a number of factors: i) substance-specific transformation rates, ii) environmental conditions, iii) point of discharge (location of drug user) and iv) sewer network properties, primarily hydraulic residence time (HRT) and the ratio of biofilm contact area to wastewater volume (A/V eq ). Assessing associated uncertainties typically requires numerous simulations. Therefore, we propose a new two-step modeling framework: 1) Quantify hydrodynamic conditions. This computationally demanding step was performed once in SWMM to derive HRT and A/V eq for each potential point of discharge (node) in three catchments of different size. 2) Estimate biomarker loss. In this step, Monte Carlo simulations were performed for defined scenarios. Depending on assumptions about drug user distribution and prevalence, a number of nodes was sampled. For each node an empirical first-order transformation model was applied with flow-path-corresponding HRT and A/V eq from step 1. Biotic and abiotic transformation rates were sampled from distributions combining variability of different biofilms. In our modeling study, median losses were >30% for amphetamine, 6-monoacetylmorphine and 6-acetylcodeine in all three catchments with high uncertainty (5%-100% loss), which would imply a systematic underestimation of consumption when neglecting in-sewer processes. Median losses for 21 other investigated biomarkers were <10% with different uncertainty ranges - "no substantial transformation" was confirmed for nine substances in a real sewer segment with a 2-h residence time. Transferability of these results must be tested for other catchments. To further reduce uncertainty, mainly additional knowledge on transformation rates, particularly in biofilm, and their distribution across a sewer network is needed to update model input objectively. Our approach allows efficient testing and, furthermore, can be expanded for many other human biomarkers. Accounting for biomarker stability during in-sewer transport will avoid biased estimates and further improve wastewater-based epidemiology., (Copyright © 2017. Published by Elsevier Ltd.)

Objective: Misuse of codeine-containing medicines in combination with new psychoactive substances (NPS) is inadequately described. This study characterises codeine consumption amongst NPS users and non-NPS users to provide warning of health issues., Methods: Online survey conducted between July 2015 and March 2016., Results: Out of 340 respondents, residing in a country in Europe and using codeine recently, 63.8% were female. Mean age: 34.9 years (SD = 12.4). Substance use included NPS (18.5%) and illicit controlled drugs (55.9%). Factors relating to codeine use found to significantly predict NPS use were consuming codeine extracted from combination tablets (OR = 16.79, 95% CI [8.67, 32.51]), obtaining codeine from friends, family, and acquaintances (OR = 3.98, 95% CI [1.82, 8.7]), use of illicit controlled drugs (OR = 34.99, 95% CI [8.39, 145.94]) and use of codeine to experience euphoria (OR = 6.41, 95% CI [3.42, 12.04])., Conclusions: Amongst NPS users, codeine is less likely to be used daily but more likely to be used for recreational purposes. Smaller populations engaging in high-risk use exist who take multiple drugs in high doses. Combinations of misused codeine and NPS highlight the need for policy to respond to a more complex drug situation., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: As a strong inducer of IgE antibodies to substituted ammonium ion epitopes (QAI), pholcodine (PHO) is a postulated cause of allergic anaphylaxis to neuromuscular blocking agents (NMBAs). Three years after withdrawal of PHO in Norway, a significant reduction in IgE sensitization and anaphylaxis reporting was seen., Objective: Six-year follow-up study on the effects of PHO withdrawal on IgE sensitization and anaphylaxis reporting., Methods: From 650 acute consecutive reports (2005-2013) to the Norwegian Network for Anaphylaxis under Anaesthesia (NARA), total number of reports on suspected anaphylactic reactions, number of reactions where NMBAs were administered, number of reactions where serum IgE antibodies (≥0.35 kU A /l) to suxamethonium (SUX) and PHO were present at time of reaction and anaphylaxis severity grades were retrieved. In addition, NMBA sales and prevalence of IgE sensitization to PHO and SUX among 'allergics' were monitored., Results: From baseline period P0 (PHO on the market) through the first (P1) and second (P2), three-year periods after withdrawal, significant falls in total reports (P < 0.001) and reports with IgE antibodies to PHO (P = 0.008) and SUX (P = 0.001) at time of reaction were found. Total NMBA sales in P2 were 83% of P0, and SUX and rocuronium (ROC) together made up 86% of sales throughout the study. Five NMBA-related anaphylactic deaths occurred during P0 and P1 and, however, none during P2. Prevalence of IgE sensitization to SUX in 'allergics' fell to 0% at 4 and 5 years after withdrawal., Conclusions: Six years after PHO withdrawal, the Norwegian population has become significantly less IgE-sensitized and clinically more tolerant to NMBAs., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A robust version of the off-resonance ROESY pulse scheme is suggested for the measurement of proton-proton distances or slow chemical exchange in small to medium-sized molecules. The method implements adiabatic ramps to establish a pair of opposite frequency off-resonance spin lock fields - with optionally randomized duration - and adiabatic inversion pulses with simultaneous gradients for efficient zero-quantum suppression. The amended pulse sequence yields pure absorption cross-peaks and works safely for small to medium-sized molecules. The applicability of the method has been demonstrated using small, rigid molecules (strychnine and codeine) and was also applied for a cyclic peptide and a small protein. We found that the pure phase cross-peaks of the new ROESY version are beneficial for distance measurements. The one-dimensional (selective) version of the new method is also powerful for measuring selected pair-wise interactions and distance determination. