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Purpose: The surgical navigation system that provides guidance throughout the surgery can facilitate safer and more radical liver resections, but such a system should also be able to handle organ motion. This work investigates the accuracy of intraoperative surgical guidance during open liver resection, with a semi-rigid organ approximation and electromagnetic tracking of the target area., Methods: The suggested navigation technique incorporates a preoperative 3D liver model based on diagnostic 4D MRI scan, intraoperative contrast-enhanced CBCT imaging and electromagnetic (EM) tracking of the liver surface, as well as surgical instruments, by means of six degrees-of-freedom micro-EM sensors., Results: The system was evaluated during surgeries with 35 patients and resulted in an accurate and intuitive real-time visualization of liver anatomy and tumor's location, confirmed by intraoperative checks on visible anatomical landmarks. Based on accuracy measurements verified by intraoperative CBCT, the system's average accuracy was 4.0 ± 3.0 mm, while the total surgical delay due to navigation stayed below 20 min., Conclusions: The electromagnetic navigation system for open liver surgery developed in this work allows for accurate localization of liver lesions and critical anatomical structures surrounding the resection area, even when the liver was manipulated. However, further clinically integrating the method requires shortening the guidance-related surgical delay, which can be achieved by shifting to faster intraoperative imaging like ultrasound. Our approach is adaptable to navigation on other mobile and deformable organs, and therefore may benefit various clinical applications., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Accurate assessment of 3D models of patient-specific anatomy of the liver, including underlying hepatic and biliary tree, is critical for preparation and safe execution of complex liver resections, especially due to high variability of biliary and hepatic artery anatomies. Dynamic MRI with hepatospecific contrast agents is currently the only type of diagnostic imaging that provides all anatomical information required for generation of such a model, yet there is no information in the literature on how the complete 3D model can be generated automatically. In this work, a new automated segmentation workflow for extraction of patient-specific 3D model of the liver, hepatovascular and biliary anatomy from a single multiphase MRI acquisition is developed and quantitatively evaluated. The workflow incorporates course 4D k-means clustering estimation and geodesic active contour refinement of the liver boundary, based on organ's characteristic uptake of gadolinium contrast agents overtime. Subsequently, hepatic vasculature and biliary ducts segmentations are performed using multiscale vesselness filters. The algorithm was evaluated using 15 test datasets of patients with liver malignancies of various histopathological types. It showed good correlation with expert manual segmentation, resulting in an average of 1.76 ± 2.44 mm Hausdorff distance for the liver boundary, and 0.58 ± 0.72 and 1.16 ± 1.98 mm between centrelines of biliary ducts and liver veins, respectively. A workflow for automatic segmentation of the liver, hepatic vasculature and biliary anatomy from a single diagnostic MRI acquisition was developed. This enables automated extraction of 3D models of patient-specific liver anatomy, and may facilitating better perception of organ's anatomy during preparation and execution of liver surgeries. Additionally, it may help to reduce the incidence of intraoperative biliary duct damage due to an unanticipated variation in the anatomy., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives: Surgery of advanced tumors and lymph nodes in the pelvis can be challenging due to the narrow pelvic space and vital surrounding structures. This study explores the application of a novel electromagnetic navigation system to guide pelvic surgery., Methods: This was a prospective study on surgery for malignancies in the pelvis. Preoperatively obtained imaging was used to create a patient-specific three-dimensional (3D) roadmap. In the operating room, the 3D roadmap was registered to an intraoperative computed tomography scan. A tracked pointer was used during surgery for guidance. Primary endpoint was safety and feasibility, secondary endpoints were accuracy and usability., Results: Twenty-eight colorectal, four liposarcomas, and one gynecological patient were included. There were no safety issues. Navigation was feasible in 31 patients. The mean target registration errors of 4.0 and 6.3 mm were achieved for straight and French position, respectively. In seven of seven patients with a locally advanced rectal tumor and in seven of eight patients with recurrences, negative margins were achieved. Thirty-three of 36 target lymph nodes were successfully removed. Surgeons using the system indicated faster localization of the tumor and improved decisiveness., Conclusion: This novel surgical navigation system was safe and feasible during pelvic surgery and can facilitate its users., (© 2018 Wiley Periodicals, Inc.)

