Annual banned‐substance review: Analytical approaches in human sports drug testing

A number of high profile revelations concerning anti‐doping rule violations over the past 12 months have outlined the importance of tackling prevailing challenges and reducing the limitations of the current anti‐doping system. At this time, the necessity to enhance, expand, and improve analytical test methods in response to the substances outlined in the World Anti‐Doping Agency (WADA) Prohibited List represents an increasingly crucial task for modern sports drug testing programs. The ability to improve analytical testing methods often relies on the expedient application of novel information regarding superior target analytes for sports drug testing assays, drug elimination profiles, and alternative sample matrices, together with recent advances in instrumental developments. This annual banned‐substance review evaluates literature published between October 2017 and September 2018 offering an in‐depth evaluation of developments in these arenas and their potential application to substances reported in WADA's 2018 Prohibited List.     

Annual banned‐substance review: analytical approaches in human sports drug testing

The aim of improving anti‐doping efforts is predicated on several different pillars, including, amongst others, optimized analytical methods. These commonly result from exploiting most recent developments in analytical instrumentation as well as research data on elite athletes' physiology in general, and pharmacology, metabolism, elimination, and downstream effects of prohibited substances and methods of doping, in particular. The need for frequent and adequate adaptations of sports drug testing procedures has been incessant, largely due to the uninterrupted emergence of new chemical entities but also due to the apparent use of established or even obsolete drugs for reasons other than therapeutic means, such as assumed beneficial effects on endurance, strength, and regeneration capacities. Continuing the series of annual banned‐substance reviews, literature concerning human sports drug testing published between October 2014 and September 2015 is summarized and reviewed in reference to the content of the 2015 Prohibited List as issued by the World Anti‐Doping Agency (WADA), with particular emphasis on analytical approaches and their contribution to enhanced doping controls.     

Do dried blood spots (DBS) have the potential to support result management processes in routine sports drug testing?

Dried blood spots (DBS) have been considered as complementary matrix in sports drug testing for many years. Especially concerning substances prohibited in‐competition only, the added value of DBS collected concomitantly with routine doping control urine samples has been debated, and an increasing potential of DBS has been discussed in the scientific literature. To which extent and under which prerequisites DBS can contribute to enhanced anti‐doping efforts is currently evaluated. As a proof‐of‐principle, two analytical applications, one targeting cocaine/benzoyl ecgonine and the other prednisone/prednisolone, are presented in this perspective to indicate potential added value but also presently existing limitations of the DBS approach.     

Drug metabolism in the horse: a review

A detailed understanding of equine drug metabolism is important for detection of drug abuse in horseracing and also in veterinary drug development and practice. To date, however, no comprehensive review of equine drug metabolism has been published. The majority of literature regarding equine drug metabolite profiles is derived from sports drug detection research and is generally targeted at detecting marker metabolites of drug abuse. However, the bulk of the literature on equine drug metabolism enzymology is derived from veterinary studies aimed at determining the molecular basis of metabolism. In this article, the phase 1 and 2 metabolisms of seven of the most important classes of drugs monitored in horseracing are reviewed, including: anabolic-androgenic steroids (AAS), β? -agonists, stimulants, sedatives/tranquilizers, local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDS)/cyclooxygenase-2 (COX-2) inhibitors, and opioid analgesics. A summary of the literature relating to the enzymology of drug metabolism in this species is also be presented. The future of equine drug metabolism in the area of doping research will be influenced by several factors, including: a possible move towards the increased use of blood and other alternative testing matrices; the development of assays based on intact drug conjugates; the increasing threat of 'designer' and herbal- based products; advances in the use of in vitro technologies; the increased use of liquid-chromatography/high-resolution mass spectrometry; and the possibility of screening using 'omics' approaches. Also, the recent cloning of a range of equine cytochrome P450 (CYP) enzymes opens up the potential for carrying out more detailed mechanistic pharmacological and toxicological veterinary studies.     

