Direct determination of [Formula: see text] for cylindrical ionization chambers in a 6 MV 0.35 T MR-linac.

To ensure accurate reference dosimetry with ionization chambers in magnetic resonance linear accelerators (MR-linacs), the influence of the magnetic field on the response of the ionization chambers must be considered. The most direct method considering the influence of magnetic fields in dosimetry is to apply an appropriate absorbed-dose-to-water primary standard. At PTB, a new water calorimeter has been designed which is capable to determine Dw,Q in an MR-linac. The new device allows the direct calibration of ionization chambers in terms of absorbed dose to water for MR-linac irradiation conditions. Hence, the correction factors [Formula: see text] can be determined which replace the current radiation-quality dependent correction factors [Formula: see text] for dosimetry in the presence of magnetic fields. In cooperation with Heidelberg University Hospital,[Formula: see text] factors were measured at the 6 MV 0.35 T Viewray MR-linac for different cylindrical ionization chambers with sensitive volumes ranging from 0.015 cm3 to 0.65 cm3. The chambers were placed both perpendicular and parallel in respect to the magnetic field. Standard uncertainties of about 0.5% were achieved.

Determination of k Q factors for cylindrical and plane-parallel ionization chambers in a scanned carbon ion beam by means of cross calibration.

The accuracy in the dosimetry of therapeutically used carbon ion beams is predominantly affected by the large uncertainty of the so-called k Q factor of the ionization chamber used for the measurements. Due to a lack of experimental data, the k Q factor of ionization chambers in carbon ion beams is still derived by calculation, and, for instance, a standard uncertainty of about 3% is given for k Q factors tabulated in the TRS-398 dosimetric protocol. Recently, k Q factors for two Farmer-type ionization chambers have been determined experimentally in the entrance channel of 429 MeV/u carbon ions, achieving about a threefold reduction of the uncertainty. To further improve the data basis on experimental k Q factors with low uncertainties, k Q factors for the same irradiation condition have now been determined for eight different cylindrical ionization chambers (NE2571, FC65-P, FC23-C, CC25, CC13, TM30010, TM30011, TM30012) and three different plane-parallel ionization chambers (PPC-40, PPC-05, TM34001) by means of a cross-calibration procedure. Generally, standard measurement uncertainties of 1.1% could be achieved. Deviations of less than 1.2% were found between the experimental and the tabulated k Q values. Moreover, the consideration of the experimental values with their smaller uncertainties in updated versions of the dosimetric protocols might enable a substantial reduction of the uncertainties in the dosimetry of carbon ion beams.

Direct determination of k Q factors for cylindrical and plane-parallel ionization chambers in high-energy electron beams from 6 MeV to 20 MeV.

For the ionometric determination of the absorbed dose to water, D w, in high-energy electron beams from a clinical accelerator, beam quality dependent correction factors, k Q, are required. By using a water calorimeter, these factors can be determined experimentally and potentially with lower standard uncertainties than those of the calculated k Q factors, which are tabulated in various dosimetry protocols. However, one of the challenges of water calorimetry in electron beams is the small measurement depths in water, together with the steep dose gradients present especially at lower energies. In this investigation, water calorimetry was implemented in electron beams to determine k Q factors for different types of cylindrical and plane-parallel ionization chambers (NE2561, NE2571, FC65-G, TM34001) in 10 cm × 10 cm electron beams from 6 MeV to 20 MeV (corresponding beam quality index R 50 ranging from 1.9 cm to 7.5 cm). The measurements were carried out using the linear accelerator facility of the Physikalisch-Technische Bundesanstalt. Relative standard uncertainties for the k Q factors between 0.50% for the 20 MeV beam and 0.75% for the 6 MeV beam were achieved. For electron energies above 8 MeV, general agreement was found between the relative electron energy dependencies of the k Q factors measured and those derived from the AAPM TG-51 protocol and recent Monte Carlo-based studies, as well as those from other experimental investigations. However, towards lower energies, discrepancies of up to 2.0% occurred for the k Q factors of the TM34001 and the NE2571 chamber.

Deep hypothermia therapy attenuates LPS-induced microglia neuroinflammation via the STAT3 pathway.

