Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery

Background and purpose:

This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats.

Experimental approach:

Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg⁻¹ of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg⁻¹ oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI.

Results:

A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT₀/(1 +MED). LT₀ is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 µg·mL⁻¹.

Conclusions:

The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.     

Capabilities of two- and three-dimensional FDG-PET for detecting small lesions and lymph nodes in the upper torso: a dynamic phantom study

The capabilities and limitations of two-(2D) and three-dimensional (3D) fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in detecting small tumors and lymph nodes were studied in a phantom modeling the human chest and axilla. Multiple dual-radionuclide phantom studies were performed. Five hollow spheres ranging in diameter from 3 mm to 15 mm were filled with carbon-11 and placed in the axillary and mediastinal regions of an anthropomorphic phantom containing hollow organs filled with ¹⁸F to simulate FDG uptake 1 h after injection. Dynamic imaging was performed to acquire PET images with varying target-to-background ratios. Imaging was performed in 2D and 3D acquisition modes, with and without attenuation correction, on a modern PET scanner. Lesion detectability was visually and quantitatively assessed. For objects larger than 9 mm in diameter, target-to-background ratios ranging from ∼3:1 to ∼10:1 were detectable. Objects < 9 mm in diameter required a target-to-background ratio of ≥18:1. Target-to-background ratios required for lesion detectability were equivalent for 2D and 3D PET images with and without attenuation correction. In conclusion, 2D and 3D PET with attenuation correction consistently detected ”tumors”≥ 9 mm. Lesions < 9 mm could be detected if there was high enough tumor uptake. No statistically significant differences in lesion detection were found for 2D versus 3D PET, or for attenuation-corrected versus non-attenuation-corrected images. Received 9 July and in revised form 7 September 1998     

bcl-1 REARRANGEMENT AND CYCLIN D1 PROTEIN EXPRESSION IN MANTLE CELL LYMPHOMA

Centrocytic lymphoma, or mantle cell lymphoma (MCL), is characterized by a chromosomal translocation t(11;14) (q13;q32) involving the bcl-1 locus on chromosome 11. Cyclin D1 is a cell-cycle regulatory protein essential for G1–S transition and has been identified as a potential transforming gene affected by the translocation. In this study, 32 cases of MCL were analysed for the bcl-1 rearrangement and cyclin D1 protein expression. In 17 cases, a rearrangement at the major translocation cluster of bcl-1 could be detected. Twenty-four cases exhibited nuclear cyclin D1 expression that was not detectable in other B-cell lymphomas ( n =40) or in normal B-cells. In nine MCL samples, cyclin D1 was expressed without a detectable bcl-1 rearrangement. The detection of a t(11;14) by means of classical cytogenetics in one of these cases, however, may suggest that this discrepancy could be due to chromosomal breakages outside the typical translocation cluster region. In two cases, a bcl-1 rearrangement was not accompanied by cyclin D1 expression. This study provides further evidence that cyclin D1 is involved in the pathogenesis of MCL and can be exploited as a diagnostic marker in the differential diagnosis of B-cell lymphomas and in the identification of MCL.     

Simultaneous MRI and PET imaging of a rat brain

Multi-modality imaging is rapidly becoming a valuable tool in the diagnosis of disease and in the development of new drugs. Functional images produced with PET fused with anatomical structure images created by MRI will allow the correlation of form with function. Our group is developing a system to acquire MRI and PET images contemporaneously. The prototype device consists of two opposed detector heads, operating in coincidence mode. Each MRI-PET detector module consists of an array of LSO detector elements coupled through a long fibre optic light guide to a single Hamamatsu flat panel position-sensitive photomultiplier tube (PSPMT). The use of light guides allows the PSPMTs to be positioned outside the bore of a 3T MRI scanner where the magnetic field is relatively small. To test the device, simultaneous MRI and PET images of the brain of a male Sprague Dawley rat injected with FDG were successfully obtained. The images revealed no noticeable artefacts in either image set. Future work includes the construction of a full ring PET scanner, improved light guides and construction of a specialized MRI coil to permit higher quality MRI imaging.     