The narrow lumbar canal. Study of a surgical series of 139 cases

Over a period of 9 years, 139 patients with a mean age of 61 years were operated upon for disorders due to narrow lumbar vertebral canal. Clinical expression varied: lumbago, movement sciatica, intermittent claudication... Importance must be attached to discordance of examination findings in apparently benign root pain (67% of cases). The two key examinations of radiologic investigation are radiculography and a CT scan. Treatment is surgical, generally by a two-stage wide laminectomy combined with abrasion of an articular facet (64%), excision of osteophytic pads (35%) and/or treatment for a soft herniated disc (26%). Recovery was obtained in 35% of cases and pronounced improvement in 49% (84% of very good and good results) as evaluated by patients and surgeons.     

The final outcome of primary infrainguinal percutaneous transluminal angioplasty in 100 consecutive patients with chronic critical limb ischemia

PURPOSE: This study was performed to determine final outcomes in patients treated with infrainguinal percutaneous transluminal angioplasty (PTA) for chronic critical limb ischemia (CLI). MATERIALS AND METHODS: The study population consisted of 100 consecutive patients (mean age, 72 y; range, 38-90 y; 40 men and 60 women) with 116 treated limbs. CLI was defined as rest pain or ischemic tissue defect combined with an ankle systolic pressure < or = 50 mm Hg. Indication for treatment was rest pain in 23 limbs (20%), ischemic ulcer in 50 (43%), and gangrene in 43 (37%). All patients were followed until they had met the study endpoints: major amputation or death. The mean follow-up period was 38 months (1-119 mo). Limb salvage, survival, and life with limb rates were determined along with their determinants. RESULTS: On average, 1.9 invasive procedures were required during the lifespan of a critically ischemic limb, including primary PTA and 32 repeat PTA procedures, 11 surgical revascularizations, and 51 amputations. The major amputation rate was 32% (n = 37). Limb salvage for endovascular treatments at 3, 5, and 8 years was 65%, 60%, and 60%, respectively (SE of estimate [SEE] 相似文献   

The IGF system in neuroblastoma xenografts: focus on IGF-binding protein-6

With a view to investigating the implication of IGF-binding protein-6 (IGFBP-6) in the growth of neuroblastomas, nude mice were injected with IGFBP-6-expressing or control IGR-N-91 human neuroblastoma cells and the resulting xenografts examined. Expression of IGFBP-3, IGFBP-4 and type 1 and type 2 IGF receptor messengers was similar in control tumours and equal-sized IGFBP-6-expressing tumours that had developed. IGF-II was more strongly expressed in control tumours, and IGFBP-6-expressing tumours contained less IGFBP-2 than controls. In both populations, there was a significant positive correlation between IGF-II and IGFBP-2 expression. In small IGFBP-6-expressing xenografts where tumour development had apparently been arrested, haematoxylin--eosin and TUNEL staining revealed numerous apoptotic cells. In situ hybridization indicated homogeneous distribution of the IGFBP-6 signal in test tumours. In cell culture, IGFBP-6-expressing cells expressed similar amounts of IGFBP-2, IGF-II and N-myc mRNAs as control cells; but media conditioned by IGFBP-6-expressing cells contained less intact IGFBP-2 protein, with no increase in its proteolytic fragment. In media treated with plasminogen, in which IGFBP-2 was proteolysed, IGFBP-6 was increased. With its especially strong affinity for IGF-II and its resistance to proteolysis, IGFBP-6 would act by sequestering IGF-II, hence inhibiting its mitogenic and anti-apoptotic effects. In excess, IGFBP-6 would displace IGF-II from IGFBP-2 whose potentiation of IGF-II action would cease and whose susceptibility to degradation would be increased. This study therefore shows that IGFBP-6 plays a role in neuroblastoma cell growth in vivo and in vitro and that stable overexpression of IGFBP-6 leads to alteration of the initial balance between the IGFBPs.     

Synthesis and in vitro and in vivo antimalarial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives

Three series of monoquinolines consisting of a 1,4-bis(3-aminopropyl)piperazine linker and a large variety of terminal groups were synthesized. Our aim was to prove that in related bisquinoline, it is the second quinoline moiety that is responsible for cytotoxicity and that it is not an absolute requirement for overcoming resistance to chloroquine (CQ). Eleven compounds displayed a higher selectivity index (ratio CC50/IC50 activity) than CQ, and one of them cured mice infected by Plasmodium berghei.