Background and Purpose
Designer β‐keto amphetamines (e.g. cathinones, ‘bath salts’ and ‘research chemicals’) have become popular recreational drugs, but their pharmacology is poorly characterized.
...Experimental Approach
We determined the potencies of cathinones to inhibit DA, NA and 5‐HT transport into transporter‐transfected HEK 293 cells, DA and 5‐HT efflux from monoamine‐preloaded cells, and monoamine receptor binding affinity.
Key Results
Mephedrone, methylone, ethylone, butylone and naphyrone acted as non‐selective monoamine uptake inhibitors, similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced the release of 5‐HT, similar to 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) and other entactogens. Cathinone, methcathinone and flephedrone, similar to amphetamine and methamphetamine, acted as preferential DA and NA uptake inhibitors and induced the release of DA. Pyrovalerone and 3,4‐methylenedioxypyrovalerone (MDPV) were highly potent and selective DA and NA transporter inhibitors but unlike amphetamines did not evoke the release of monoamines. The non‐β‐keto amphetamines are trace amine‐associated receptor 1 ligands, whereas the cathinones are not. All the cathinones showed high blood–brain barrier permeability in an in vitro model; mephedrone and MDPV exhibited particularly high permeability.
Conclusions and Implications
Cathinones have considerable pharmacological differences that form the basis of their suggested classification into three groups. The predominant action of all cathinones on the DA transporter is probably associated with a considerable risk of addiction.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•Microbeam radiation therapy is an innovative radiotherapy technique.•Radiocromic film dosimetry at micrometric scale is fundamental.•Comparison between a microdensitometer and an optical microscope ...for film dosimetry.•Definition of film dosimetry protocol for microbeam dose analysis.•The microscope allows more precise, accurate and reliable dose evaluation.
Microbeam radiation therapy is a developing technique that promises superior tumour control and better normal tissue tolerance using spatially fractionated X-ray beams only tens of micrometres wide.
Radiochromic film dosimetry at micrometric scale was performed using a microdensitometer, but this instrument presents limitations in accuracy and precision, therefore the use of a microscope is suggested as alternative. The detailed procedures developed to use the two devices are reported allowing a comparison.
Films were irradiated with single microbeams and with arrays of 50 µm wide microbeams spaced by a 400 µm pitch, using a polychromatic beam with mean energy of 100 keV. The film dose measurements were performed using two independent instruments: a microdensitometer (MDM) and an optical microscope (OM).
The mean values of the absolute dose measured with the two instruments differ by less than 5% but the OM provides reproducibility with a standard deviation of 1.2% compared to up to 7% for the MDM. The resolution of the OM was determined to be ~ 1 to 2 µm in both planar directions able to resolve pencil beams irradiation, while the MDM reaches at the best 20 µm resolution along scanning direction. The uncertainties related to the data acquisition are 2.5–3% for the OM and 9–15% for the MDM.
The comparison between the two devices validates that the OM provides equivalent results to the MDM with better precision, reproducibility and resolution. In addition, the possibility to study dose distributions in two-dimensions over wider areas definitely sanctions the OM as substitute of the MDM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Synchrotron Radiotherapy (SyncRT) is a preclinical radiation treatment which delivers synchrotron x-rays to cancer targets. SyncRT allows for novel treatments such as Microbeam Radiotherapy, which ...has been shown to have exceptional healthy tissue sparing capabilities while maintaining good tumour control. Veterinary trials in SyncRT are anticipated to take place in the near future at the Australian Synchrotron's Imaging and Medical Beamline (IMBL). However, before veterinary trials can commence, a computerised treatment planning system (TPS) is required, which can quickly and accurately calculate the synchrotron x-ray dose through patient CT images. Furthermore, SyncRT TPS's must be familiar and intuitive to radiotherapy planners in order to alleviate necessary training and reduce user error. We have paired an accurate and fast Monte Carlo (MC) based SyncRT dose calculation algorithm with Eclipse
, the most widely implemented commercial TPS in the clinic. Using Eclipse
, we have performed preliminary SyncRT trials on dog cadavers at the IMBL, and verified calculated doses against dosimetric measurement to within 5% for heterogeneous tissue-equivalent phantoms. We have also performed a validation of the TPS against a full MC simulation for constructed heterogeneous phantoms in Eclipse
, and showed good agreement for a range of water-like tissues to within 5%-8%. Our custom Eclipse
TPS for SyncRT is ready to perform live veterinary trials at the IMBL.
Microbeam radiation therapy (MRT) is a new radiation treatment modality in the pre-clinical stage of development at the ID17 Biomedical Beamline of the European synchrotron radiation facility (ESRF) ...in Grenoble, France. MRT exploits the dose volume effect that is made possible through the spatial fractionation of the high dose rate synchrotron-generated x-ray beam into an array of microbeams. As an important step towards the development of a dosimetry protocol for MRT, we have applied the International Atomic Energy Agency's TRS 398 absorbed dose-to-water protocol to the synchrotron x-ray beam in the case of the broad beam irradiation geometry (i.e. prior to spatial fractionation into microbeams). The very high dose rates observed here mean the ion recombination correction factor, ks, is the most challenging to quantify of all the necessary corrections to apply for ionization chamber based absolute dosimetry. In the course of this study, we have developed a new method, the so called 'current ramping' method, to determine ks for the specific irradiation and filtering conditions typically utilized throughout the development of MRT. Using the new approach we deduced an ion recombination correction factor of 1.047 for the maximum ESRF storage ring current (200 mA) under typical beam spectral filtering conditions in MRT. MRT trials are currently underway with veterinary patients at the ESRF that require additional filtering, and we have estimated a correction factor of 1.025 for these filtration conditions for the same ESRF storage ring current. The protocol described herein provides reference dosimetry data for the associated Treatment Planning System utilized in the current veterinary trials and anticipated future human clinical trials.