Deep hypothermia therapy (HT) is a standard method for neuroprotection during complex pediatric cardiac surgery involving extracorporeal circulation and deep hypothermic cardiac arrest. The procedure, however, can provoke systemic inflammatory response syndrome (SIRS), one of the most severe side effects associated with pediatric cardiac surgery. To date, the cellular inflammatory mechanisms induced by deep HT remain to be elucidated. Therefore, we investigated the effects of deep HT (17°C) and rewarming on the inflammatory response in lipopolysaccharide (LPS) stimulated BV-2 murine microglia. Additionally, we also investigated the application of Stattic, a signal transducer and activator of transcription 3 (STAT3) activation inhibitor, as an alternative to physical cooling to attenuate the LPS-induced inflammatory response. Deep HT had no cytotoxic effect but attenuated microglia migration. IκBα degradation was delayed by deep HT resulting in the attenuation of pNF-κB p65 migration into the nucleus and significant decreases in pro-inflammatory IL-6, TNF-α, and MCP-1 expressions and secretions, as well as decreased anti-inflammatory IL-10 and SOCS3 expressions. Additionally, pStat3 was significantly down regulated under deep hypothermic conditions, also corresponding with the significant reduction in IL-6 and TNF-α expressions. Similar to the effects of HT, the application of Stattic under normothermic conditions resulted in significantly reduced IL-6 and TNF-α expressions. Moreover, attenuation of the inflammatory response resulted in decreased apoptosis in a direct co-culture of microglia and neurons. HT reduces the inflammatory response in LPS-stimulated BV-2 microglial cells, alluding to a possible mechanism of therapeutic hypothermia-induced neuroprotection. In the future, attenuating the phospho-STAT3 pathway may lead to the development of a neuroprotectant with greater clinical efficacy.

Direct determination of k Q for Farmer-type ionization chambers in a clinical scanned carbon ion beam using water calorimetry.

Until now, the dosimetry of carbon ions with ionization chambers has not reached the same level of accuracy as that of high-energy photons. This is mainly caused by the approximately threefold larger uncertainty of the k Q factor of ionization chambers, which, due to the lack of experimental data, is still derived by calculations. Measurements of absorbed dose to water, D w, by means of water calorimetry have now been performed in the entrance channel of a scanned 6 cm × 6 cm radiation field of 429 MeV/u carbon ions, allowing the direct calibration of ionization chambers and thus the experimental determination of k Q. Within this work, values for k Q have been determined for the Farmer-type ionization chambers FC65-G and TM30013. A detailed investigation of the radiation field enabled the accurate determination of correction factors needed for both calorimetric and ionometric measurements. Finally, a relative standard measurement uncertainty of 0.8% (k = 1) could be achieved for the experimental k Q values. For both chambers, the experimental k Q factors were found to be about 1% larger than those tabulated in the German DIN 6801-1 protocol, whereas compared to the theoretical values stated in the TRS-398 protocol, the experimental k Q value agrees within 0.4% for the TM30013 chamber but is about 1% lower in the case of the FC65-G chamber.

Homozygous deletion of RAG1, RAG2 and 5' region TRAF6 causes severe immune suppression and atypical osteopetrosis.

Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5' region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.

CT Metal Artifact Reduction in the Spine: Can an Iterative Reconstruction Technique Improve Visualization?

BACKGROUND AND PURPOSE: Metal-related artifacts from spine instrumentation can obscure relevant anatomy and pathology. We evaluated the ability of CT images reconstructed with and without iterative metal artifact reduction to visualize critical anatomic structures in postoperative spines and assessed the potential for implementation into clinical practice. MATERIALS AND METHODS: We archived CT projection data in patients with instrumented spinal fusion. CT images were reconstructed by using weighted filtered back-projection and iterative metal artifact reduction. Two neuroradiologists evaluated images in the region of spinal hardware and assigned a score for the visualization of critical anatomic structures by using soft-tissue and bone windows (critical structures totally obscured, n = 0; anatomic recognition with high diagnostic confidence, n = 5). Using bone windows, we measured the length of the most pronounced linear artifacts. For each patient, neuroradiologists made recommendations regarding the optimal use of iterative metal artifact reduction and its impact on diagnostic confidence. RESULTS: Sixty-eight patients met the inclusion criteria. Visualization of critical soft-tissue anatomic structures was significantly improved by using iterative metal artifact reduction compared with weighted filtered back-projection (median, 1 ± 1.5 versus 3 ± 1.3, P < .001), with improvement in the worst visualized anatomic structure in 88% (60/68) of patients. There was not significant improvement in visualization of critical osseous structures. Linear metal artifacts were reduced from 29 to 11 mm (P < .001). In 87% of patients, neuroradiologists recommended reconstructing iterative metal artifact reduction images instead of weighted filtered back-projection images, with definite improvement in diagnostic confidence in 32% (22/68). CONCLUSIONS: Iterative metal artifact reduction improves visualization of critical soft-tissue structures in patients with spinal hardware. Routine generation of these images in addition to routine weighted filtered back-projection is recommended.

