The rise of Xanax in South African schools: Toward a framework for connecting drugs and education

This article addresses the dramatic rise in the illicit use of Xanax, an anti-anxiety medication, among South African school learners from roughly the mid 2010s. Based on interviews conducted in secondary schools in Durban, I argue for the importance of locating the benzodiazepine in relation to other known drugs that include cannabis, heroin, alcohol, ecstasy, mandrax, and cocaine. Xanax is typically seen as a stronger version of cannabis/weed but not as potent as drugs such as heroin, which drive students away from school. Xanax pills are also easy to conceal and, for women in particular, do not involve the stigma of smoking. A second argument rests on taking seriously learners’ statements that they use drugs to distract themselves from everyday problems and stresses. Locating schools in the context of a youth unemployment rate of more than 50 percent, I argue that Xanax fits with the ambiguous position of learners who are aware of the illusive connections between schooling and desirable work but are reluctant to turn their back on institutions that, in the absence of alternatives, offer some hope for social mobility.     

Pharmacokinetic evaluation and studies on the clinical efficacy of guar gum‐–based oral drug delivery systems of albendazole and albendazole‐β‐cyclodextrin for colon‐targeting in human volunteers

The present investigation assessed the in vivo properties of the guar gum–based colon‐targeted matrix tablets of albendazole‐β‐cyclodextrin (KA), albendazole matrix tablet (GA), and an immediate‐release albendazole tablet (CA) in humans. A single oral dose was administered in healthy human volunteers and a completely randomized, two‐way, three‐period crossover design was adopted. The data were statistically analyzed and a value of P<0.05 was considered statistically significant. In healthy human volunteers, guar gum colon‐targeted tablets showed delayed t_max and absorption time, decreased absorption rate constant, and unaltered t_1/2indicating that albendazole is not released in stomach and small intestine, but is delivered to the colon, resulting in a slow absorption of the drug and making the drug available for local action in the colon. The increase in C_max and AUC_0‐∞ of KA shows that the bioavailability of albendazole in humans could be definitely improved by complexing the drug with β‐cyclodextrin. Furthermore, an open, parallel, single‐blind clinical study was conducted in patient volunteers who had helminthiasis. Clinical studies showed that the guar gum colon‐targeted tablets could reduce eggs per gram faster than conventional tablets could, resulting in improved clinical symptoms, Hb content, and decreased total count as compared to conventional tablets of albendazole. The investigation shows that albendazole, when complexed with β‐cyclodextrin, improves in vivo bioavailability of the drug and colon targeting using guar gum ensures drug delivery in the colonic fluids, and therefore improves clinical efficacy in human beings with helminthiasis. Drug Dev. Res. 67:154–165, 2006. © 2006 Wiley‐Liss, Inc.     

The identification and analytical characterization of 2,2′‐difluorofentanyl

New psychoactive substances (NPS) have expanded their distribution and become widely available in the global market in recent years. The illicit use of fentanyl and its analogs has become an important worldwide concern linked to their high potency and risk of fatal overdose. This study describes the analytical characterization of a new fentanyl derivative N‐(1‐(2‐fluorophenethyl)‐4‐piperidinyl)‐N‐(2‐fluorophenyl)propionamide (2,2′‐difluorofentanyl). Identification was based on ultra‐high‐performance liquid chromatography–quadrupole time‐of‐flight–mass spectrometry (UHPLC–QTOF–MS), gas chromatography–mass spectrometry (GC–MS), Fourier transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. To our knowledge, this study is the first to report on analytical data for this compound. The most abundant fragment ion in the electrospray ionization (ESI) mass spectrum under collision‐induced dissociation (CID) mode was formed by the cleavage between the piperidine ring and the N‐phenyl‐amide moiety of the protonated molecule. Two diagnostic ions in the electron ionization (EI) mass spectrum were formed by the loss of a tropylium ion (M‐91), and by the degradation of the piperidine ring and dissociate of the COC₂H₅ moiety altogether, respectively.     

Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines: An update comprising flunitrazolam,norflurazepam, and 4'‐chlorodiazepam (Ro5–4864)

The number of newly appearing benzodiazepine derivatives on the new psychoactive substances (NPS) drug market has increased over the last couple of years totaling 23 ‘designer benzodiazepines’ monitored at the end of 2017 by the European Monitoring Centre for Drugs and Drug Addiction. In the present study, three benzodiazepines [flunitrazolam, norflurazepam, and 4′‐chlorodiazepam (Ro5–4864)] offered as ‘research chemicals' on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds, the structural formula declared by the vendor was confirmed by gas chromatography?mass spectrometry (GC–MS), liquid chromatography?tandem mass spectrometry (LC MS/MS), liquid chromatography?quadrupole time of flight?mass spectrometry (LC?QTOF?MS) analysis and nuclear magnetic resonance (NMR) spectroscopy. The metabolic steps of flunitrazolam were monohydroxylation, dihydroxylation, and reduction of the nitro function. The detected in vitro phase I metabolites of norflurazepam were hydroxynorflurazepam and dihydroxynorflurazepam. 4’‐Chlorodiazepam biotransformation consisted of N‐dealkylation and hydroxylation. It has to be noted that 4′‐chlorodiazepam and its metabolites show almost identical LC–MS/MS fragmentation patterns to diclazepam and its metabolites (delorazepam, lormetazepam, and lorazepam), making a sufficient chromatographic separation inevitable. Sale of norflurazepam, the metabolite of the prescribed benzodiazepines flurazepam and fludiazepam, presents the risk of incorrect interpretation of analytical findings.     

Synthesis of 5,5,6,6‐D4‐L‐lysine‐aflatoxin Bl for use as a mass spectrometric internal standard

Human exposure to the hepatocarcinogenic mycotoxin aflatoxin B_l results in modification of serum albumin lysine ε‐amino residues to form lysine‐aflatoxin adducts. A perdeuterated reference standard is now required to quantitatively measure this adduct in epidemiologic studies of liver cancer using isotopic dilution mass spectrometry. A convenient method for the preparation of D4‐L ‐lysine‐AFB_l using commercially available 5,5,6,6‐D4‐l ‐lysine is demonstrated for the first time. The application of two standard α‐amino protection methods is also reported that simplifies the production of natural isotopic abundance lysine‐AFB_l over the currently used method employing N_α‐acetyl‐l ‐lysine. t‐Boc‐N_α‐lysine was used to prepare lysine‐AFB_l; however, a preferred method for directing reaction of AFB_l‐dialdehyde to the ε‐amino group of 5,5,6,6‐D4‐l ‐lysine utilized cupric ions that were spontaneously removed during the reverse phase HPLC purification of D4‐lysine‐AFB_l using 1% HOAc. This strategy eliminates the need to otherwise synthesize and purify t‐Boc‐N_α‐ or N_α‐acetyl‐5,5,6,6‐D4‐lysine and then TFA or enzymatically deprotect overnight to obtain the target compound. Copyright © 2004 John Wiley & Sons, Ltd.     

High specific activity tritium labeling of anti‐tumor agent CEP‐2563

[Ester Methylene‐³H] CEP‐2563 ( 9 ) was synthesized by the tritiation of precursor 6 with NaB³H₄ followed by esterification with BOC‐Lys(BOC)‐β‐Ala‐OH and deprotection. Copyright © 2005 John Wiley & Sons, Ltd.     

