The aim of this work was to study the biodistribution, metabolism and radiation dosimetry of rats injected with 18FFNM using PET/CT images. This novel radiotracer targeting NMDA receptor has ...potential for investigation for neurological and psychiatric diseases.
Free fraction and stability in fresh human plasma were determined in vitro. PET/CT was performed on anesthetized rats. Organs were identified and 3D volumes of interest (VOIs) were manually drawn on the CT in the center of each organ. Time activity curves (TACs) were created with these VOIs, enabling the calculation of residence times. To confirm these values, ex vivo measurements of organs were performed. Plasma and urine were also collected to study in vivo metabolism. Data was extrapolated to humans, effective doses were estimated using ICRP-60 and ICRP-89 dosimetric models and absorbed doses were estimated using OLINDA/EXM V1.0 and OLINDA/EXM V2.0 (which use weighting factors from ICRP-103 to do the calculations).
The 18FFNM was stable in human plasma and the diffusible free fraction was 53%. As with memantine, this tracer is poorly metabolized in vivo. Ex vivo distributions validated PET/CT data as well as demonstrating a decrease of radiotracer uptake in the brain due to anesthesia. Total effective dose was around 6.11 μSv/MBq and 4.65 μSv/MBq for female and male human dosimetric models, respectively.
This study shows that the presented compound exhibits stability in plasma and plasma protein binding very similar to memantine. Its dosimetry shows that it is suitable for use in humans due to a low total effective dose compared to other PET radiotracers.
Pancreatic cancer remains one of the greatest challenges in oncology for which therapeutic intervention is urgently needed. We previously demonstrated that the intra-tumoral gene transfer of ...somatostatin receptor 2, to combat tumor aggressiveness, or of deoxycytidine kinase and uridylate monophosphate kinase, to sensitize to gemcitabine chemotherapy, has anti-tumoral potential in experimental models of cancer. Here, we describe the development of the CYL-02 non-viral gene therapy product that comprises a DNA-plasmid encoding for the three aforementioned genes, which expression is targeted to tumor cells, and complexed with polyethyleneimine non-viral vector. We performed pre-clinical toxicology, bio-distribution, and therapeutic activity studies of CYL-02 in two rodent models of pancreatic cancer. We found that CYL-02 is safe, does not increase gemcitabine toxicity, is rapidly cleared from blood following intravenous administration, and sequestered in tumors following intra-tumoral injection. CYL-02 drives the expression of therapeutic genes in cancer cells and strongly sensitizes tumor cells to gemcitabine, both in vitro and in vivo, with significant inhibition of tumor cells dissemination. This study was instrumental for the later use of CYL-02 in patients with advanced pancreatic cancer, demonstrating that rigorous and thorough preclinical investigations are informative for the clinical transfer of gene therapies against this disease.
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Cordelier et al. describe the preclinical development of a non-viral gene therapy product for patients with pancreatic cancer that encodes genes that inhibit tumor growth and sensitize to chemotherapy, from biodistribution to toxicity and therapeutic efficacy. This work stemmed for first-in-man clinical trials.
Abstract We report here a fatal intoxication case involving ammonium vanadate. A 24-year-old woman was admitted to the Emergency Department for abdominal pain, nausea, vomiting, multiple daily ...diarrheas, hypoglycaemia (0.2 g/L) and severe acute renal failure with glomerular filtration rate estimated at 21 ml/min. This patient had taken an undetermined amount of ammonium vanadate 12 h after ingesting. She died next morning in the context of respiratory distress despite intensive care and oxygen therapy. The autopsy revealed widespread asphyxia syndrome and erosive gastritis. Determination of vanadium concentration in blood was carried out by means of mass spectrometer (ICP-MS) using rhodium (103 Rh) as the internal standard. The vanadium concentration was 6.22 mg/L, corresponding to 6000 times higher than normal concentration in the general population. The latency and the brutality of clinical picture degradation seem to be in consideration of systemic poisoning by vanadium leading to inhibition of the cellular respiratory process.
