Identification and quantitation of two new naphthoylindole drugs-of-abuse, (1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM-2202) and (1-(4-pentenyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone, with other synthetic cannabinoids in unregulated “herbal” products circulated in the Tokyo area

During our continual surveillance of unregulated drugs in May–June 2011, we found two new compounds as adulterants in herbal products obtained at shops in the Tokyo area. These compounds were identified by liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The first compound identified was a naphthoylindole (1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM-2202, 1), which is a side-chain hydroxyl analogue of JWH-018. The second compound was (1-(4-pentenyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (2), which is side-chain double bond analogue of JWH-018. This is the first report to identify 1 and 2 in a commercial “herbal” product to our knowledge. For quantitation of the above compounds 1 and 2, and chemical analysis for previously reported compounds (AM-2201, 3; JWH-203, 4; JWH-019, 7; JWH-210, 8; mitragynine, 9), each product was extracted with methanol under ultrasonication to prepare solutions for analysis by liquid chromatography with ultraviolet detection. For the sake of identifying JWH-203 (4) and its positional isomers [JWH-203-3-chloroisomer (5) and 4-chloroisomer (6)] correctly, simultaneous liquid chromatography analysis on fluorocarbon-bonded silica gel column was performed. And a case report of commercially available products containing synthetic cannabinoids 7 and 8, and a natural occurring alkaloid 9, was also shown. Each of 6 commercially circulated products contained compounds 1–4 and 7–9; the amounts of the compounds ranged from 4.1 to 222 mg per pack.     

Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter

Purpose Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT.Methods (S,S)-^123/125I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of ³H-nisoxetine and (S,S)-¹²⁵I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-¹²⁵I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-¹²³I-IPBM were carried out in the common marmoset.Results (S,S)-¹²⁵I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-¹²⁵I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-¹²⁵I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-¹²³I-IPBM allowed brain NET imaging in the common marmoset with SPECT.Conclusion These results suggest that (S,S)-¹²³I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.     

Fluorinated benzamide neuroleptics—2. Synthesis and radiosynthesis of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-3-substituted-2-methoxybenzamides

Synthesis of a fluorinated benzamide neuroleptic, (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-fluoropropyl)-2,3-dimethoxybenzamide starting from 3-(3,4-dimethoxyphenyl)-1-propanol in 20–25% overall yield is reported. Radiosynthesis of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3[¹⁸F]fluoropropyl)-2-methoxybenzamide([¹⁸F]FPHB) and (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3[¹⁸F]fluoropropyl)-2,3-dimethoxybenzamide([¹⁸F]FPHB) was carried out by nucleophilic substitution reaction of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl-5-(3-tosyloxypropyl)-2-methoxybenzamide and (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide respectively, with no carrier added [¹⁸F]fluoride. Both, [¹⁸F]FPHB and [¹⁸F]FPHB were obtained in approx. 20–30% yields (EOS/EOB, decay corrected). Specific activities of 900–1700 Ci/mmol for [¹⁸F]FPHB and 800–1400 Ci/mmol for [¹⁸F]FPMB were obtained by reverse phase HPLC purification. Total synthesis and purification time required for either [¹⁸F]FPHB or [¹⁸F]FPMB was 120 min from EOB.     

Nicotinic α4β2 receptor imaging agents. Part III. Synthesis and biological evaluation of 3-(2-(S)-azetidinylmethoxy)-5-(3'-18F-fluoropropyl)pyridine (18F-nifzetidine)

Thalamic and extrathalamic nicotinic α4β2 receptors found in the brain have been implicated in Alzheimer's disease, Parkinson's disease, substance abuse and other disorders. We report here the development of 3-(2-(S)-azetidinylmethoxy)-5-(3′-fluoropropyl)pyridine (nifzetidine) as a new putative high-affinity antagonist for nicotinic α4β2 receptors. Nifzetidine in rat brain homogenate assays containing α4β2 sites labeled with ³H-cytisine exhibited a binding affinity: Ki=0.67 nM. The fluorine-18 analog, 3-(2-(S)-azetidinylmethoxy)-5-(3′-¹⁸F-fluoropropyl)pyridine (¹⁸F-nifzetidine), was synthesized in 20%–40% yield, and apparent specific activity was estimated to be above 2 Ci/μmol. Rat brain slices indicated selective binding of ¹⁸F-nifzetidine to thalamus, subiculum, striata, cortex and other regions consistent with α4β2 receptor distribution. This selective binding was displaced >85% by 150 μM nicotine. Positron emission tomography (PET) imaging studies of ¹⁸F-nifzetidine in anesthetized rhesus monkey showed slow uptake in the various brain regions. Retention of ¹⁸F-nifzetidine was maximal in the thalamus and lateral geniculate followed by regions of the temporal and frontal cortex. Cerebellum showed the least uptake. Thalamus to cerebellum ratio was about 2.3 at 180 min postinjection and continued to rise. ¹⁸F-Nifzetidine shows promise as a new PET imaging agent for α4β2 nAChR. However, the slow kinetics suggests a need for >3-h PET scans for quantitative studies of the α4β2 nAChRs.     