Improved Image Quality in Head and Neck CT Using a 3D Iterative Approach to Reduce Metal Artifact.

BACKGROUND AND PURPOSE: Metal artifacts from dental fillings and other devices degrade image quality and may compromise the detection and evaluation of lesions in the oral cavity and oropharynx by CT. The aim of this study was to evaluate the effect of iterative metal artifact reduction on CT of the oral cavity and oropharynx. MATERIALS AND METHODS: Data from 50 consecutive patients with metal artifacts from dental hardware were reconstructed with standard filtered back-projection, linear interpolation metal artifact reduction (LIMAR), and iterative metal artifact reduction. The image quality of sections that contained metal was analyzed for the severity of artifacts and diagnostic value. RESULTS: A total of 455 sections (mean ± standard deviation, 9.1 ± 4.1 sections per patient) contained metal and were evaluated with each reconstruction method. Sections without metal were not affected by the algorithms and demonstrated image quality identical to each other. Of these sections, 38% were considered nondiagnostic with filtered back-projection, 31% with LIMAR, and only 7% with iterative metal artifact reduction. Thirty-three percent of the sections had poor image quality with filtered back-projection, 46% with LIMAR, and 10% with iterative metal artifact reduction. Thirteen percent of the sections with filtered back-projection, 17% with LIMAR, and 22% with iterative metal artifact reduction were of moderate image quality, 16% of the sections with filtered back-projection, 5% with LIMAR, and 30% with iterative metal artifact reduction were of good image quality, and 1% of the sections with LIMAR and 31% with iterative metal artifact reduction were of excellent image quality. CONCLUSIONS: Iterative metal artifact reduction yields the highest image quality in comparison with filtered back-projection and linear interpolation metal artifact reduction in patients with metal hardware in the head and neck area.

Experimental determination of kQ factors for cylindrical ionization chambers in 10 cm × 10 cm and 3 cm × 3 cm photon beams from 4 MV to 25 MV.

For the ionometric determination of absorbed dose to water, Dw, in megavoltage photon beams from a linear accelerator, beam-quality-dependent correction factors, kQ, are used for the ionization chambers. By using a water calorimeter, these factors can be determined experimentally and with substantially lower standard uncertainties compared to calculated values of the kQ, which are published in various dosimetry protocols. In this investigation, kQ for different types of cylindrical ionization chambers (NE 2561, NE 2571, FC 65 G) were determined experimentally in 10 cm × 10 cm photon beams from 4 MV to 25 MV (corresponding beam quality index TPR20,10 from 0.64 to 0.80). The measurements were carried out at the linear accelerator facility of the Physikalisch-Technische Bundesanstalt. It is shown that the kQ factors for a single ionization chamber in 10 cm × 10 cm photon beams can be measured with a relative standard uncertainty of 0.31%. In addition to these measurements in 10 cm × 10 cm fields, kQ factors for the NE 2561 chamber were also determined in smaller 3 cm × 3 cm photon beams between 6 MV and 25 MV. In this case, relative standard uncertainties between 0.35 % and 0.38 % are achieved for the kQ factors. It is found for this ionization chamber, that the ratio of the kQ factors in 3 cm × 3 cm and in 10 cm × 10 cm beams increases with increasing TPR20,10 to reach a value of 1.0095 at TPR20,10 = 0.8 with a relative standard uncertainty of 0.4 %.

Difference in the relative response of the alanine dosimeter to megavoltage x-ray and electron beams.