Abstract Introduction The N -methyl- d -aspartate receptor (NMDAr) is an ionotropic receptor that mediates excitatory transmission. NMDAr overexcitation is thought to be involved in neurological and ...neuropsychiatric disorders such as Alzheimer disease and schizophrenia. We synthesized 18 F-fluoroethylnormemantine (18 F-FNM), a memantine derivative that binds to phencyclidine (PCP) sites within the NMDA channel pore. These sites are primarily accessible when the channel is in the active and open state. Methods Radiosynthesis was carried out using the Raytest® SynChrom R&D fluorination module. Affinity of this new compound was determined by competition assay. We ran a kinetic study in rats and computed a time–activity curve based on a volume-of-interest analysis, using CARIMAS® software. We performed an ex vivo autoradiography, exposing frozen rat brain sections to a phosphorscreen. Adjacent sections were used to detect NMDAr by immunohistochemistry with an anti-NR1 antibody. As a control of the specificity of our compound for NMDAr, we used a rat anesthetized with ketamine. Correlation analysis was performed with ImageJ software between signal of autoradiography and immunostaining. Results Fluorination yield was 10.5% (end of synthesis), with a mean activity of 3145 MBq and a specific activity above 355 GBq/μmol. Affinity assessment allowed us to determine 19 F-FNM IC50 at 6.1 10 − 6 M. 18 F-FMN concentration gradually increased in the brain, stabilizing at 40 minutes post injection. The brain-to-blood ratio was 6, and 0.4% of the injected dose was found in the brain. Combined ex vivo autoradiography and immunohistochemical staining demonstrated colocalization of NMDAr and 18 F-FNM ( r = 0.622, p < 0.0001). The highest intensity was found in the cortex and cerebellum, and the lowest in white matter. A low and homogeneous signal corresponding to unspecific binding was observed when PCP sites were blocked with ketamine. Conclusions 18 F-FNM appears to be a promising tracer for imaging NMDAr activity for undertaking preclinical studies in perspective of clinical detection of neurological or neuropsychological disorders
Methcathinone: A new postindustrial drug Belhadj-Tahar, Hafid; Sadeg, Nouredine
Forensic science international,
10/2005, Letnik:
153, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Methcathinone, a methyl derivative of cathinone, is an illicit drug also known as ephedrone. It is a stimulant found in the “khat” plant,
Catha edulis, which can easily be synthesized from ...pseudoephedrine. Its intoxication is difficult to diagnose and cure properly for two reasons: (i) target consumers are usually “well-educated people” aware of the risks and precautionary measures and (ii) intoxication by cathinone derivatives of synthetic or natural (derived from the khat) origin induce misleading symptoms. As a result, documented reports of methcathinone intoxication that are based on reliable analyses are rare. This paper describes a case of reiterated coma due to an overdose of methcathinone dissolved in alcohol that was taken with bromazepam. A 29-year-old woman was admitted to an emergency department for a coma of toxic origin. Medical files showed that it was her second such episode to occur that month. Moreover, the family indicated signs of depression, incoherent behaviour and intake of “amphetamine-like” drugs. Clinical examination revealed a Glasgow coma score of 9, symmetrical reactive pupils with mydriasis and no convulsions. The patient presented with rapid respirations and her blood pressure was 93/53
mmHg. The ionogram and the blood gas analyses were normal, while the blood alcohol level was 0.167
g/dL. Urinalysis revealed the presence of benzodiazepines and a high concentration of amphetamines (methcathinone: 17.24
mg/L, ephedrine: 11.60
mg/L and methylephedrine: 11.10
mg/L). In addition, serum analysis revealed bromazepam (8.89
mg/L), methcathinone (0.50
mg/L) and methylephedrine (0.19
mg/L). This case showed that the consumption of bromazepam and alcohol altered the typical clinical symptoms of cathinone derivative intoxication, namely hypertension and convulsions. Methylephedrine, an impurity resulting from the alkylation of a primary amine, can be considered a chemical tag indicating fraudulent synthetic origin of the drug. This case describes a documented example of new addictive behaviour of “well-educated” people involving the intake of methcathinone, a postindustrial psychostimulant intentionally combined with an anticonvulsant benzodiazepine. However, this specific case suggests that in spite of a very high bromazepam concentration in presence of the potentiator alcohol, the vital respiratory function would be probably maintained, thanks to the association with methcathinone.
