Dispensing‐label errors in hospital: types and potential causes

Objective The aim was to evaluate the potential causes of dispensing‐label errors at a hospital. Methods The study took place at a 1200‐bed NHS Foundation Trust with two main pharmacy dispensaries (one manual and one automated). Face‐to‐face interviews were conducted with staff involved in label‐generation errors to obtain in‐depth understanding of dispensing‐label errors. Interviews were tape‐recorded, transcribed and analysed with the aid of Nvivo into themes. Key findings Factors suggested as causing label‐generation errors were illegible handwriting, lack of knowledge, hurrying through tasks, distractions, interruptions and the use of past medical records in generating labels. Self‐checking every stage of the labelling process was suggested as the key to detecting and preventing errors. Conclusions The study highlights the vulnerability of the label‐generation process to errors, with potential causes linked to organisational, environmental, task, team and individual factors.     

The synthesis of 14C‐labeled, 13CD2‐labeled saxagliptin,and its 13CD2‐labeled 5‐hydroxy metabolite

¹⁴C‐labeled saxagliptin, ¹³CD₂‐labeled saxagliptin, and its ¹³CD₂‐labeled 5‐hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of ¹⁴C‐labeled saxagliptin was obtained with a specific activity of 53.98 μCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [¹⁴C]CH₂I₂ starting material. By following similar synthetic routes, 580.0 mg of ¹³CD₂‐labeled saxagliptin and 153.1 mg of ¹³CD₂‐labeled 5‐hydroxysaxagliptin metabolite were prepared. Copyright © 2014 John Wiley & Sons, Ltd.     

Syntheses of isotope‐labeled tobacco‐specific nitrosamines and their metabolites

We report here on the syntheses of three deuterium‐labeled tobacco‐specific nitrosamines namely [2,4,5,6‐d₄]nitrosonornicotine([2,4,5,6‐d₄]NNN), 4‐(methylnitrosamino)‐1‐(3‐[2,4,5,6‐d₄]pyridyl)‐1‐butanone ([2,4,5,6‐d₄]NNK), and 4‐(methylnitrosamino)‐1‐(3‐[2,4,5,6‐d₄]pyridyl)‐1‐butanol ([2,4,5,6‐d₄]NNAL). A metabolite of NNK and myosmine, 4‐hydroxy‐1‐(3‐[2,4,5,6‐d₄]pyridyl)‐1‐butanone, was also synthesized. The synthetic strategy reported here is similar to that reported in the literature for the preparation of corresponding unlabeled compounds. The commercially available [2,4,5,6‐d₄]ethylnicotinate was used as starting material. During the course of these syntheses [2,4,5,6‐d₄]myosmine and [2,4,5,6‐d₄]nornicotine were obtained as stable intermediates. These isotope‐labeled compounds are useful internal standards for quantification of TSNA and their metabolites in smokers in molecular epidemiological studies. Copyright © 2008 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.     

Microwave‐enhanced,solvent‐free synthesis of singly and doubly 13C‐labelled trans‐cinnamic acid at the α‐ and β‐carbon positions

¹³C‐labelled trans‐cinnamic acid (3‐phenyl‐2‐propenoic acid) has been synthesized in one step using benzaldehyde‐carbonyl‐¹³C and malonic acid‐2‐¹³C in the presence of ammonium acetate under microwave irradiation and solvent‐free conditions. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of 19‐trideuterated ent‐testosterone and the GABAA receptor potentiators ent‐androsterone and ent‐etiocholanolone

19‐Trideuteromethyl enantiomers of androgens namely ent‐testosterone, ent‐androsterone and ent‐etiocholanolone were prepared by total synthesis. The isotope labeling at the C‐19 angular methyl group was achieved by using deuterated methyl iodide (99.5% d₃) for introduction of C‐19 before closure of the steroid A‐ring. This method yields 19,19,19‐trideuterated steroids without increasing the number of steps involved in the total synthesis of ent‐androgens. Analysis by mass spectrometry (MS) showed no loss of deuterium during incorporation of C‐19 into ent‐testosterone. The availability of the compounds will enable these ent‐androgens to be distinguished by MS from their natural enantiomers in future pharmacokinetic and metabolic studies. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of [2H]‐labelled phase‐I‐metabolites using 1‐[2H]‐pyridinium hydrochloride

Simultaneous O‐demethylation and hydrogen/deuterium exchange of aryl‐methyl‐ethers can be obtained using 1‐[²H]‐pyridinium hydrochloride as reagent at 220°C for 6 h. This reaction was applied to dextromethorphan and various non‐steroidal anti‐inflammatory drugs. Copyright © 2005 John Wiley & Sons, Ltd.     