Frequency of D1S80 and HLA DQα alleles in a Chinese population

Allele frequency distributions for the D1S80 (MCT118) and HLA DQ loci were determined in a Chinese population sample using the polymerase chain reaction (PCR). A total of 25 alleles and 100 phenotypes were observed for D 1 S80. The frequency of allele 18 was higher than allele 24 only in this Chinese population when compared to other reported populations. A total of 6 alleles and 21 possible phenotypes were observed for HLA DQ. The power of discrimination was 0.97 and 0.93 for D1S80 and HLA DQ, respectively.     

Spectroscopic characterization and crystal structures of two cathinone derivatives: 1-(4-chlorophenyl)-2-(1-pyrrolidinyl)-pentan-1-one (4-chloro-α-PVP) sulfate and 1-(4-methylphenyl)-2-(dimethylamino)-propan-1-one (4-MDMC) hydrochloride salts,seized on illicit drug market

Purpose

Two compounds newly found in the seizures by drug enforcement agencies were identified and characterized by various instrumental analytical methods.

Methods

The obtained powder samples were analyzed by gas chromatography–mass spectrometry (GC–MS), liquid chromatography–mass spectrometryⁿ (LC–MSⁿ), nuclear magnetic resonance (NMR) spectroscopy, infrared and Raman spectroscopy and X-ray crystallography.

Results

The two compounds were tentatively identified as 4-chloro-α-PVP and 4-MDMC by GC–MS, and LC–MS/MS. The confirmation of the results was made by NMR spectroscopy. The X-ray crystallography gave information that 4-chloro-α-PVP and 4-MDMC were in salted forms with sulfate and hydrochloride, respectively; in addition, both compounds existed as racemic mixtures.

Conclusions

We could identify 4-chloro-α-PVP and 4-MDMC in the seizure powder samples by various analytical methods. X-ray crystallography was especially useful for identifying the salted forms and enantiomeric forms.

     

Analysis of azepane isomers of AM-2233 and AM-1220, and detection of an inhibitor of fatty acid amide hydrolase [3′-(aminocarbonyl)(1,1′-biphenyl)-3-yl]-cyclohexylcarbamate (URB597) obtained as designer drugs in the Tokyo area

During our careful survey of unregulated drugs from November 2011 to January 2012 in the Tokyo area, we found two new compounds in commercial products. The first was identified as the benzoylindole (2-iodophenyl)[1-(1-methylazepan-3-yl)-1H-indol-3-yl]methanone (2), which is the azepane isomer of AM-2233 (1). Compound 2 was isolated by silica gel column chromatography, and was identified through a combination of liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The second compound was identified as [3′-(aminocarbonyl)(1,1′-biphenyl)-3-yl]-cyclohexylcarbamate (URB597, 5) by comparing analytical data with that of the authentic compound. For quantitation of these three compounds, each commercial product was extracted with methanol under ultrasonication to prepare the solution for analysis by liquid chromatography with ultraviolet detection. The occurrence of compounds 1 and 2, and AM-1220 (3) and its azepane isomer (4) in 29 commercial products found in the Tokyo area are also shown in this report.     

The Bücherer-Strecker synthesis of d- and l-(1-11C)tyrosine and the in vivo study of l-(1-11C)tyrosine in human brain using positron emission tomography

The synthesis of d-and l-(1-¹¹C)tyrosine, starting with ¹¹C-cyanide, is reported. dl-(1-¹¹C)Tyrosine was prepared by the Bücherer-Strecker reaction, from carrier added ¹¹C-cyanide with an incorporation of 80% in 20 min. The isolation of the pure d- and l-amino acid isomers from the enantiomeric mixture was accomplished within 15 min by preparative HPLC using a chiral stationary phase and a phosphate buffer as the mobile phase. Typically, the total synthesis time was 50 min (including purification) from end of trapping of ¹¹C-cyanide, with a radiochemical yield of d- and l-amino acid of 40%–60%. The d- and l-(1-¹¹C)tyrosine were both obtained optically pure, with a carrier added specific activity of 0.3–0.5 Ci/mmol and a radiochemical purity better than 99%. The ¹¹C labelled l-tyrosine was used in an in vivo study in the human brain using positron emission tomography (PET).     