Purpose: Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell percentage and high-quality RNA. As a consequence, a certain amount of samples drop out. If tumor characteristics are different between samples included and excluded from GE profiling, this can lead to bias. Therefore, we assessed whether patient and tumor characteristics differ between tumors suitable or unsuitable for generating GE profiles in breast cancer., Methods: In a consecutive cohort of 738 breast cancer patients who received neoadjuvant chemotherapy at the Netherlands Cancer Institute, GE profiling was performed. We compared tumor characteristics and treatment outcome between patients included and excluded from GE profiling. Results were validated in an independent cohort of 812 patients treated with primary surgery., Results: GE analysis could be performed in 53% of the samples. Patients with tumor GE profiles more often had high-grade tumors [odds ratio 2.57 (95%CI 1.77-3.72), p < 0.001] and were more often lymph node positive [odds ratio 1.50 (95%CI 1.03-2.19), p = 0.035] compared to the group for which GE profiling was not possible. In the validation cohort, tumors suitable for gene expression analysis were more often high grade., Conclusions: In our gene expression studies, tumors suitable for GE profiling had more often an unfavorable prognostic profile. Due to selection of samples with a high tumor percentage, we automatically select for tumors with specific features, i.e., tumors with a higher grade and lymph node involvement. It is important to be aware of this phenomenon when performing gene expression analysis in a research or clinical context.

The use of nutritional supplements is highly prevalent among athletes. In this cross-sectional study, we assessed the prevalence of nutritional supplement use by a large group of Dutch competitive athletes in relation to dietary counseling. A total of 778 athletes (407 males and 371 females) completed a web-based questionnaire about the use of nutritional supplements. Log-binomial regression models were applied to estimate crude and adjusted prevalence ratios (PR) for the use of individual nutritional supplements in athletes receiving dietary counseling as compared with athletes not receiving dietary counseling. Of the athletes, 97.2% had used nutritional supplements at some time during their sports career, whereas 84.7% indicated having used supplements during the last 4 weeks. The top ranked supplements used over the last 4 weeks from dietary supplements, sport nutrition products and ergogenic supplements were multivitamin and mineral preparations (42.9%), isotonic sports drinks (44.1%) and caffeine (13.0%). After adjustment for elite status, age, and weekly exercise duration, dietary counseling was associated with a higher prevalence of the use of vitamin D, recovery drinks, energy bars, isotonic drinks with protein, dextrose, beta-alanine, and sodium bicarbonate. In contrast, dietary counseling was inversely associated with the use of combivitamins, calcium, vitamin E, vitamin B2, retinol, energy drinks and BCAA and other amino acids. In conclusion, almost all athletes had used nutritional supplements at some time during their athletic career. Receiving dietary counseling seemed to result in better-informed choices with respect to the use of nutritional supplements related to performance, recovery, and health.

Background: Mammographic screening has led to the identification of more women with nonpalpable breast cancer, many of them to be treated with breast-preserving surgery. To accomplish radical tumor excision, adequate localization techniques such as radioactive seed localization (RSL) are required. For RSL, a radioactive I-seed is implanted central in the tumor to enable intraoperative localization using a γ-probe. In case of extensive tumor or multifocal carcinoma, multiple I-seeds can be used to delineate the involved area. Preoperative imaging is performed different from surgical positioning; therefore, exact I-seed depth remains unknown during surgery., Patients and Methods: Twenty patients (mean age, 56.8 years) with 25 implanted I-seeds scheduled for RSL were included. Sixteen patients had 1 I-seed implanted in the primary lesion, 3 patients had 2 I-seeds, and 1 patient had 3 I-seeds. Freehand SPECT localized I-seeds by measuring γ-counts from different directions, all registered by an optical tracking system. A reconstruction and visualization algorithm enabled 3-dimensional (3D) navigation toward the I-seeds., Results: Freehand SPECT visualized all I-seeds in primary tumors and provided preincision depth information. The deviation, mean (SD), between the freehand SPECT depth and the surgical depth estimation was 1.9 (2.1) mm (range, 0-7 mm). Three-dimensional freehand SPECT was especially useful identifying multiple implanted I-seeds because the conventional γ-probe has more difficulty discriminating I-seeds transcutaneous., Conclusions: Freehand SPECT with 3D navigation is a valuable tool in RSL for both single and multiple implanted I-seeds in breast-preserving cancer surgery. Freehand SPECT provides continuous updating 3D imaging with information about depth and location of the I-seeds contributing to adequate excision of nonpalpable breast cancer.