Persistence of heroin use despite methadone treatment: Poor coping self‐efficacy predicts continued heroin use

Aim. To evaluate the association between coping self‐efficacy and persistent use of heroin by patients enrolled in a methadone treatment program. Design and Methods. Cross‐sectional survey. One hundred and ninety‐one patients attending outpatient methadone clinics in South‐East England, United Kingdom. Validated questionnaires were used to assess drug use (Maudsley Addiction Profile), alcohol use (Alcohol Use Disorders Identification Test), mental health (Hospital Anxiety and Depression Scale) and coping self‐efficacy (brief 8‐item Drug Taking Confidence Questionnaire). Results. Half of the participants (95/191) reported heroin use in the preceding 14‐day period. Heroin use during methadone treatment was associated with financial problems (P = 0.008), spending time with other drug users (P < 0.001), cocaine use (P = 0.002), low mood (P = 0.002) and dissatisfaction with the daily methadone dose (P = 0.014). Compared with ‘Heroin‐abstinent’ patients, the ‘Heroin’ group reported significantly lower mean coping self‐efficacy scores (t = 9.8, d.f. = 182, P < 0.001, effect size 1.17). After correcting for the effects of co‐variants in a logistic regression model, the main determinants of persistent heroin use were ‘coping self‐efficacy’[B ?0.05; standard error (SE) 0.008; Wald 36.6; odds ratio (OR) 0.95, 95% confidence interval (CI) 0.94, 0.97; P < 0.001] and ‘dissatisfaction with methadone dose’ (B 0.93; SE 0.46; Wald 4.1; OR 2.5, 95% CI 1.03, 6.25; P = 0.042). Satisfaction with methadone dose showed no association with self‐efficacy. Discussion and Conclusions. While heroin use during methadone treatment can partly be explained by inadequate dosing, our data suggest a more complex picture with significant contribution from poor coping self‐efficacy. Efforts aimed at enhancing and maintaining the patients' self‐efficacy and social skills are likely to improve heroin and other drug use outcomes with added benefits for treatment completion rates and the throughput of methadone programs.[Senbanjo R, Wolff K, Marshall EJ, Strang J. Persistence of heroin use despite methadone treatment: Poor coping self‐efficacy predicts continued heroin use. Drug Alcohol Rev 2009]     

Identification of pyrolysis products of the new psychoactive substance 2‐amino‐1‐(4‐bromo‐2,5‐dimethoxyphenyl)ethanone hydrochloride (bk‐2C‐B) and its iodo analogue bk‐2C‐I

2‐Amino‐1‐(4‐bromo‐2,5‐dimethoxyphenyl)ethanone hydrochloride (bk‐2C‐B) has recently emerged as a new psychoactive substance (NPS). It is most commonly consumed orally, although there are indications that it might also be ingested by inhalation or ‘smoking’. Information about the stability of bk‐2C‐B when exposed to heat is unavailable and the potential for pyrolytic degradation and formation of unknown substances available for inhalation prompted an investigation using a simulated ‘meth pipe’ scenario. Twelve products following pyrolysis of bk‐2C‐B were detected and verified by organic synthesis of the corresponding standards. In addition, 2‐amino‐1‐(4‐iodo‐2,5‐dimethoxyphenyl)ethanone hydrochloride (bk‐2C‐I) was characterized for the first time and subjected to pyrolysis as well. Similar products were formed, which indicated that the replacement of the bromo with the iodo substituent did not affect the pyrolysis pattern under the conditions used. Two additional products were detected in the bk‐2C‐I pyrolates, namely 1‐(2,5‐dimethoxyphenyl)‐ethanone and 1‐iodo‐4‐ethenyl‐5‐methoxyphenol. The potential ingestion of pyrolysis products with unknown toxicity adds an element of concern. Copyright © 2017 John Wiley & Sons, Ltd.     

Return of the lysergamides. Part II: Analytical and behavioural characterization of N6‐allyl‐6‐norlysergic acid diethylamide (AL‐LAD) and (2’S,4’S)‐lysergic acid 2,4‐dimethylazetidide (LSZ)