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

In this work calcium stearate (CaSt) multi-particulates loaded with codeine phosphate (COP) were developed in an attempt to provide extended release (ER) combined with alcohol dose dumping (ADD) resistance. The pellets were prepared via wet/extrusion spheronization and ER characteristics were obtained after fluid bed drying at 30°C. Pore blockers (i.e., xanthan, guar gum and TiO2) were integrated to control the uptake of ethanolic media, the CaSt swelling and consequently, the COP release. While all three pore blockers are insoluble in ethanol, xanthan dissolves, guar gum swells and TiO2 does not interact with water. The incorporation of 10 and 15% TiO2 still provided ER characteristics and yielded ADD resistance in up to 40v% ethanol. The in-vitro data were subjected to PK simulations, which revealed similar codeine plasma levels when the medication is used concomitantly with alcoholic beverages. Taken together the in-vitro and in-silico results demonstrate that the incorporation of appropriate pore blockers presents a promising strategy to provide ADD resistance of multi-particulate systems., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Context: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch., Objective: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children., Materials and Methods: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife., Results and Discussion: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm 2 ), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm 2 of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm 2 CDB and 58.12 µg/cm 2 APAP in 24 h., Conclusion: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

This study investigated the photocatalytic degradation of codeine by UV-irradiated TiO2. The degradation kinetics was determined under varied conditions including the TiO2 loading, codeine concentration, and pH. Codeine and several reaction intermediates including morphine were identified and tracked during degradation using HPLC/MS-MS technique, along with TOC and IC measurements. Specifically, removal of 100 μg/L of spike codeine was complete in 3 min by contact with a 0.1 g/L suspension of TiO2 under UV irradiation at pH 7. The degradation kinetics of codeine was first-order with respect to both the catalyst TiO2 and the reactant codeine, with enhanced reaction rates with increasing pH up to pH 9. Mineralization of codeine was possible upon prolonged contact; near complete mineralization of 10 mg/L of codeine was achieved in 90 min with 0.1 g/L TiO2 under irradiation at pH 5, during which the organic nitrogen was converted to NH3-N (74%) and NO3-N (22%). Based on the identified intermediates, two degradation pathways were proposed of which one involved ipso-substitution followed by cleavage of the aromatic ring and another involved repeated hydroxylation of the codeine molecule followed by its fragmentation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Context: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch., Objective: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children., Materials and Methods: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife., Results and Discussion: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm(2)), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm(2) of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm(2) CDB and 58.12 µg/cm(2) APAP in 24 h., Conclusion: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Owing to the special characteristics and abilities polymeric networks have received special interest for a range of biomedical applications especially for drug delivery systems. This study was devoted to preparation of new polymeric compounds based on maleic anhydride and 3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane copolymer (poly maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) (PMAU) patterned as a network for bioconjugation and tested as drug carrier systems. The PMAU copolymer was improved in its functionality by opening the maleic anhydride ring with different amounts of erythritol, which is free of side effects in regular use and a multifunctional compound, and also confers antioxidant character for the new compounds. The new polymeric matrices were loaded with acetaminophen, codeine and their fixed dose combinations. The investigation demonstrated the capability of the new structures to be used as polymer networks for linking bioactive compounds and to perform controlled delivery. The physico-chemical investigations--Fourier transform infrared