Background and Purpose: Criteria for ultrasound-guided fine-needle aspiration cytology (USgFNAC) for the detection of occult lymph node metastasis in patients with clinically negative head and neck cancer are based on the morphology of cervical lymph nodes. To improve the selection of lymph nodes for USgFNAC, we examined the feasibility of fused freehand single-photon emission tomography ultrasound-guided fine-needle cytology (freehand SPECT-USgFNAC) of sentinel nodes in patients with early stage oral and head and neck skin cancer., Materials and Methods: Six patients with early-stage head and neck cancer (4 oral and 2 head and neck skin cancers) and a clinically negative neck who were scheduled for transoral or local excision and a sentinel node procedure underwent USgFNAC and freehand SPECT-USgFNAC preoperatively., Results: All freehand SPECT sonographic examinations were technically successful in terms of identifying sentinel nodes. All aspirates of sentinel nodes obtained by freehand SPECT-USgFNAC contained substantial radioactivity, confirming puncture of the sentinel nodes. USgFNAC evaluated 13 lymph nodes; freehand SPECT-USgFNAC, 19 nodes; and sentinel node biopsy, 13 nodes. Three sentinel nodes were histopathologically positive and were selected for aspiration cytology by freehand SPECT-USgFNAC, but not by conventional ultrasound. The cytologic examination findings of the aspirations were negative or inconclusive., Conclusions: Freehand SPECT ultrasound can identify sentinel nodes and could potentially improve USgFNAC in patients with head and neck cancer by better selection of lymph nodes at highest risk of having metastases (sentinel nodes), but its sensitivity is limited by sampling error and insufficient aspirated material for cytology., (© 2015 by American Journal of Neuroradiology.)

Purpose: Freehand single-photon emission computed tomography (SPECT) (fh-SPECT) for optical tracked 3-dimensional radioactivity mapping raises popularity for sentinel node biopsy and other radio-guided procedures. However, the device seems to be complex, requiring both training and a standardized scan protocol. Therefore, the aim of this study was to compare handling reproducibility between novice and expert users; subsequently, using additional scans, we evaluated a standardized scan protocol to be tested in novice users after receiving training., Materials and Methods: Three groups (untrained novices, experts, and trained novices), each one composed of 5 fh-SPECT users, were given the same short introduction and the assignment to perform 3 fh-SPECT scans with the same time per scan. For the scans, a reproducible phantom with an iodine-125 point source was used. Furthermore, we performed probe-trajectory evaluation including pattern, speed, and length of scans based on recorded videos and digital target tracking., Results: The training period encompasses 30 minutes per novice user. The mean error in 3 directions based on 45 measurements was 7.4 mm for untrained novices and 3.2 mm for expert users. The trained novice group had a mean error of 2.9 mm (a significant 61% reduction), comparable to the expert group. The reproducibility values, expressed in SD, were 4.1 mm for the untrained novice group, 1.3 mm for the expert group, and 1.1 mm for the trained novices (73% improvement). The standardized scan protocol was demonstrated by means of trajectory evaluation, a scan path better systematized., Conclusion: Scanning with fh-SPECT for radio-guided surgery requires a specific training period to increase handling and reproducibility of 3-dimensional imaging, and to enhance its accuracy in the operating room.

Wire-guided localization is the most commonly used technique for intraoperative localization of non-palpable breast cancer. Radioactive seed localization (RSL) is becoming more popular and seems to be a reliable alternative for intraoperative lesion localization. The purpose of the present meta-analysis was to evaluate the use of RSL. Primary study outcomes were irradicality and re-excision rates. In total 3168 patients were included. The clinical adaptation shows growing confidence in RSL and further growth is expected., (© 2014 Wiley Periodicals, Inc.)

Purpose: Radioactive seed localization (RSL) uses an iodine-125 ((125)I) seed as a marker for tumour location. The (125)I seed is implanted into the tumour and enables intraoperative localization with a conventional gamma probe. However, specimen margins in relation to the (125)I seed are estimated on the basis of gamma-probe readings only. A novel device, freehand SPECT, is capable of measuring the distance from the resection plane to the (125)I seed. The aim of this feasibility study was to establish the accuracy of this device in predicting resection margins in ex-vivo tumour specimens excised with RSL guidance., Patients and Methods: In this feasibility study 10 patients with nonpalpable breast cancer scheduled for wide local excision with RSL were included. After surgery, the specimens containing the breast tumour and the (125)I seed were scanned using freehand SPECT. Measurements from five directions were taken and compared with distances measured by means of an ex-vivo computed tomographic (CT) scan and related to the pathology report., Results: The difference between freehand SPECT and CT measurements was 2.9±2.7 mm (mean±SD). One patient had a positive margin based on freehand SPECT. This specimen contained a focal irradical resection ventral of the tumour based on the pathology report. The smallest distance to the (125)I seed was 4 mm for the freehand SPECT and 5 mm for the CT scan., Conclusion: Accurate ex-vivo measurements of the tumour resection margins using (125)I seeds and freehand SPECT are feasible in patients undergoing breast-conserving surgery. Incorporation of the freehand-SPECT device in RSL protocols may enable a real-time estimation of resection margins, which may be useful for surgeons to adjust resection planes.