Lysergic acid N ,N ‐diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances known and numerous analogs have been explored to varying extents in previous decades. In 2013, N ⁶‐allyl‐6‐norlysergic acid diethylamide (AL‐LAD) and (2’S ,4’S )‐lysergic acid 2,4‐dimethylazetidide (LSZ) appeared on the ‘research chemicals’/new psychoactive substances (NPS) market in both powdered and blotter form. This study reports the analytical characterization of powdered AL‐LAD and LSZ tartrate samples and their semi‐quantitative determination on blotter paper. Included in this study was the use of nuclear magnetic resonance (NMR) spectroscopy, gas chromatography‐mass spectrometry (GC‐MS), low and high mass accuracy electrospray MS(/MS), high performance liquid chromatography diode array detection and GC solid‐state infrared analysis. One feature shared by serotonergic psychedelics, such as LSD, is the ability to mediate behavioural responses via activation of 5‐HT_2A receptors. Both AL‐LAD and LSZ displayed LSD‐like responses in male C57BL/6 J mice when employing the head‐twitch response (HTR) assay. AL‐LAD and LSZ produced nearly identical inverted‐U‐shaped dose‐dependent effects, with the maximal responses occurring at 200 µg/kg. Analysis of the dose responses by nonlinear regression confirmed that LSZ (ED₅₀ = 114.2 nmol/kg) was equipotent to LSD (ED₅₀ = 132.8 nmol/kg) in mice, whereas AL‐LAD was slightly less potent (ED₅₀ = 174.9 nmol/kg). The extent to which a comparison in potency can be translated directly to humans requires further investigation. Chemical and pharmacological data obtained from NPS may assist research communities that are interested in various aspects related to substance use and forensic identification. Copyright © 2016 John Wiley & Sons, Ltd.     

‘100 years of peptide synthesis’: ligation methods for peptide and protein synthesis with applications to β‐peptide assemblies*

Abstract: A brief survey of the history of peptide chemistry from Theodore Curtius to Emil Fischer to Bruce Merrifield is first presented. The discovery and development of peptide ligation, i.e. of actual chemical synthesis of proteins are described. In the main chapter, ‘ Synthesis of Proteins by Chemical Ligation ’ a detailed discussion of the principles, reactivities and mechanisms involved in the various coupling strategies now applied (ligation, chemical ligation, native chemical ligation) is given. These include coupling sites with cysteine and methionine (as well as the seleno analogs), histidine, glycine and pseudo‐prolines, ‘unrestricted’ amino‐acid residues (using the Staudinger reaction), as well as solid‐phase segment coupling by thioligation of unprotected peptides. In another section, ‘ Synthesis of β‐peptides by Thioligation ’, couplings involving β²‐ and β³‐peptides are described (with experimental details).     

Synthesis of (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐ 3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate‐1‐14C

γ‐Cyhalothrin ( 1a ), (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate, is a single‐isomer, synthetic pyrethroid insecticide marketed by Pytech Chemicals GmbH, a joint venture between Dow AgroSciences and Cheminova A/S. As a part of the registration process there was a need to incorporate a carbon‐14 label into the cyclopropyl ring of this molecule. A high yielding radiochemical synthesis of γ‐cyhalothrin was developed from readily available carbon‐14 labeled N‐t‐Boc protected glycine. This seven step synthesis, followed by a preparative normal phase HPLC separation of diastereomers, provided 21.8 mCi of γ‐cyhalothrin‐1‐¹⁴C ( 1b ) with >98% radiochemical purity. Copyright © 2007 John Wiley & Sons, Ltd.     