Objectives: A liquid/liquid extraction technique on solid support of Δ9-tetradydrocannabinol (THC), 11-hydroxy-Δ9-tetradydrocannabinol (11-OH-THC) and 11-nor-Δ9-tetradydrocannabinol-9-carboxylic acid ...(THC-COOH) in plasma was developed in order to be assayed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). Methods: The samples were extracted by liquid/liquid extraction over solid support of an extraction cartridge. The extracts were thereafter dried down and injected into the HPLC-MS/MS system set with a positive electrospray mode using a Waters XTerra MS C18 3.5-μm 2.1 × 150 mm column. Results: The extraction recovery levels were 66%, 70% and 71% for THC, and 75%, 93% and 101% for 11-OH-THC at concentrations of 2.5, 5 and 10 ng/mL, respectively. They were 86% and 78% for THC-COOH at concentrations of 5 and 10 ng/mL. The limits of detection (LOD) were 0.09, 0.08 and 0.91 ng/mL for THC, 11-OH-THC and THC-COOH, respectively. The limits of quantification (LOQ) were 0.16, 0.15 and 3.24 ng/mL for THC, 11-OH-THC and THC-COOH, respectively. The inter-series incertitude CV determined for concentrations of 1, 2.5 and 10 ng/mL were 12.1%, 12.0% and 6.4% for THC, 14.5%, 11.1% and 7.2% for 11-OH-THC, and 14.9%, 26.2% and 11.3% for THC-COOH. Conclusion: The novel extraction method for THC, 11-OH-THC and THC-COOH developed in this work is rapid, sensitive and specific. It may be a valuable tool for predictive toxicology, high-throughput metabolism and pharmacokinetic studies of cannabinoids.
Objectifs : Une technique d’extraction liquide/liquide sur support solide du Δ9-tetradydrocannabinol (THC), 11-hydroxy-Δ9-tetradydrocannabinol (11-OH-THC) et de l’acide 11-nor-Δ9-tetradydrocannabinol-9-carboxylique (THC-COOH) dans le plasma est développée afin d’être dosés par chromatographie liquide haute pression couplée à une spectrométrie de masse en tandem (HPLC-MS/MS). Méthodes : L’échantillon est extrait par extraction liquide/liquide sur support solide, puis séché et injecté dans le système HPLC-MS/MS en mode electrospray positif et sur une colonne Waters XTERRA MS C18 3,5 μm 2,1 × 150 mm. Résultats : Les rendements d’extraction sont de 66 %, 70 % et 71 % pour le THC, 75 %, 93 % et 101 % pour le 11-OH-THC aux concentrations de 2,5, 5 et 10 ng/mL et de 86 % et 78 % pour le THC-COOH aux concentrations de 5 et 10 ng/mL. Les limites de détection (LOD) sont de 0.09 ng/mL pour le THC, 0,08 ng/mL pour le 11-OH-THC et 0,91 ng/mL pour le THC-COOH. Les limites de quantification (LOQ) sont de 0,16 ng/mL pour le THC, 0,15 ng/mL pour le 11-OH-THC et 3,24 ng/mL pour le THC-COOH. Les CV d’incertitude inter-séries, déterminés aux concentrations de 1, 2,5 et 10 ng/mL, sont de 12,1 %, 12,0 % et 6,4 % pour le THC, 14,4 %, 11,1 % et 7,2 % pour le 11-OH-THC et de 14,9 %, 26,2 % et 11,3 % pour le THC-COOH. Conclusion : La technique d’extraction du THC, 11-OH-THC et THC-COOH dans le plasma développée dans cette étude est rapide, sensible et spécifique. Il s’agit d’un outil utile pour les études de toxicologie prédictive, de métabolisme et de pharmacocinétique des cannabinoïdes.
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