spectroscopy (FTIR) spectra, contact angle, zeta potential (ZP - z, PMAU and its derivatives samples loaded with medicines present decreased values of zeta potential attesting the bioconjugate formation and as well their stability), and hydrodynamic radius, near infrared chemical imaging evaluation (new specific bands being registered for bio-conjugate with acetaminophen around of 1150-1200 nm and 1700 nm, and also between 1150 and 1200 nm in case of the codeine bio-conjugate), scanning electron microscopy (SEM) studies, X-ray diffraction analysis--evidenced the formation of the bioconjugates in relation to the chemical composition of the polymer matrices, while in vitro release study and in vivo tests confirm the capacity for drug delivery of the prepared bioactive systems., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To estimate the possibilities of using and systematizing computed tomographic findings in patients with toxic phosphorus necrosis of the jaw., Material and Methods: The investigation enrolled 87 patients diagnosed as having toxic phosphorus osteonecrosis. Radiation examination consisted of two stages: primary and repeated radiologic examinations in the postoperative period (final examination before hospital discharge). All the patients underwent skull X-ray and multislice computed tomography (MSCT)., Results: Clinical and radiation examination revealed toxic phosphorus osteonecrosis of the maxilla and mandible in 29 (33%) cases. Osteonecrosis affected only the mandible in 40 (46%) cases and only the maxilla in 18 (21%) cases. In all the patients, computed tomography showed main trends in the X-ray semiotics of toxic phosphorus necrosis of the facial skeleton, such as periostitis; osteosclerosis; development a lesion having a “soap-bubble” appearance; nonspecific and inflammatory bone destruction. The bone, being destroyed, was replaced by pus; inflammatory granulations were absent; osteonecrosis occurred. These processes were characterized by the absence of an obvious demarcation zone along the edges of the process. Sequestration commonly occurred to form sinus tracts. The process involved the adjacent bones; there were reactive changes in the accessory sinuses., Conclusion: MSCT data are of highly informative value in evaluating the status of bone tissue and teeth and in detecting a concomitant abnormality in patients with osteonecrosis of the facial skeleton and may be used to plan surgical treatment for this category of patients.

An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine acetaminophen (AAP) and dihydrocodeine (DHC) in human plasma simultaneously. Plasma samples were prepared using protein precipitation with acetonitrile, the two analytes and the internal standard midazolam were separated on an Acquity UPLC BEH C18 column and mass spectrometric analysis was performed using a QTrap5500 mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions of m/z 151.2→110.0 and m/z 302.3→199.2 were used to quantify for AAP and DHC, respectively. The linearity of this method was found to be within the concentration range of 50-10000ng/mL for AAP, and 1-100ng/mL for DHC in human plasma, respectively. The lower limit of quantification (LLOQ) was 50ng/mL and 1ng/mL for AAP and DHC in human plasma, respectively. The relative standard deviations (RSD) of intra and inter precision were less than 10% for both AAP and DHC. The analysis time of per sample was 1.0min. The developed and validated method was successfully applied to a pharmacokinetic study of AAP (500mg) with DHC (20mg) capsule in Chinese healthy volunteers (N=20)., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The objective of the present study was to investigate interactions between alcohol and hot-melt extruded pellets and the resulting drug release behavior. The pellets were composed of vegetable calcium stearate as matrix carrier and paracetamol or codeine phosphate as model drugs. Two solid lipids (Compritol® and Precirol®) were incorporated into the matrix to form robust/compact pellets. The drug release characteristics were a strong function of the API solubility, the addition of solid lipids, the dissolution media composition (i.e., alcohol concentration) and correspondingly, the pellet wettability. Pellets comprising paracetamol, which is highly soluble in ethanol, showed alcohol dose dumping regardless of the matrix composition. The wettability increased with increasing ethanol concentrations due to higher paracetamol solubilities yielding increased dissolution rates. For pellets containing codeine phosphate, which has a lower solubility in ethanol than in acidic media, the wettability was a function of the matrix composition. Dose dumping occurred for formulations comprising solid lipids as they showed increased wettabilities with increasing ethanol concentrations. In contrast, pellets comprising calcium stearate as single matrix component showed robustness in alcoholic media due to wettabilities that were not affected by the addition of ethanol. The results clearly indicate that the physico-chemical properties of the drug and the matrix systems are crucial for the design of ethanol-resistant dosage forms. Moreover, hydrophobic calcium stearate can be considered a suitable matrix system that minimizes the risk of ethanol-induced dose dumping for certain API's., (Copyright © 2015 Elsevier B.V. All rights reserved.)