The poppy seed defense: a novel solution

A major toxicological challenge is distinguishing whether morphine in urine, in the absence of 6‐monoacetylmorphine (6‐MAM), originates from ‘street’ heroin use or poppy seed ingestion. Manufacturing byproducts from the synthesis of illicit heroin include those that originate from the reaction of acetic anhydride with the alkaloid impurity, thebaine, which undergoes skeletal rearrangement, resulting in compounds with a 2‐(N‐methylacetamido)ethyl side‐chain. The hypothesis that the tertiary amide in this side‐chain is resistant to endogenous hydrolysis was supported from in‐vitro experiments; a glucuronide metabolite (designated ‘ATM4G’) was identified that may be used as a marker of ‘street’ heroin administration. Liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) analysis for this metabolite was then performed on selected urine specimens from 22 known heroin users, these being negative on routine testing for 6‐MAM by gas chromatography‐mass spectrometry (GC‐MS), using the generally applied reporting threshold of 10 ng/mL, but positive for the presence of morphine. Peaks corresponding to the retention time for the metabolite marker were clearly observed for 16 of the 22 samples, with variations of the ratios of its three dependent ions being within ± 30% of that produced in vitro. Conversely, 6‐MAM was detected in only 3 samples, but at concentrations <1 ng/mL. Such a high frequency for the presence of the metabolite marker in urine, in the absence of 6‐MAM, is noteworthy and suggests that detection of this metabolite may offer an important advance in forensic toxicology, allowing the development of a new and more definitive test for heroin abuse and thus a potential solution to the so‐called ‘poppy seed defense’. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of highly potent lymphocyte function‐associated antigen‐1 antagonists labeled with carbon‐14 and with stable isotopes,part 3

The drug candidates ( 2 ) and ( 3 ) are highly potent LFA‐1 inhibitors. They were efficiently prepared labeled with carbon‐14 using a palladium‐catalyzed carboxylation of an iodo‐precursor ( 5 ) and sodium formate‐¹⁴C to afford acid [¹⁴C]‐( 6 ), which was coupled via an amide bond to chiral amines ( 7 ) and ( 8 ) in 52% and 48% overall yield, respectively, and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [²H₈]‐( 7 ) was synthesized in three steps from 2‐cyanopyridine‐²H₄ using Kulinkovich‐Szymonik aminocyclopropanation, followed by coupling to L ‐alanine‐2,3,3,3‐²H₄‐N‐t‐BOC, and then removal of the BOC‐protecting group. Amide bond formation with acid ( 6 ) gave [²H₈]‐( 2 ) in 36% overall yield. The amine [¹³C₄,¹⁵N]‐( 8 ) was obtained in two steps using L‐threonine‐¹⁴C₄,¹⁵N and then coupled to acid [¹³C]‐( 6 ) to give [¹³C₅,¹⁵N]‐( 3 ) in 56% overall yield.     

Synthesis of New ‘Hybrid’ Compounds Based on Benzofuroxans and Aminoalkylnaphthalimides

Pathogenic bacteria and fungi eventually develop resistance to existing drugs, and therefore, we need constant development of new drugs. The research is aimed at addressing fundamental scientific problems—the search for new biologically active compounds among several benzofuroxan‐containing ‘hybrid’ products. N‐substituted naphthalimides were chosen as a second pharmacophore. Benzofuroxanes biological effects were studied by means of bacterial lux‐biosensors. Compounds III a, IV a, III c, and IV c displayed more expressed bacteriotoxic action in comparison with the initial substances Ia‐c and represent a certain interest for using as antibacterial substances.     

Radiosynthesis of 7‐chloro‐N,N‐dimethyl‐5‐[11C]methyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide, [11C]SSR180575, a novel radioligand for imaging the TSPO (peripheral benzodiazepine receptor) with PET

SSR180575 (7‐chloro‐N,N,5‐trimethyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide) is the lead compound of an original pyridazinoindole series of potent and highly selective TSPO (peripheral benzodiazepine receptor) ligands. Isotopic labeling of SSR180575 with the short‐lived positron‐emitter carbon‐11 (T_1/2: 20.38 min) at its 5‐methylpyridazino[4,5‐b]indole moiety as well as at its N,N‐dimethylacetamide function by methylation of the corresponding nor‐analogues was investigated. Best results in terms of radiochemical yields and purities were obtained for the preparation of [indole‐N‐methyl‐¹¹C]SSR180575, where routine production batches of 4.5–5.0 GBq of radiochemically pure (>99%) i.v. injectable solutions (specific radioactivities: 50–90 GBq/ µ mol) could be prepared within a total synthesis time of 25 min (HPLC purification included) starting from a 55 GBq [¹¹C]CO₂ cyclotron production batch (non‐decay‐corrected overall radiochemical yields: 8–9%). The process comprises (1) trapping at ?10°C of [¹¹C]methyl triflate in DMF (300 µ l) containing 0.2–0.3 mg of the indole precursor for labeling and 4 mg of K₂CO₃ (excess); (2) heating at 120°C for 3 min; (3) dilution of the residue with 0.5 ml of the HPLC mobile phase and (4) purification using semi‐preparative reversed‐phase HPLC (Zorbax^® SB‐C‐18). In vivo pharmacological properties of [indole‐N‐methyl‐¹¹C]SSR180575 as a candidate for imaging neuroinflammation with positron emission tomography are currently evaluated. Copyright © 2010 John Wiley & Sons, Ltd.     