Evaluation of 7 DNA markers (D1S80, HLA-DQα, LDLR,GYPA, HBGG,D7S8 and GC) in a Japanese population

A Japanese population was tested for the 7 DNA markers D 1 S 80, HLA-DQ, low-density lipoprotein receptor (LDLR), glycophorin A (GYPA), hemoglobin G gammaglobin (HBGG), D7S8 and group specific component (GC). Each of these 7 markers was found to be useful for paternity testing and individual identification in a Japanese population.     

3-(2′-[18F]fluoroethyl)spiperone,a potent dopamine antagonist: Synthesis,structural analysis and in-vivo utilization in humans

The synthesis of 3-(2′-[¹⁸F]fluoroethyl)spiperone (1c), a radiotracer useful for imaging the brain dopamine receptor system in vivo using positron emission tomography, is described. Precursors of 1c, the functional 3-N-alkyl derivatives of spiperone (4), were prepared by the alkylation of the amide group in spiperone (2a) by 1,2-disubstituted ethanes under phase transfer conditions. A comprehensive evaluation of the reaction of the derivatives 4a–h with no-carrier-added K ¹⁸F/Kryptofix clearly indicated that the ketalized derivatives 4e–h were the choice of the precursors for 1c. The i.r., MS and NMR spectral data suggested that under phase transfer reaction conditions, the amide nitrogen was preferentially alkylated. To provide a firm basis for comparison with related analogues, an x-ray analysis was performed on a single crystal of 3-(2′-fluoroethyl)spiperone (1d). The tomographic behavior of 1c in human brain tissue was measured for more than 7 h and was consistent with the labeling of dopamine D-2 receptors.     

3′-Deoxy-3′-[18F]fluorothymidine (FLT) uptake in breast cancer cells as a measure of proliferation after doxorubicin and docetaxel treatment

IntroductionThe nucleoside analogue [¹⁸F]fluorothymidine (FLT) has been designed as a marker of cell proliferation that can be imaged in vivo by positron emission tomography. Clinical pilot studies have demonstrated decreasing FLT uptake following antiproliferative chemotherapy of breast cancer. However, the significance of posttreatment FLT uptake has not been evaluated at the cell level. The aim of this study was to investigate whether FLT uptake detects proliferation inhibition induced by docetaxel or doxorubicin treatment in an in vitro breast cancer model.MethodsBreast cancer cells (MCF-7) were treated with docetaxel or doxorubicin for 24 h at drug doses inducing 25–99% inhibition of clonogenic survival (IC₂₅ to IC₉₉). Cellular FLT uptake was estimated at 4 h and at 1, 3 and 5 days interval from chemotherapy. [³H]Thymidine incorporation and S-phase fraction were measured for comparison. Analysis of variance and the Bland–Altman difference plot were employed for statistical analysis.ResultsAfter treatment, FLT uptake was declined in dependence of the proliferation inhibition mediated by both chemotherapeutic agents (all P<.0001). The decrease of FLT was greater after doxorubicin treatment than after the corresponding docetaxel dose. With doxorubicin (IC₉₉), FLT accumulation was reduced by 70% as early as 4 h after treatment. FLT uptake was closely correlated to [³H]thymidine incorporation and S-phase fraction (r=.84 to .93).ConclusionsRight after docetaxel or doxorubicin treatment, FLT uptake corresponds to the reduction of tumor cell proliferation induced. [¹⁸F]FLT appears promising for monitoring chemosensitivity in breast cancer.     

Citius and longius (faster and longer) with no α‐actinin‐3 in skeletal muscles?

The muscle protein alpha-actinin-3 (ACTN3) is normally thought to be expressed in type II muscle fibres and to be necessary for high-power, high-velocity muscle contractions, such as those typically seen in speed/power athletes. The authors report the case of a Spanish elite long jumper (two times Olympian, personal best of 8.26 m) whose genotype for the ACTN3 gene is 577XX (ACTN3 deficient). These data suggest that there might be notable exceptions to the concept that ACTN3 is the "gene for speed".     

Detainees in police custody in the Paris,France area: medical data and high-risk situations (a prospective study over 1 year)

Background and objective

The annual number of detainees held in police custody in France is approximately 700,000. Medical data regarding arrestees are scarce across countries. We present the medical characteristics of detainees kept in police custody, including addictive behaviours and high-risk medical situations.