In order to increase the usefulness of the alanine dosimeter as a tool for quality assurance measurements in radiotherapy using MV x-rays, the response with respect to the dose to water needs to be known accurately. This quantity is determined experimentally relative to (60)Co for 4, 6, 8, 10, 15 and 25 MV x-rays from two clinical accelerators. For the calibration, kQ factors for ionization chambers with an uncertainty of 0.31% obtained from calorimetric measurements were used. The results, although not inconsistent with a constant difference in response for all MV x-ray qualities compared to (60)Co, suggest a slow decrease from approximately 0.996 at low energies (4-6 MV) to 0.989 at the highest energy, 25 MV. The relative uncertainty achieved for the relative response varies between 0.35% and 0.41%. The results are confirmed by revised experimental data from the NRC as well as by Monte Carlo simulations using a density correction for crystalline alanine. By comparison with simulated and measured data, also for MeV electrons, it is demonstrated that the weak energy dependence can be explained by a transition of the alanine dosimeter (with increasing MV values) from a photon detector to an electron detector. An in-depth description of the calculation of the results and the corresponding uncertainty components is presented in an appendix for the interested reader. With respect to previous publications, the uncertainty budget had to be modified due to new evidence and to changes of the measurement and analysis method used at PTB for alanine/ESR.

Calorimetric determination of the absorbed dose to water for medium-energy x-rays with generating voltages from 70 to 280 kV.

For medium energy x-rays produced with tube voltages from 70 to 280 kV, the absorbed dose to water, D(w), has been determined by means of water calorimetry with relative standard uncertainties ranging from 0.45% to 0.98% at 280 and 70 kV. The results were confirmed by Monte Carlo calculations, in which the ratios of D(w) at 5 cm depth in a reference water phantom to the air kerma free in air, K(a), at the same point in space were compared to the corresponding ratios determined experimentally. The general agreement between measurement and calculation was better than 1%. These results confirm earlier investigations in which the absorbed dose to graphite was determined by means of a graphite extrapolation chamber. For the Monte Carlo calculations, an attempt was made to present a complete uncertainty budget, taking into account type B contributions also.

[Acute calcinosis of the hand in an infant]. / Das akute Kalksalzdepot der Hand beim Kleinkind.

We report on an acute calcinosis in infants as a differential diagnosis to a trauma or an infect of the wrist.

The comparative performance of four respiratory motion predictors for real-time tumour tracking.

Prediction of respiratory motion is essential for real-time tracking of lung or liver tumours in radiotherapy to compensate for system latencies. This study compares the performance of respiratory motion prediction based on linear regression (LR), neural networks (NN), kernel density estimation (KDE) and support vector regression (SVR) for various sampling rates and system latencies ranging from 0.2 to 0.6 s. Root-mean-squared prediction errors are evaluated on 12 3D lung tumour motion traces acquired at 30 Hz during radiotherapy treatments. The effect of stationary predictor training versus continuous predictor retraining as well as full 3D motion processing versus independent coordinate-wise motion processing is investigated. Model parameter optimization is performed through a grid search in the model parameter space for each predictor and all considered latencies, sampling rates, training schemes and 3D data-processing modes. Comparison of the predictors is performed in the clinically applicable setting of patient-independent model parameters. The considered predictors roughly halve the prediction errors compared to using no prediction. When averaging over all sampling rates and latencies, prediction errors normalized to errors of using no prediction of 0.44, 0.46, 0.49 and 0.55 for NN, SVR, LR and KDE are observed. The small differences between the predictors emphasize the relative importance of adequate model parameter optimization compared to the actual prediction model selection. Thorough model parameter tuning is therefore essential for fair predictor comparisons.

A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs.

The IOP lowering effects of NCX 139, a new chemical entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the respective des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan(®)) and the prostaglandin agonist, latanoprost (Xalatan(®)) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC(50)=0.70±0.06 µM; E(max)=80.6±2.9%). Like bimatoprost (IC(50)=3.07±1.3 µM) or latanoprost (IC(50)=0.48±0.15 µM), NCX 139 displaced (3)H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estimated potency of 0.77±0.13 µM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent reduction of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δ(max)=-12.8±2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the respective des-nitro derivative (Δ(max)=-4.6±1.0 and -2.7±1.3 mmHg, respectively for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compound targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.