"Krokodil" is the street name for the homemade injectable mixture that has been used as a cheap substitute for heroin. Its use begun in Russia and Ukraine and nowadays is being spread over several other countries. Desomorphine is the semi-synthetic opioid claimed to be the main component of krokodil and considered to be responsible for its psychoactive characteristics. The starting materials for desomorphine synthesis are codeine tablets, alkali solutions, organic solvent, acidified water, iodine and red phosphorus, all of which are easily available in retail outlets, such as supermarkets, drugstores, etc. The resulting product is a light brown liquid that is called krokodil. People who inject krokodil present a great variety of serious signs and symptoms, including thrombophlebitis, ulcerations, gangrene, and necrosis, quickly evolving to limb amputation and death. These effects are thought to result from the toxic components produced as byproducts during the homemade drug synthesis. In this work, we reviewed several aspects of krokodil use, including its epidemiology, pharmacology and the chemical properties of the main active ingredient (desomorphine). To enhance our understanding of the clinical and toxic effects and to support the implementation of harm reduction measures, we also describe the "bathtub chemistry" of krokodil and the content of the final solution., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products.

A porous silicon/palladium nanostructure was prepared and used as a new electrode material for the simultaneous determination of acetaminophen (ACT) and codeine (COD). Palladium nanoparticles were assembled on porous silicon (PSi) microparticles by a simple redox reaction between the Pd precursor and PSi in an aqueous solution of hydrofluoric acid. This novel nanostructure was characterized by different spectroscopic and electrochemical techniques including scanning electron microscopy, X-ray diffraction, energy dispersive X-ray spectroscopy, fourier transform infrared spectroscopy and cyclic voltammetry. The high electrochemical activity, fast electron transfer rate, high surface area and good antifouling properties of this nanostructure enhanced the oxidation peak currents and reduced the peak potentials of ACT and COD at the surface of the proposed sensor. Simultaneous determination of ACT and COD was explored using differential pulse voltammetry. A linear range of 1.0-700.0 µmol L(-1) was achieved for ACT and COD with detection limits of 0.4 and 0.3 µmol L(-1), respectively. Finally, the proposed method was used for the determination of ACT and COD in blood serum, urine and pharmaceutical compounds., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Considering the enzymatic activity of the cytochrome P450 2D6 on substrates such as codeine, the current paper includes the development of an enzymatic biosensor for detection of this drug. Home-made screen-printed electrodes were used as electrochemical transducers of the biosensor, in which the enzyme was covalently attached to the carbon surface of the working electrode, this type of modification being the most suitable for the immobilization of the biological element. Chronoamperometric measurements were carried out under optimum conditions of pH and working potential, pH 7 and +200 mV vs. screen-printed Ag/AgCl electrode, giving a reduction signal related to the concentration of codeine in solution. Consecutive additions of a solution of codeine were performed to obtain calibration curves in order to validate the electrochemical method in terms of precision and calculate its capability of detection. These biosensors were used for the determination of codeine in urine and commercial pharmaceutical samples., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The long-term stability of benzodiazepines, opioids, central stimulants and medicinal drugs in authentic postmortem blood samples was studied. All together, 73 samples were reanalyzed after storage at -20°C for 16-18 years. At reanalysis samples containing diazepam, nordiazepam and flunitrazepam demonstrated only small changes during long-term storage when mean and median drug concentrations were compared, while clonazepam concentrations tended to decrease. Samples containing amphetamine, morphine, codeine and 'acidic' medicinal drugs as paracetamol and meprobamate also showed small changes over 16-18 years in mean and median drug concentrations at a group level. For many drugs, however, single samples could demonstrate marked concentration changes, both increases and decreases during storage. For 'alkaline' medicinal drugs, concentration losses were observed in most cases., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The α-benzylation of a deprotonated bicyclic α-aminonitrile, followed by Noyori's asymmetric transfer hydrogenation combined with the Grewe cyclization onto a symmetrical A-ring precursor, are the key steps of a short and high-yielding enantioselective synthesis of the morphinan (-)-dihydrocodeine. This compound can be converted to (-)-thebaine in high yield by known transformations, while (-)-codeine and (-)-morphine are available from an advanced intermediate.