Methods

We conducted a prospective study over 1 year in a suburban area near Paris.

Results

A total of 19,098 medical examinations were performed on 13,317 individuals. The examinations mainly concerned male subjects (18,116 of 19,098, 95 %). Median age was 24 years (range 13–83). Medical examination was requested by the detainee in 6,638 of 16,801 cases (40 %). Assaults were reported in 4,052 of 17,312 cases (23 %) and occurred at the time of arrest in most cases (2,243, 13 %). A total of 2,394 of 13,317 detainees (18 %) had at least one chronic somatic disorder including asthma (603, 5 %), diabetes (263, 2 %) and arterial hypertension (205, 2 %). A history of psychiatric disorder was reported by 6 % of individuals (674 of 11,787). Regular alcohol drinking was reported by 58 % of detainees. Illicit drug use mainly involved cannabis (4,021 cases, 30 %). In 14,661 of 19,098 cases (77 %), detainees were considered to be unconditionally fit for detention in custody, and 274 detainees (1 %) were declared unfit to be detained.

Conclusion

The present study showed a high frequency of alcohol or substance use and reported assaults or traumatic lesions in arrestees. Attending physicians should pay particular attention to addictive behaviours and traumatic injuries in arrestees, both for immediate care and for prevention.     

Genetic characterization of 32 X-InDels in a population sample from São Paulo State (Brazil)

International Journal of Legal Medicine - X-chromosomal markers can be useful in some forensic cases, where the analysis of the autosomal markers is not conclusive. In this study, a population...     

Quantitative and qualitative characterization of vascularization and hemodynamics in head and neck tumors with a 3D magnetic resonance time-resolved echo-shared angiographic technique (TREAT)—initial results

The purpose of this paper is to characterize and quantify the vascularization and hemodynamic characteristics of head and neck tumors (HNT) with a dynamic 3D time-resolved echo-shared angiographic technique (TREAT) using the regular contrast agent (CA) bolus. Sixteen patients with HNT underwent 3D-TREAT during the CA administration on a 1.5-T magnetic resonance (MR) scanner. Using a parallel imaging acceleration factor of 2, 20 3D data sets at a temporal resolution of 2.3 s/frame were acquired. The quality of tumor delineation, vascularization type, and enhancement pattern were evaluated. Quantitative assessment included measurement of the contrast-to-noise ratio (CNR), determination of signal-intensity-over-time (SIT) curves, time-to-peak enhancement within the carotid arteries and the tumor, and the delay between both. TREAT was compared to conventional digital subtraction angiography (DSA) in six patients. Tumor delineation with TREAT was very good or good in 11/16 patients, and better with TREAT than with DSA in 3/6 cases. The CNR was significantly different for glomus tumors versus hypovascularized malignant tumors with TREAT (p=0.0001), but not on T1-weighted gradient echo (T1w GE) images. Qualitative assessment of tumor vascularization on dynamic TREAT shows good correlation (r=0.75) to quantitative SIT curves. We conclude that TREAT imaging permits the characterization of tumor vascularity and holds promise as a supplementary diagnostic tool in the differential diagnosis of HNT. H.J. Michaely and K.A. Herrmann both contributed equally to this work.     

Comparison of iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane for imaging of the dopamine transporter in the living human brain

Several cocaine congeners are of potential for imaging the dopamine transporter (DAT). Previous studies have shown that iodine-123 labelled 2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-CIT) is a promising radiotracer for imaging the serotonin (5-HT) and dopamine (DA) transporters in the living human brain with single-photon emission tomography (SPET). [¹²³I]-CIT was found to be not very practical for 1-day DAT imaging protocols since peak DAT uptake occurs later than 8 h. Here we report a pilot comparison of [¹²³I]-CIT and 2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([¹²³I]-CIT FP), using SPET imaging in four healthy male subjects. Peak uptake of [¹²³I]-CIT-FP into the basal ganglia occurred earlier (3–4 h after injection of tracer) than that of [¹²³I]-CIT (>8 h). However, the specific DAT binding of [¹²³I]-CIT-FP in the basal ganglia was somewhat less (0.813±0.047) than that of [¹²³I]-CIT (0.922±0.004). Imaging quality is excellent with both tracers and they are potentially of value for brain imaging in various neuropsychiatric disorders.     

IGF-I,IGFBP-2, and -3: do they have a role in detecting rhGH abuse in trained men?