Impact quantification of the daVinci telemanipulator system on surgical workflow using resource impact profiles.

BACKGROUND: It has yet to be determined whether surgical assist systems benefit surgical workflow. This question should be answered qualitatively and quantitatively and must be supported by evidence gathered from structured and rigorous analyses. METHODS: A method is presented to quantify the benefits of the daVinci telemanipulator system to surgical workflow. Based on the modeling of surgical processes, resource impact profiles (RIPs) were generated. RIPs are statistical mean intervention courses for a sample of surgical process models that were performed using a specific surgical assist system as a resource. A total of 12 laparoscopic and 12 telemanipulator-supported Nissen fundoplications were modeled and analyzed to quantify the impact of the surgical assist system. RESULTS: Few statistically significant benefits of the system to surgical workflow were found. It was found that the daVinci system is not superior to the conventional laparoscopic strategy if the surgeon follows the same workflow. CONCLUSIONS: RIPs are a valuable method to estimate the impact of a surgical assist system on the surgical workflow. For the use case investigated, changes in workflow may be necessary to fully benefit from the advantages of using a telemanipulator in Nissen fundoplications. Conversely, the telemanipulator may only reach its full potential in more complex operations.

University leadership for innovation in global health and HIV/AIDS diagnostics.

Medical products used in the developed world often fail to adequately serve resource-limited settings where electricity, transportation and health care workers are not readily available. We suggest that the problem is not only a lack of coordinated financial resources to purchase existing medical products, but also a lack of products that are specifically designed for resource-limited settings. While donor organisations with a focus on global health are increasingly willing to bear the additional financial risk for the research and development of such high-impact medical products, corporations are still reluctant to take their best scientists and engineers away from more commercially attractive projects. Universities, on the other hand, given their teaching and research missions, are well positioned to engage in such high-risk development projects. A group of biomedical, engineering, business and social science researchers at Northwestern University (NU) propose a creative model to address significant social and health needs. The team's initial product focus is a rapid test for diagnosing infants with HIV. The NU model aligns the incentives and expertise of industry, donors and academia to innovate medical products, such as the infant HIV diagnostic test, for resource-limited settings.

Hematopoietic stem cell transplantation for pediatric autoimmune disease: where we stand and where we need to go.

In children, autoimmune diseases and their therapies cause significant morbidity, especially in those with severe or refractory disease. The constant development of new immunosuppressants and targeted biological therapies leads to a unique 'moving target' with regard to the gold standard of treatment for these patients. However, incidental findings of cure after hematopoietic stem cell transplant (HSCT) in patients with concomitant benign or malignant hematologic disorders and autoimmune disease raise the question of whether HSCT can be used as upfront therapy for patients with severe autoimmune diseases. Animal data have been helpful in investigating both the efficacy of this modality and the mechanisms underlying cure. The potential for a therapeutic 'graft vs autoimmunity' (GVA) effect with an allogeneic approach highlights the already acknowledged need for clinical trials of allogeneic vs autologous transplant in these diseases where an autologous transplant would be the 'intuitive' albeit potentially erroneous choice. We critically review the data generated in the field thus far, and emphasize the need for an organized, interdisciplinary approach to conduct prospective clinical trials to answer these and other questions and advance the field.

Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor variant complexes.

