determining-glucose-metabolism-kinetics-using-18f-fdg-micro-petct

Determining Glucose Metabolism Kinetics Using <sup>18</sup>F-FDG Micro-PET/CT

This paper describes the use of 18F-FDG and micro-PET/CT imaging to determine in vivo glucose metabolism kinetics in mice (and is transferable to rats). ...

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The present study investigates the effect of pioglitazone treatment on blood pressure, vascular reactivity and antioxidant enzymes in L-NAME induced hypertension in normal and STZ-diabetic rats. Diabetes was induced in male Sprague Dawley rats (200+/-15 g) by single intravenous injection of 55 mg/kg of streptozotocin (STZ). Rats were randomized into diabetic and nondiabetic groups, Nomega-nitro-L-arginine-methyl ester (L-NAME, 50 mg/kg) was administered in drinking water for 4 weeks. They were treated with pioglitazone (10 mg/kg/day, p.o.) for 4 weeks and following protocol was carried out. Blood pressure, blood glucose levels and body weight were measured. Thoracic aorta was isolated and dose response curve of phenylephrine (PE) with intact and denuded endothelium was recorded. Dose response curve of acetylcholine (Ach) and sodium nitroprusside (SNP) was recorded in precontracted rings. Lipid peroxidation, superoxide dismutase, catalase, and reduced glutathione were estimated in liver, kidney, and aorta. Pioglitazone produced no significant effect on blood glucose levels, body weight and blood pressure of L-NAME administered nondiabetic and diabetic rats. Pioglitazone treatment had no significant effect on PE induced contraction and Ach induced relaxation in L-NAME diabetic and nondiabetic rats. SNP completely relaxed aortic rings of all the groups. Higher oxidative stress in case of diabetic rats was significantly (p<0.05) reduced by pioglitazone treatment. Although pioglitazone reduced oxidative stress in diabetic rats, there was no significant effect on blood pressure as there was complete absence of nitric oxide due to administration of L-NAME. Hence from the present study it can be concluded that reduction in blood pressure in case of STZ-diabetic rats is nitric oxide mediated.

Effect of pioglitazone on L-NAME induced hypertension in diabetic rats.

It was envisaged to combine high antipyretic activity of paracetamol into commonly used NSAIDs. To achieve this goal new chemical entities were synthesized by chemically combining paracetamol and NSAIDs, and biologically evaluated for their antipyretic, analgesic, anti-inflammatory and ulcerogenic potential. The acid chloride of parent NSAIDs was reacted with excess of p-aminophenol to yield the desired p-amidophenol derivatives (1B-7B). Acetate derivatives (1C-7C) of these phenols (1B-7B) were also prepared by their treatment with acetic anhydride, in order to see the impact of blocking the free phenolic group on the biological activity of the derivatives. All the synthesized p-amidophenol derivatives showed improved antipyretic activity than paracetamol with retention of anti-inflammatory activity of their parent NSAIDs. These compounds elicited no ulcerogenicity unlike their parent drugs.

Synthesis of new chemical entities from paracetamol and NSAIDs with improved pharmacodynamic profile.

Isavuconazole is a triazole with broad-spectrum activity against medically important fungal pathogens. We investigated the pharmacokinetics and pharmacodynamics of isavuconazole in a murine model of disseminated candidiasis. We determined the pharmacokinetics in both plasma and kidney. The relationship between tissue concentrations and the resultant antifungal effect was described using a mathematical model. The pharmacodynamic parameter that optimally links drug exposure with the antifungal effect was determined using dose fractionation studies. The impact of the immune status of mice receiving isavuconazole was determined in persistently and temporarily neutropenic animals. The pharmacokinetics of 1.6 to 28 mg isavuconazole/kg of body weight were linear. Exposure-response relationships demonstrated near-maximal effect following the administration of >15 mg/kg. The mathematical model showed that exposures in the kidney were 5.77 times higher than those in plasma, and there was persistence of the drug at this site despite concentrations in plasma falling to undetectable levels. The in vitro and in vivo postantifungal effects were 2 to 5 and 8.41 h, respectively. The area under the concentration-time curve (AUC)/MIC ratio was the parameter that optimally linked drug exposure with the observed antifungal effect. The total drug AUC/MIC ratios associated with a 90% probability of survival in temporarily and persistently neutropenic mice were 270 and 670, respectively. Once corrected for protein binding, these values are similar to the magnitude of drug exposure associated with a high probability of a successful therapeutic outcome for other triazoles. This study provides the experimental foundation for the use of isavuconazole in patients with disseminated candidiasis.

Pharmacokinetics and pharmacodynamics of a novel triazole, isavuconazole: mathematical modeling, importance of tissue concentrations, and impact of immune status on antifungal effect.

A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for antiinflammatory activity by the rat paw edema method. p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 micromol L(-1) and COX-1 enzyme inhibition of 44% at 88 micromol L(-1) concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 pmol L(-1)) and higher COX-1 enzyme inhibition (53% at 88 micromol L(-1)) but, marked in vivo anti-inflammatory activity (71% at 25 mg kg(-1)) vs. celecoxib (48% at 12.5 mg kg(-1)). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.

Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: search for better COX-2 inhibitors.