PURPOSE: Although the illegal use of recombinant human growth hormone (rhGH) to enhance performance is increasing among athletes, no official test for its detection has yet been implemented. The aim of this work was to study how prolonged rhGH administration in trained subjects influences the insulin-like growth factor (IGF) system, in order to evaluate new methods in antidoping tests. METHODS: Morning serum growth hormone (GH), IGF-I, IGF binding protein (BP)-2, IGFBP-3, IGF-I/IGFBP-2, and IGFBP-3/IGFBP-2 ratios were evaluated before, during (8th and 15th days), and at the end and after cessation (+3, +6, +9, +12, and +15 d) of a 3-wk treatment with different doses of rhGH (0.09 IU.kg BW(-1).d(-1) for 6 or 3 d a week, i.e., the A and B trials, respectively) in seven well-trained subjects not involved in competitive sports. The blood collections pre- and during treatment were performed immediately before the daily rhGH dose. RESULTS: In both trials, significant increases of IGF-I (higher in the A trial) and IGFBP-3 serum concentrations during rhGH administration were observed. Serum IGFBP-3 remained significantly increased in the A trial 3 d after treatment cessation. In the A trial only, two subjects had IFG-I concentrations exceeding the upper limit of the reference range. No modifications of serum GH, IGFBP-2 and IGF-I/IGFBP-2, and IGFBP-3/IGFBP-2 ratios were observed. The z-score evaluation for IGFBP-3 detected GH exposure in 100% of subjects only at end treatment in A trial. CONCLUSION: Although IGF-I and IGFBP-3 seem potentially the most specific markers of rhGH assumption, our data suggest that for antidoping purposes a single evaluation of their absolute serum concentration is not a sufficiently secure method to detect rhGH abuse in all subjects, especially in the case of low rhGH doses.     

Effects of structural differences between radioiodine-labeled 1-(2′-fluoro-2′-deoxy-d-arabinofuranosyl)-5-iodouracil (FIAU) and 1-(2′-fluoro-2′-deoxy-d-ribofuranosyl)-5-iodouracil (FIRU) on HSV1-TK reporter gene imaging

The goal of this investigation was to evaluate the effects of structural differences between FIAU and FIRU on their ability to serve as a potential tracer for reporter gene imaging. To examine the characteristics of different configurations of FIAU and FIRU, a series of evaluations were done on HSV1-TK gene-expressing cells and on mice with HSV1-TK gene-expressing tumor. The results showed that, as an imaging agent for HSV1-TK-expressing cells, radiolabeled FIAU was more efficient for in vivo imaging than FIRU.     

Serum concentrations of C reactive protein, alpha1 antitrypsin, and complement (C3, C4, C1 esterase inhibitor) before and during the Vuelta a Espańa

Objectives

To determine serum concentrations of proinflammatory (C reactive protein, complement C3 and C4) and anti‐inflammatory (α₁ antitrypsin, C1 esterase inhibitor (C1‐INH)) acute phase proteins in elite cyclists before and during a three week cycle tour.

Methods

Seventeen professional cyclists participating in the Vuelta a Espańa volunteered for the study. Their mean (SD) physical characteristics were: age 28 (1) years; height 1.7 (0.06) m; weight 65 (7) kg; body fat 7.6 (0.8)%; Vo₂max 75.3 (2.3) ml/kg/min. Venepuncture was performed on each subject 24 hours before the tour began (T0), on day 11 (the first rest day; T1) and day 21 (the second to last stage of the tour; T2). Samples at T1 and T2 were taken about 17 hours after the previous stage. Analysis of variance was used to determine changes over time. Where significance was found, a Tukey post hoc test was performed.

Results

C reactive protein concentrations were consistently within the normal range, although there was a 228%, non‐significant increase at T1. C3 concentrations fell within the normal range at all times assessed. C4 concentrations before the race were within the normal range and were significantly increased 10 days (T1) into the race. C1‐INH concentrations did not change significantly throughout the race. α₁ Antitrypsin concentration before the race was at the lower end of the normal range and was only significantly raised at T2.

Conclusions

Although not as pronounced as those reported in marathon/ultramarathon runners, elite cyclists participating in a three week cycle tour experienced increases in selected proinflammatory and anti‐inflammatory acute phase proteins, indicating an acute phase/inflammatory response. It is tenable that the increase in α₁ antitrypsin and C1‐INH (anti‐inflammatory mediators) at T2 served to attenuate the acute phase/inflammatory response. The lower than normal resting concentrations of the acute phase proteins supports the notion that chronic aerobic exercise induces an anti‐inflammatory state.