Background: This study was designed to explore the feasibility of replacing the conventional peri-/intratumoural ultrasound (US)-guided technetium-99m albumin nanocolloid ((99m)Tc-nanocolloid) administration by an injection of the same tracer guided by a freehand single-photon emission computed tomography (SPECT) device in patients with non-palpable breast cancer with an iodine-125 ((125)I) seed as tumour marker, who are scheduled for a sentinel lymph node biopsy (SLNB). This approach aimed to decrease the workload of the radiology department, avoiding a second US-guided procedure., Methods: In ten patients, the implanted (125)I seed was primarily localised using freehand SPECT and subsequently verified by conventional US in order to inject the (99m)Tc-nanocolloid. The following 34 patients were injected using only freehand SPECT localisation. In these patients, additional SPECT/CT was acquired to measure the distance between the (99m)Tc-nanocolloid injection depot and the (125)I seed. In retrospect, a group of 21 patients with US-guided (99m)Tc-nanocolloid administrations was included as a control group., Results: The depth difference measured by US and freehand SPECT in ten patients was 1.6 ± 1.6 mm. In the following 36 (125)I seeds (34 patients), the average difference between the (125)I seed and the centre of the (99m)Tc-nanocolloid injection depot was 10.9 ± 6.8 mm. In the retrospective study, the average distance between the (125)I seed and the centre of the (99m)Tc-nanocolloid injection depot as measured in SPECT/CT was 9.7 ± 6.5 mm and was not significantly different compared to the freehand SPECT-guided group (two-sample Student's t test, p = 0.52)., Conclusion: We conclude that using freehand SPECT for (99m)Tc-nanocolloid administration in patients with non-palpable breast cancer with previously implanted (125)I seed is feasible. This technique may improve daily clinical logistics, reducing the workload of the radiology department.

Selective σ2 ligands continue to be an active target for medications to attenuate the effects of psychostimulants. In the course of our studies to determine the optimal substituents in the σ2-selective phenyl piperazines analogues with reduced activity at other neurotransmitter systems, we discovered that 1-(3-chlorophenyl)-4-phenethylpiperazine actually had preferentially increased affinity for dopamine transporters (DAT), yielding a highly selective DAT ligand., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The phenylethylene diamines are a class of sigma receptor ligands with excellent selectivity over other biological systems and with anti-cocaine actions that involve antagonism of sigma1 receptors. In order to increase the potency of the aromatic methoxyl substituted analogues, trifluoromethoxyl groups were introduced to prevent metabolic demethylation. The para-substituted trifluoromethoxyl substituted analogues were shown to have increased sigma receptor affinity and represent the most potent anti-cocaine phenylethylene diamines yet described.

Earlier studies have demonstrated that antagonism of sigma1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of sigma2 receptors is unclear because experimental tools to selectively target this subtype are unavailable. To begin addressing this need, we characterized UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) and (+/-)-SM 21 (3alpha-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies. Receptor binding studies confirmed that UMB24 and (+/-)-SM 21 display preferential affinity for sigma2 over sigma1 receptors. In behavioral studies, pretreatment of Swiss Webster mice with UMB24 or (+/-)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity, but not lethality. When administered alone, (+/-)-SM 21 produced no significant effects compared to control injections of saline, but UMB24 had locomotor depressant actions. Together, the data suggest that sigma2 receptor antagonists have the potential to attenuate some of the behavioral effects of cocaine, and further development of more selective, high affinity ligands are warranted.