Probing the regioselective C‐deuteriation of lithium enolates derived from 2‐methyl‐tetralone in the presence of substituted tertiary amines

Results are reported on the regioselective C‐deuteriation of 2‐methyl‐tetralone using a series of D‐sources and tertiary amines as potential mediators. The results presented further aid the understanding of kinetic deuteriation of both ‘base‐containing’ and ‘base‐free’ enolates. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of all‐trans‐[10′‐3H]‐8′‐apo‐β‐carotenoic acid

The enzyme, 15,15′‐β‐carotene dioxygenase (BCDOX), facilitates the oxidation of β‐carotene to yield retinal. This is a remarkable process in which one of 11 double bonds in β‐carotene is selectively oxidized. To further probe the mechanistic aspects of BCDOX, the synthesis of all‐trans‐[10′‐³H]‐8′‐apo‐β‐carotenoic acid is reported. This compound will be used as a photoaffinity labeling reagent to probe the β‐carotene binding pocket within BCDOX. The synthesis outlines a simple and efficient route for the incorporation of tritium at the 10′ olefinic carbon of 8′‐apo‐β‐carotenoic acid. Copyright © 2002 John Wiley & Sons, Ltd.     

An affinity label for δ‐opioid receptors derived from [d‐Ala2]deltorphin I*

Abstract: A series of potential affinity label derivatives of the amphibian opioid peptide [d ‐Ala²]deltorphin I were prepared by incorporation at the para position of Phe³ (in the ‘message’ sequence) or Phe⁵ (in the ‘address’ sequence) of an electrophilic group (i.e. isothiocyanate or bromoacetamide). The introduction of the electrophile was accomplished by incorporating Fmoc‐Phe(p‐NHAlloc) into the peptide, followed later in the synthesis by selective deprotection of the Alloc group and modification of the resulting amine. While para substitution decreased the δ‐opioid receptor affinity, selected analogs retained nanomolar affinity for δ receptors. [d ‐Ala²,Phe(p‐NCS)³]deltorphin I exhibited moderate affinity (IC₅₀ = 83 nm ) and high selectivity for δ receptors, while the corresponding amine and bromoacetamide derivatives showed pronounced decreases in δ‐receptor affinity (80‐ and >1200‐fold, respectively, compared with [d ‐Ala²]deltorphin I). In the ‘address’ sequence, the Phe(p‐NH₂)⁵ derivative showed the highest δ‐receptor affinity (IC₅₀ = 32 nm ), while the Phe(p‐NHCOCH₂Br)⁵ and Phe(p‐NCS)⁵ peptides displayed four‐ and tenfold lower δ‐receptor affinities, respectively. [d ‐Ala²,Phe(p‐NCS)³]deltorphin I exhibited wash‐resistant inhibition of [³H][d ‐Pen²,D‐Pen⁵]enkephalin (DPDPE) binding to δ receptors at a concentration of 80 nm . [d ‐Ala², Phe(p‐NCS)³]deltorphin I represents the first affinity label derivative of one of the potent and selective amphibian opioid peptides, and the first electrophilic affinity label derivative of an agonist containing the reactive functionality in the ‘message’ sequence of the peptide.