This paper describes the development of a simple and sensitive method with reduced run time for the estimation of biodegradation product of an anthraquinone dye, Drimarene blue K(2)RL. The chromatographic analysis was performed using a reversed-phase high performance liquid chromatography (HPLC) with a Lichrospher® RP-18 column, 5 μm particle size, 25 cm × 4.6 mm internal diameter using a 70:20:10 (v/v) mixture of acetonitrile-ammonium acetate buffer (0.02 M) with 0.8% Trifluoroacetic acid (pH 2.5) and methanol as eluent. Flow rate was adjusted to 1.2 mL min(-1). The metabolites (phthalic acid, benzoic acid, 1, 4-dihydroxyanthraquinone, and 2,3-dihydro-9,10-dihydroxy-1,4-anthracenedione) were identified by running HPLC grade standards in defined concentrations. The retention time of the compounds were 2.0, 2.5, 5.2, and 7.2 min for phthalic acid, benzoic acid, 1, 4-dihydroxyanthraquinone, and 2,3-dihydro- 9,10-dihydroxy-1,4-anthracenedione, respectively. The reliability, sensitivity, and validation of the method were checked by calculating recoveries of the individual compounds in the acetonitrile and dye degradation media. The lower limits of detection for anthraquinone metabolites and the separation of acid and anthraquinone metabolites in short time were achieved.

An HPLC method development for the assessment of degradation products of anthraquinone dye.

The Inveon small-animal SPECT system comes with several types of multipinhole collimator plates. We evaluate here the performance measurements of the Inveon SPECT system using 6 different collimators: 3 dedicated for mouse imaging and 3 for rat imaging.

Imaging capabilities of the Inveon SPECT system using single-and multipinhole collimators.

The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer's disease to anxiety. Here we show that global C57BL/6-Tspo(tm1GuWu(GuwiyangWurra))-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from (GuwiyangWurra)TSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of (GuwiyangWurra)TSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs.

Positron emission tomography and functional characterization of a complete PBR/TSPO knockout.

In PET imaging, research groups have recently proposed different experimental set ups allowing multiple animals to be simultaneously imaged in a scanner in order to reduce the costs and increase the throughput. In those studies, the technical feasibility was demonstrated and the signal degradation caused by additional mice in the FOV characterized, however, the impact of the signal degradation on the outcome of a PET study has not yet been studied. Here we thoroughly investigated, using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies, different experimental designs for whole-body and brain acquisitions of two mice and assessed the actual impact on the detection of biological variations as compared to a single-mouse setting. First, we extended the validation of the PET-SORTEO Monte Carlo simulation platform for the simultaneous simulation of two animals. Then, we designed [18F]FDG and [11C]Raclopride input mouse models for the simulation of realistic whole-body and brain PET studies. Simulated studies allowed us to accurately estimate the differences in detection between single- and dual-mode acquisition settings that are purely the result of having two animals in the FOV. Validation results showed that PET-SORTEO accurately reproduced the spatial resolution and noise degradations that were observed with actual dual phantom experiments. The simulated [18F]FDG whole-body study showed that the resolution loss due to the off-center positioning of the mice was the biggest contributing factor in signal degradation at the pixel level and a minimal inter-animal distance as well as the use of reconstruction methods with resolution modeling should be preferred. Dual mode acquisition did not have a major impact on ROI-based analysis except in situations where uptake values in organs from the same subject were compared. The simulated [11C]Raclopride study however showed that dual-mice imaging strongly reduced the sensitivity to variations when mice were positioned side-by-side while no sensitivity reduction was observed when they were facing each other. This is the first study showing the impact of different experimental designs for whole-body and brain acquisitions of two mice on the quality of the results using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies.

Simultaneous scanning of two mice in a small-animal PET scanner: a simulation-based assessment of the signal degradation.

Type 2 diabetes is characterised by decreased HDL levels, as well as the level of apolipoprotein A-I (apoA-I), the main apolipoprotein of HDLs. Pharmacological elevation of HDL and apoA-I levels is associated with improved glycaemic control in patients with type 2 diabetes. This is partly due to improved glucose uptake in skeletal muscle.

Article	Year
Effect of pioglitazone on L-NAME induced hypertension in diabetic rats. Vascular pharmacology\| PubMed ID: 16168716	2005
Synthesis of new chemical entities from paracetamol and NSAIDs with improved pharmacodynamic profile. Bioorganic & medicinal chemistry\| PubMed ID: 16962330	2006
Pharmacokinetics and pharmacodynamics of a novel triazole, isavuconazole: mathematical modeling, importance of tissue concentrations, and impact of immune status on antifungal effect. Antimicrobial agents and chemotherapy\| PubMed ID: 19451288	2009
Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: search for better COX-2 inhibitors. Acta pharmaceutica (Zagreb, Croatia)\| PubMed ID: 19839404	2007
An HPLC method development for the assessment of degradation products of anthraquinone dye. Environmental monitoring and assessment\| PubMed ID: 20680441	2011
Imaging capabilities of the Inveon SPECT system using single-and multipinhole collimators. Journal of nuclear medicine : official publication, Society of Nuclear Medicine\| PubMed ID: 24009279	2013
Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nature communications\| PubMed ID: 25406832	2014
Simultaneous scanning of two mice in a small-animal PET scanner: a simulation-based assessment of the signal degradation. Physics in medicine and biology\| PubMed ID: 26797268	2016
In vivo PET imaging with [(18)F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes. Diabetologia\| PubMed ID: 27193916	2016

Arvind Parmar

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