While the solubility parameter is fairly straightforward when assigning BCS classification, the intestinal permeability (Peff) is more complex than generally recognized. In this paper we emphasize this complexity through the analysis of codeine, a commonly used antitussive/analgesic drug. Codeine was previously classified as a low-permeability compound, based on its lower LogP compared to metoprolol, a marker for the low-high permeability class boundary. In contrast, high fraction of dose absorbed (Fabs) was reported for codeine, which challenges the generally recognized Peff-Fabs correlation. The purpose of this study was to clarify this ambiguity through elucidation of codeine's BCS solubility/permeability class membership. Codeine's BCS solubility class was determined, and its intestinal permeability throughout the small intestine was investigated, both in vitro and in vivo in rats. Codeine was found to be unequivocally a high-solubility compound. All in vitro studies indicated that codeine's permeability is higher than metoprolol's. In vivo studies in rats showed similar permeability for both drugs throughout the entire small-intestine. In conclusion, codeine was found to be a BCS Class I compound. No Peff-Fabs discrepancy is involved in its absorption; rather, it reflects the risk of assigning BCS classification based on merely limited physicochemical characteristics. A thorough investigation using multiple experimental methods is prudent before assigning a BCS classification, to avoid misjudgment in various settings, e.g., drug discovery, formulation design, drug development and regulation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Rationale: Pyridinium chlorochromate (PCC) is the active ingredient of 'Urine Luck', a commercially available in vitro adulterating agent used to conceal the presence of drugs in a urine specimen. The exposure of codeine and its major glucuronide metabolite codeine-6-glucuronide (C6G) to PCC was investigated to determine whether PCC is an effective masking agent for these opiate compounds., Methods: Following the addition of PCC to both spiked and authentic codeine and C6G-positive urine specimens, the samples were monitored using liquid chromatography/mass spectrometry (LC/MS). Stable reaction products were identified and characterized using high-resolution MS analysis and, where possible, nuclear magnetic resonance (NMR) analysis., Results: It was determined that PCC effectively oxidizes codeine and C6G, thus altering the original codeine-to-C6G ratio in the urine specimen. Four reaction products were identified for codeine: codeinone, 14-hydroxycodeinone, 6-O-methylcodeine and 8-hydroxy-7,8-dihydrocodeinone. Similarly, three reaction products were identified for C6G: codeinone, codeine and a lactone of C6G (tentative assignment)., Conclusions: Besides addressing the complications added to interpretation, more investigation is warranted to further determine their potential for use as markers for monitoring the presence of codeine and C6G in urine specimens adulterated with PCC., (Copyright © 2014 John Wiley & Sons, Ltd.)

Codeine phosphate forms three hydrates and two anhydrates. The sesquihydrate and hemihydrate, which differ by one water molecule, are stable at room temperature. The influence of this molecule on the internal crystal structure and how it translates into the external crystal shape are reported.