Methamphetamine interacts with sigma (sigma) receptors, suggesting that the drug produces some of its physiological and behavioral effects through these sites. Therefore, in the present report, receptor binding and pharmacological studies were performed to characterize the interaction between methamphetamine and sigma receptors. Of the two major sigma receptor subtypes, sigma1 and sigma2, competition binding studies showed that methamphetamine has a 22-fold preferential affinity for the sigma1 subtype. Saturation binding studies using the sigma1 selective radioligand [3H]+-pentazocine showed that in the presence of methamphetamine, there was a significant change in Kd, but not Bmax, suggesting competitive interactions. In behavioral studies, pretreatment of Swiss Webster mice with the sigma1 receptor antagonists, BD1063 or BD1047, significantly attenuated the locomotor stimulatory effects of methamphetamine. Mice that were administered an antisense oligodeoxynucleotide to down-regulate brain sigma1 receptors also exhibited a reduced locomotor stimulatory response to methamphetamine, as compared to control mice receiving mismatch oligonucleotides. Together, the data suggest that sigma1 receptors are involved in the acute actions of methamphetamine and that antagonism of this subtype is sufficient to prevent the locomotor stimulatory effects of methamphetamine.

Previous studies have shown that BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and related analogs attenuate the toxicity and stimulant effects of cocaine through antagonism of sigma receptors. In the present study, six analogs of BD1008 (UMB 98-103) were synthesized and evaluated in receptor binding and behavioral studies. Competition binding studies confirmed that all six compounds have high affinity for sigma1 receptors, moderate affinity for sigma2 receptors, and low to negligible affinity for monoamine transporters, opioid, N-methyl-D-aspartate, dopamine, and 5-HT receptors. In behavioral pharmacological studies, pretreatment of mice with UMB 100, UMB 101, or UMB 103 significantly attenuated cocaine-induced convulsions and lethality. Together with earlier studies, the data suggest that analogs of BD1008 are promising medication development leads for reducing the toxicity of cocaine.

Earlier studies show that antagonism of sigma receptors using high to moderate affinity compounds or antisense oligodeoxynucleotides targeting the sigma(1) subtype significantly attenuates the behavioral effects of cocaine in mice. In this study, the novel sigma receptor ligand YZ-069 [N-phenylpropyl-N'-(3,4-dichlorophenethyl)piperazine] and four analogs (representing nitrophenyl and methoxyphenyl derivatives) were evaluated in receptor binding and behavioral studies to further delineate structural features that convey favorable anticocaine actions. In receptor binding studies, all of the compounds had low nanomolar affinities for sigma(1) and sigma(2) receptors but only micromolar affinities for monoamine transporters. Consistent with the favorable affinities of the compounds for sigma receptors, they also significantly attenuated cocaine-induced convulsions in mice. The compounds with the 3,4-dichlorophenyl and methoxyphenyl substitutions provided better protection against cocaine-induced convulsions than the nitrophenyl derivative. This is consistent with the reduced lipophilicity of the nitro substitution, which would reduce its ability to cross the blood-brain barrier. The position of the substituent on the phenyl ring had no significant effect on binding affinity or behavioral protective actions. Together with earlier studies, the data suggest that favorable features of sigma receptor ligands with anticocaine actions include high affinity for brain sigma receptors, antagonistic actions at the receptor, and lipophilicity to facilitate crossing the blood-brain barrier.

Pharmacological and molecular biological tools were used to validate the involvement of sigma receptors in the actions of cocaine. Radioligand binding studies demonstrated significant levels of sigma receptors in the brain and heart, where cocaine interacts preferentially with the sigma(1) subtype. In behavioral pharmacological studies using mice, nine novel sigma receptor antagonists significantly attenuated cocaine-induced convulsions, while structural analogs with weak interactions with sigma receptors were ineffective. In contrast to the protection provided by the antagonists, a classical sigma receptor agonist exacerbated the convulsive effects of cocaine. The antagonists also attenuated cocaine-induced lethality, with the best compound protecting against death even when administered as a post-treatment. At doses where the antagonists had no effect on baseline locomotor activity, they significantly attenuated the locomotor stimulatory effects of cocaine, suggesting their ability to block the psychomotor as well as the toxic effects of cocaine. To further validate that the anti-cocaine effects were achieved by interfering with cocaine's access to sigma receptors, antisense oligodeoxynucleotides against sigma(1) receptors were shown to attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the studies support the involvement of sigma receptors, particularly the sigma(1) subtype, in the behavioral effects of cocaine.