Microbeam radiation therapy (MRT) is a developing radiotherapy, based on the use of beams only a few tens of micrometres wide, generated by synchrotron X‐ray sources. The spatial fractionation of the ...homogeneous beam into an array of microbeams is possible using a multislit collimator (MSC), i.e. a machined metal block with regular apertures. Dosimetry in MRT is challenging and previous works still show differences between calculated and experimental dose profiles of 10–30%, which are not acceptable for a clinical implementation of treatment. The interaction of the X‐rays with the MSC may contribute to the observed discrepancies; the present study therefore investigates the dose contribution due to radiation interaction with the MSC inner walls and radiation leakage of the MSC. Dose distributions inside a water‐equivalent phantom were evaluated for different field sizes and three typical spectra used for MRT studies at the European Synchrotron Biomedical beamline ID17. Film dosimetry was utilized to determine the contribution of radiation interaction with the MSC inner walls; Monte Carlo simulations were implemented to calculate the radiation leakage contribution. Both factors turned out to be relevant for the dose deposition, especially for small fields. Photons interacting with the MSC walls may bring up to 16% more dose in the valley regions, between the microbeams. Depending on the chosen spectrum, the radiation leakage close to the phantom surface can contribute up to 50% of the valley dose for a 5 mm × 5 mm field. The current study underlines that a detailed characterization of the MSC must be performed systematically and accurate MRT dosimetry protocols must include the contribution of radiation leakage and radiation interaction with the MSC in order to avoid significant errors in the dose evaluation at the micrometric scale.
The study of the interaction of synchrotron X‐ray radiation with a multislit collimator is a critical factor for the creation of microbeams in radiation therapy. This study is a fundamental step forward in the understanding and definition of a reliable protocol for dosimetry at the micrometric scale to be used in microbeam radiation therapy.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND AND PURPOSE The use of ±3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is associated with cardiovascular complications and hyperthermia.
EXPERIMENTAL APPROACH We assessed the effects ...of the α1‐ and β‐adrenoceptor antagonist carvedilol on the cardiostimulant, thermogenic and subjective responses to MDMA in 16 healthy subjects. Carvedilol (50 mg) or placebo was administered 1 h before MDMA (125 mg) or placebo using a randomized, double‐blind, placebo‐controlled, four‐period crossover design.
KEY RESULTS Carvedilol reduced MDMA‐induced elevations in blood pressure, heart rate and body temperature. Carvedilol did not affect the subjective effects of MDMA including MDMA‐induced good drug effects, drug high, drug liking, stimulation or adverse effects. Carvedilol did not alter the plasma exposure to MDMA.
CONCLUSIONS AND IMPLICATIONS α1‐ and β‐Adrenoceptors contribute to the cardiostimulant and thermogenic effects of MDMA in humans but not to its psychotropic effects. Carvedilol could be useful in the treatment of cardiovascular and hyperthermic complications associated with ecstasy use.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The pharmacokinetics and pharmacodynamics of a highly concentrated cyclodextrin‐based intranasal (i.n.) midazolam formulation containing the absorption‐enhancer chitosan were studied in 12 healthy ...volunteers and compared with intravenous (i.v.) midazolam. The pharmacodynamic (PD) effects were assessed using quantitative electroencephalography (EEG). Maximal plasma concentrations of 63 and 110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n. midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam, the times to onset of significant EEG effects in the β2 band (18–25 Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively. A sigmoid maximum‐effect (Emax) model indicated disequilibrium between plasma and effect‐site concentrations, with equilibration half‐lives of 2.1–4.8 min. The observed pharmacokinetic–PD (PK–PD) properties suggest that i.n. midazolam deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose, e.g., in out‐of‐hospital emergency settings with no immediate i.v. access.
Clinical Pharmacology & Therapeutics (2012); 91 5, 856–862. doi:10.1038/clpt.2011.316
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Protein ubiquitination is critical for many cellular processes, through its ability to regulate protein degradation and various signaling mechanisms. In the ubiquitin (Ub) system, substrate ...specificity is achieved through the E3 family of Ub ligases. Because alterations of the ubiquitination machinery have been reported in human cancers, the selective interference with Ub ligases might represent a powerful therapeutic tool. Here, we report the first wide survey of misregulation of Ub ligases in cancer. We analysed 82 Ub ligases in nine types of cancer by in situ hybridization on tissue microarrays. We found 27 instances in which an Ub ligase was altered in a given type of tumor, when compared with normal tissues: 21 cases of overexpression and 6 cases of underexpression. We further analysed selected Ub ligases in large cohorts of breast and non-small-cell lung carcinomas. In five, of six, of these extended analyses (HUWE1, CCNB1IP1, SIAH1 and SIAH2 in breast cancer and CCNB1IP1 in lung cancer), we found that the levels of Ub ligases correlated significantly with relevant prognostic factors, and with clinical outcome. Our findings show that the alteration of Ub ligases is a frequent event in cancer and identify candidate targets for molecular therapies.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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