In the present paper, the simultaneous determination of codeine (CO) and caffeine (CF) is described by the use of single-walled carbon nanotubes modified carbon-ceramic electrode (SWCNT/CCE); prepared via a simple and rapid method. The results show that the SWCNT/CCE exhibits excellent electrochemical catalytic activity toward the oxidation of these compounds with respect to the bare CCE and offers two anodic peaks at 1.05 and 1.38 V vs. saturated calomel electrode for oxidation of CO and CF, respectively. Differential pulse voltammetry was used for simultaneous determination of CO and CF at micromolar concentration level. In the optimum conditions, it is found that the calibration graphs for CO and CF are linear in the concentration ranges 0.2-230 and 0.4-300 μM with detection limits of 0.11 and 0.25 μM for CO and CF, respectively. The SWCNT/CCE presents good stability, reproducibility, and repeatability and the proposed method has been successfully applied for determination of CO and CF in some pharmaceutical, drinking and biological samples with high recovery rate., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We have previously found that phenanthrenic opioids, including codeine, modulate morphine glucuronidation in the rat. Here codeine and five of its derivatives were compared in their effects on the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine by rat liver microsomal preparations, and by primary cultures of rat hepatocytes previously incubated for 72 h with either codeine or its derivatives. Acetylcodeine and pivaloylcodeine shared the capability of the parent compound of inhibiting the synthesis of M3G by liver microsomes through a noncompetitive mechanism of action. Their IC50 were 3.25, 2.27, and 4.32 μM, respectively. Dihydrocodeine, acetyldihydrocodeine, and lauroylcodeine were ineffective. In all the experimental circumstances M6G was undetectable in the incubation medium. In primary hepatocyte cultures codeine only inhibited M3G formation, but with a lower efficacy than that observed with microsomes (IC50 20.91 vs 4.32 μM). Preliminary results show that at micromolar concentrations codeine derivatives exhibit a low rate of affinity for μ opiate receptors. In conclusion, acetyl and pivaloyl derivatives of codeine noncompetitively inhibit liver glucuronidation of morphine interacting with microsomes. This study further strengths the notion that phenanthrenic opioids can modulate morphine glucuronidation independently from their effects on μ opiate receptors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This study compared the peripheral analgesic effects of a novel opioid agonist 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), to that of non-peptide (morphine, fentanyl) and peptide opioid agonists (Met-enkephalin; met-ENK and β-endorphin; β-END) in a model of localized inflammatory pain evoked by intraplantar (i.pl.) Freund's complete adjuvant (FCA). Nociceptive responses to local opioid agonists were measured by pressure paw-withdrawal procedures. In addition, the antinociceptive efficacy and potency of these test compounds in vivo was compared to that in vitro using the rat vas deferens (RVD) bioassay. Intraplantar 14-O-MeM6SU (0.32-2.53 nmol/rat), morphine (14.95-112.15 nmol/rat), fentanyl (0.19-2.36 nmol/rat), met-ENK (0.10-10 nmol/rat) and β-END (0.77-5.00 nmol/rat) dose dependently increased paw pressure thresholds exclusively in inflamed hindpaws. At higher doses analgesic effects were also seen in noninflamed paws for 14-O-MeM6SU, morphine and fentanyl but not for met-ENK or β-END. The maximal possible local analgesic effect (%) measured in inflamed paws was 50.6 ± 2.7, 18.23 ± 1.78, 37.44 ± 2.17, 36.00 ± 1.43, and 40.69 ± 0.91 for 14-O-MeM6SU, morphine, fentanyl, met-ENK and β-END, respectively. Interestingly, i.pl. administered opioid peptides met-ENK and β-END displayed a peripheral analgesic ceiling effect. This local antinociception was antagonized by co-administered opioid antagonist naloxone-methiodide (NAL-M). Similar to the analgesic testing, the RVD showed the following efficacy order of the test compounds: 14-O-MeM6SU>β-END>fentanyl>met-ENK≫morphine. Taken together, 14-O-MeM6SU was more potent than morphine, fentanyl and met-ENK and β-END and displayed superiority in the maximum antinociceptive effects. The superiority of local antinociceptive effects of 14-O-MeM6SU might be due to both pharmacodynamic and pharmacokinetic factors., (Copyright © 2013 Elsevier B.V. All rights reserved.)