BACKGROUND AND PURPOSE: A prostamide analogue, bimatoprost, has been shown to be effective in reducing intraocular pressure, but its precise mechanism of action remains unclear. Hence, to elucidate the molecular mechanisms of this effect of bimatoprost, we focused on pharmacologically characterizing prostaglandin FP receptor (FP) and FP receptor variant (altFP) complexes. EXPERIMENTAL APPROACH: FP receptor mRNA variants were identified by reverse transcription-polymerase chain reaction. The FP-altFP4 heterodimers were established in HEK293/EBNA cells co-expressing FP and altFP4 receptor variants. A fluorometric imaging plate reader was used to study Ca2+ mobilization. Upregulation of cysteine-rich angiogenic protein 61 (Cyr61) mRNA was measured by Northern blot analysis, and phosphorylation of myosin light chain (MLC) by western analysis. KEY RESULTS: Six splicing variants of FP receptor mRNA were identified in human ocular tissues. Immunoprecipitation confirmed that the FP receptor is dimerized with altFP4 receptors in HEK293/EBNA cells co-expressing FP and altFP4 receptors. In the studies of the kinetic profile for Ca2+ mobilization, prostaglandin F2alpha (PGF2alpha) elicited a rapid increase in intracellular Ca2+ followed by a steady state phase. In contrast, bimatoprost elicited an immediate increase in intracellular Ca2+ followed by a second phase. The prostamide antagonist, AGN211335, selectively and dose-dependently inhibited the bimatoprost-initiated second phase of Ca2+ mobilization, Cyr61 mRNA upregulation and MLC phosphorylation, but did not block the action of PGF2alpha. CONCLUSION AND IMPLICATIONS: Bimatoprost lacks effects on the FP receptor but may interact with the FP-altFP receptor heterodimer to induce alterations in second messenger signalling. Hence, FP-altFP complexes may represent the underlying basis of bimatoprost pharmacology.

Prostamides (prostaglandin-ethanolamides) and their pharmacology.

The prostamides are part of a large and continually expanding series of pharmacologically unique neutral lipids. They are COX-2 derived oxidation products of the endocannabinoid/endovanniloid anandamide. Prostamide pharmacology is unique and, as in the case of the endocannabinoids anandamide and 2-arachidonylglycerol, bears little resemblance to that of the corresponding free acids. By virtue of its close relationship to the anti-glaucoma drug bimatoprost, prostamide F(2alpha) has received the greatest research attention. Prostamide F(2alpha) and bimatoprost effects appear independent of prostanoid FP receptor activation, according to a litany of agonist studies. Studies involving freshly isolated and separate feline iridial smooth muscle cells revealed that bimatoprost and FP receptor agonists stimulated different cells, without exception. This suggests the existence of receptors that preferentially recognize prostamide F(2alpha). The recent discovery of prostamide antagonists has provided further support for prostamide receptors as discrete entities. The prototypical prostamide antagonists, AGN 204396 and 7, blocked the effects of prostamide F(2alpha) and bimatoprost but not those of PGF(2alpha) and FP receptor agonists in the feline iris. Second generation more potent prostamide antagonists, such as AGN 211334, should allow the role of prostamides in health and disease to be elucidated. From the therapeutics standpoint, the prostamide F(2alpha) analogue bimatoprost is the most efficacious ocular hypotensive agent currently available for the treatment of glaucoma.

Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris.

BACKGROUND AND PURPOSE: The prostamides (prostaglandin-ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX-2 from the respective endocannabinoids anandamide and 2-arachidonyl glycerol. Agonist studies suggest that their pharmacologies are unique and unrelated to prostanoid receptors. This concept was further investigated using antagonists. EXPERIMENTAL APPROACH: The isolated feline iris was used as a key preparation, where prostanoid FP receptors and prostamide activity co-exist. Activity at human recombinant FP and other prostanoid receptors was determined using stable transfectants. KEY RESULTS: In the feline iris, AGN 204396 produced a rightward shift of the dose-response curves for prostamide F2alpha and the prostamide F2alpha analog bimatoprost but did not block the effects of PGF2alpha and synthetic FP receptor agonists. Studies on human recombinant prostanoid receptors confirmed that AGN 204396 did not behave as a prostanoid FP receptor antagonist. AGN 204396 exhibited no antagonism at DP and EP1-4, but was a highly effective TP receptor antagonist. Contrary to expectation, the FP receptor antagonist AL-8810 efficaciously contracted the cat iris. AGN 204396 did not affect AL-8810 induced contractions, demonstrating that AL-8810 and AGN 204396 are pharmacologically distinct. Unlike AL-8810, the ethylamide derivate of AL-8810 was not an agonist. Al-8810 did not block prostamide F2alpha activity. Finally, AGN 204396 did not block PGE2-glyceryl ester activity. CONCLUSIONS AND IMPLICATIONS: The ability of AGN 204396 to selectively block prostamide responses suggests the existence of prostamide sensitive receptors as entities distinct from receptors recognizing PGF2alpha and PGE2-glyceryl ester.