The distinctive profile of risk factors of nasopharyngeal carcinoma in comparison with other head and neck cancer types

Background

Nasopharyngeal carcinoma (NPC) and other head and neck cancer (HNCA) types show a great epidemiological variation in different regions of the world. NPC has multifactorial etiology and many interacting risk factors are involved in NPC development mainly Epstein Barr virus (EBV). There is a need to scrutinize the complicated network of risk factors affecting NPC and how far they are different from that of other HNCA types.

Methods

122 HNCA patients and 100 control subjects were studied in the region of the Middle East. Three types of HNCA were involved in our study, NPC, carcinoma of larynx (CL), and hypopharyngeal carcinoma (HPC). The risk factors studied were the level of EBV serum IgG and IgA antibodies measured by ELISA, age, sex, smoking, alcohol intake, histology, and family history of the disease.

Results

EBV serum level of IgG and IgA antibodies was higher in NPC than CL, HPC, and control groups (p < 0.01). NPC was associated with lymphoepithelioma (LE) tumors, males, regular alcohol intake, and regular smoking while CL and HPC were not (p < 0.05). CL and HPC were associated with SCC tumors (p < 0.05). Furthermore, NPC, unlike CL and HPC groups, was not affected by the positive family history of HNCA (p > 0.05). The serum levels of EBV IgG and IgA antibodies were higher in LE tumors, regular smokers, younger patients, and negative family history groups of NPC patients than SCC tumors, non-regular smokers, older patients and positive family history groups respectively (p < 0.05) while this was not found in the regular alcoholics (p > 0.05).

Conclusion

It was concluded that risk factors of NPC deviate much from that of other HNCA. EBV, smoking, alcohol intake, LE tumors, male patient, and age > 54 years were hot risk factors of NPC while SCC and positive family history of the disease were not. Earlier incidence, smoking, LE tumors, and negative family history of the disease in NPC patients were associated much clearly with EBV. It is proposed that determining the correct risk factors of NPC is vital in assigning the correct risk groups of NPC which helps the early detection and screening of NPC.     

Performance of a dual, solid-state intraoperative probe system with 18F, 99mTc, and (111)In.

The use of tracer-avid radiopharmaceuticals and handheld, intraoperative, radiation-sensitive probes to localize areas of tumors promises to improve surgical treatments of cancer. Currently several beta- and gamma-ray-emitting radiopharmaceuticals are proposed for use in these procedures. Therefore, intraoperative-probe systems should be capable of optimum performance with several different radionuclides. The goal of this study was to evaluate the performance of a dual, solid-state probe with three of these radionuclides (18F, 99mTc, and (111)In). METHODS: The detector unit of the intraoperative-probe system used in this investigation consisted of a stack of two ion-implanted silicon detectors separated by 0.5 mm. The system could be operated in two modes: beta optimized, in which the difference between the signals from the two detectors was calculated to correct the beta signal for photon contamination, and photon-optimized mode, in which the signals were summed. Detection sensitivity and an index measuring beta detection selectivity were measured in both acquisition modes with the three different radionuclides. The gamma-ray detection sensitivity of a commercially available probe was measured with 99mTc and compared with the results with a solid-state probe. RESULTS: Beta and photon emissions (gamma-rays and annihilation photons) produced by all three radionuclides were detected by the probe. In beta-optimized acquisition mode, the greatest beta-detection sensitivity was achieved with 18F; photon sensitivity was greatest for measurements with (111)In. The lowest detection sensitivities (beta and photon) were obtained with 99mTc. With the probe system in gamma-optimized mode, the greatest beta and photon sensitivities were achieved with 18F; the lowest were obtained with 99mTc. The gamma-detection sensitivity measured with 99mTc in gamma mode (5.59 +/- 0.41 counts per second [cps]/kBq) compared surprisingly well with the results from the commercial probe (8.75 +/- 0.47 cps/kBq). CONCLUSION: The results from this investigation demonstrate the flexibility and versatility of the dual, solid-state probe system used in this study. These capabilities may be used to improve existing techniques or lead to new methods for performing radionuclide-guided surgeries.