Expedient synthesis of deuterium‐labelled amides within micro‐reactors

The pharmaceutical industry relies heavily on the synthesis of small quantities (10–500 mg) of stable, isotopically labelled compounds in the evaluation of new drug candidates for metabolism studies. As a result of the phenomenal cost of labelled materials even the preparation of small quantities can be extremely expensive. In this paper, for the first time, we report that micro‐reactor technology may be used to prepare stable deuterium‐labelled compounds by conducting all optimization experiments using unlabelled precursors and simply substituting the labelled derivatives once the optimization is complete. Here, we wish to present a simple, general procedure for the synthesis of amides containing isotopic labels demonstrated using [C‐²H₃]acetyl chloride 1 . The reaction is carried out within a micro‐reactor set‐up which we believe offers superiority over other reported methods viz requiring stoichiometric quantities of reagents, high containment of the system and generality of the technique, obtaining products in high yields. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of [13C2, 15N]‐1,3‐2H‐1‐benzyl‐(Z)‐3‐(benzylidene)indolin‐2‐one

Parkinson disease (PD) is a neurodegenerative disorder characterized by the accumulation of α‐synuclein into Lewy bodies. 3‐Benzylidine‐indolin‐2‐one represents a class of compounds, which are known to inhibit the accumulation of α‐synuclein. In this paper, we report the synthesis of [¹³C] and [¹⁵N] labelled 1‐benzyl‐(Z)‐3‐(benzylidene)indolin‐2‐one from commercially available [¹³C₂]‐chloroacetic acid and [¹⁵N]‐aniline in five steps. The product will be used to study its metabolites in human liver microsomes by liquid chromatography‐tandem mass spectrometry.     

Synthesis of unlabelled and stable‐isotope–labelled glucuronide metabolites of dapagliflozin and synthesis of stable‐isotope–labelled dapagliflozin

Two regioisomeric glucuronide metabolites of dapagliflozin (BMS‐512148) were synthesized and used to elucidate the structures of dapagliflozin metabolites observed in human urine samples. The structures of the synthetic metabolites were assigned by heteronuclear multiple‐bond correlation, ROESY, and total correlation spectroscopy experiments. Analogues of these metabolites containing carbon‐13 as a stable label were also prepared for use as internal standards for the analysis of urine samples obtained from patients participating in clinical studies.     

Preparation of labelled 2‐methoxy‐3‐alkylpyrazines: synthesis and characterization of deuterated 2‐methoxy‐3‐isopropylyrazine and 2‐methoxy‐3‐isobutylpyrazine

Efficient synthetic routes for a number of deuterated analogues of 2‐methoxy‐3‐isopropylpyrazines and 2‐methoxy‐3‐isobutylpyrazines have been developed involving the condensation of glyoxal with an α‐amino acid amide followed by methylation with iodomethane. In this way [²H₃]2‐methoxy‐3‐isopropylpyrazine, 2‐methoxy‐3‐isopropyl‐[²H₂]pyrazine, [²H₃]2‐methoxy‐3‐isopropyl‐[²H₂]pyrazine, [²H₃]2‐methoxy‐3‐isobutylpyrazine; 2‐methoxy‐3‐isobutyl‐[²H₂]pyrazine and [²H₃]2‐methoxy‐3‐isobutyl‐[²H₂]pyrazine were prepared and characterized by NMR and MS. Copyright © 2002 John Wiley & Sons, Ltd.     

99mTc‐labeled DTPA‐colchicine dimer with improved tumor uptake

This work reports the synthesis, radiolabeling, and biological studies of ^99mTc‐diethylene triamine pentaacetic acid (DTPA)‐colchicine dimer in tumor‐bearing mice. The novel colchicine dimer was successfully synthesized by conjugation of DTPA to 2 colchicine biomolecules. The ligand could be labeled by ^99mTc in high yield to get ^99mTc‐DTPA‐colchicine dimer, which was hydrophilic and stable at room temperature. Biodistribution and imaging studies in tumor‐bearing mice showed that ^99mTc‐DTPA‐colchicine dimer accumulated in the tumor with improved uptake and retention. The results indicate the need for synthetic modification of the parent colchicine derivative and the ^99mTc‐chelate with a view to improve the tumor‐targeting efficacy and in vivo kinetic profiles.