Cocaine's ability to interact with sigma receptors suggests that these proteins mediate some of its behavioral effects. Therefore, three novel sigma receptor ligands with antagonist activity were evaluated in Swiss Webster mice: BD1018 (3S-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane), BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), and LR132 (1R,2S-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamine). Competition binding assays demonstrated that all three compounds have high affinities for sigma1 receptors. The three compounds vary in their affinities for sigma2 receptors and exhibit negligible affinities for dopamine, opioid, GABA(A) and NMDA receptors. In behavioral studies, pre-treatment of mice with BD1018, BD1063, or LR132 significantly attenuated cocaine-induced convulsions and lethality. Moreover, post-treatment with LR132 prevented cocaine-induced lethality in a significant proportion of animals. In contrast to the protection provided by the putative antagonists, the well-characterized sigma receptor agonist di-o-tolylguanidine (DTG) and the novel sigma receptor agonist BD1031 (3R-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane) each worsened the behavioral toxicity of cocaine. At doses where alone, they produced no significant effects on locomotion, BD1018, BD1063 and LR132 significantly attenuated the locomotor stimulatory effects of cocaine. To further validate the hypothesis that the anti-cocaine effects of the novel ligands involved antagonism of sigma receptors, an antisense oligodeoxynucleotide against sigma1 receptors was also shown to significantly attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the data suggests that functional antagonism of sigma receptors is capable of attenuating a number of cocaine-induced behaviors.

Cocaine binds to sigma receptors with comparable affinity to its well-established interaction with dopamine transporters. Previous studies have shown BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) to have high affinity and selectivity for sigma receptors, and to additionally attenuate the locomotor stimulatory effects of cocaine. Therefore, in the present study, three N-alkyl substituted analogs of BD1008 were characterized in receptor binding and behavioral studies: BD1060 (N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)ethylamine), BD1067 (N-[2-(3,4-dichlorophenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)ethylamine), and BD1052 (N-[2-(3,4-dichlorophenyl)ethyl]-N-allyl-2-(1-pyrrolidinyl)ethylamine). Similarly to BD1008, all three analogs exhibited high affinity and selectivity for sigma receptors. In behavioral studies, BD1008, BD1060 or BD1067 attenuated cocaine-induced convulsions and lethality in Swiss Webster mice. The protective effects appear to be mediated through sigma receptor antagonism because traditional sigma receptor antagonists with high to moderate affinity for these receptors also attenuated the behavioral toxicity of cocaine. In contrast, traditional and novel sigma receptor agonists such as di-o-tolylguanidine and BD1052 worsened the behavioral toxicity of cocaine. To further characterize the actions of the N-alkyl substituted compounds, they were microinjected into the rat red nucleus, a functional assay of sigma receptor activity, where they produced agonist vs. antagonist actions that were consistent with their effects on cocaine-induced behaviors. Together, the data demonstrate that BD1008, BD1060 or BD1067 can attenuate the behavioral toxicity of cocaine, most likely through functional antagonism of sigma receptors.

Acute dystonic reactions are motor side effects that occur soon after the initiation of neuroleptic treatment. Although earlier studies indicate that these abnormal movements can be induced in animals and humans via activation of sigma receptors, the relative contribution of the different sigma receptor subtypes is unknown. Since sigma(1) and sigma(2) receptor are differentially represented in motor regions of the brain, the affinities of 17 neuroleptics for these sigma receptor subtypes were determined using competition binding studies. The results revealed that most neuroleptics do not exhibit selectivity for either of the sigma receptor subtypes, as reflected by a significant correlation between the affinities of the neuroleptics for sigma(1) vs. sigma(2) receptors. Moreover, when the sigma binding affinities of the neuroleptics were correlated with the tendency of the drugs to produce acute dystonic reactions in humans, there was a significant correlation for both subtypes. Together with earlier studies in animals, the data suggest that neuroleptic-induced motor side effects can be mediated through both sigma(1) and sigma(2) receptors.

An efficient synthesis of isoxazole containing isosteres of epibatidine is described. The synthesis proceeded from N-tert-butoxycarbonyl (Boc)-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane (9). Compound 9 was reacted with the dilithium salt of an appropriately substituted oxime in tetrahydrofuran (THF). Cyclodehydration of the resultant beta-keto oxime and deprotection of the N-Boc group in 5 N aqueous HCl afforded the isoxazole containing isosteres of epibatidine (6-8). The binding affinities of these compounds were determined at the nicotinic acetylcholine receptor for the displacement of [3H]cystisine. The unsubstituted isoxazole containing isostere (6) showed the lower binding potency compared to the 3'-methylisoxazole isostere (7). Substitution with a phenyl group at the 3'-position of the isoxazole significantly reduced the binding potency. The in vivo toxicological studies of these analogs were also performed. The LD50 of the analogs ranged in the order: Me > H > Ph.