Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine.

3,4-Methylenedioxymethamphetamine (MDMA) has shown efficacy as a medication adjunct for treating post-traumatic stress disorder (PTSD). However, MDMA is also used in non-medical contexts that pose risk for cardiovascular and neurological complications. It is well established that MDMA exerts its effects by stimulating transporter-mediated release of the monoamines, 5­hydroxytryptamine (5-HT), norepinephrine, and dopamine. Current research efforts are aimed at developing MDMA-like monoamine releasers with better efficacy and safety profiles. To this end, we investigated neurochemical and behavioral effects of novel analogs of the designer drug, 5-(2-methylaminopropyl)benzofuran (5-MAPB). We used in vitro transporter assays in rat brain synaptosomes to examine transmitter uptake inhibition and releasing properties for enantiomers of 5-(2-methylaminobutyl)benzofuran (5-MABB) and 6-(2-methylaminobutyl)benzofuran (6-MABB) as compared to MDMA. We then tested these same compounds in male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg) from saline. In vitro results revealed that S isomers of 5- and 6-MABB are efficacious releasing agents at transporters for 5-HT (SERT), norepinephrine (NET), and dopamine (DAT). By contrast, R isomers are efficacious releasers at SERT, partial releasers at NET, but lack releasing activity at DAT. In vivo results showed that all compounds produce dose-dependent increases in MDMA-lever responding and full substitution at the highest dose tested. The diminished NET and DAT releasing activities for R isomers of 5- and 6-MABB are associated with reduced potency for inducing behavioral effects. Collectively, these findings indicate that the aminoalkyl benzofuran scaffold may be a viable template for developing compounds with MDMA-like properties. Significance Statement Despite the clinical utility of MDMA, the drug is associated with certain cardiovascular risks and metabolic side effects. Developing a therapeutic alternative with MDMA-like monoamine releasing activity is of interest. Our in vitro and in vivo findings indicate that the aminoalkyl benzofuran scaffold may be useful for developing compounds with MDMA-like properties.

Characterization of 3,4-methylenedioxypyrovalerone discrimination in female Sprague-Dawley rats.

3,4-Methylenedioxypyrovalerone (MDPV), one of several synthetic cathinones, is a popular constituent of illicit 'bath salts'. In preclinical studies utilizing drug discrimination methods with male rodents, MDPV has been characterized as similar to both cocaine and 3,4-methylenedioxymethamphetamine-hydrochloride (MDMA). Whereas few drug discrimination studies have utilized female rats, the current study evaluated the discriminative stimulus effects of MDPV in 12 adult female Sprague-Dawley rats trained to discriminate 0.5 mg/kg MDPV from saline under a fixed ratio 20 schedule of food reinforcement. Stimulus substitution was assessed with MDPV and its enantiomers, other synthetic cathinones [alpha pyrrolidinopentiophenone-hydrochloride(α-PVP), 4-methylmethcathinone (4-MMC)], other dopamine agonists (cocaine, [+)-methamphetamine] and serotonin agonists [MDMA, lysergic acid diethylamide (LSD)] Stimulus antagonism was assessed with the dopamine D1 receptor antagonist, Sch 23390 and the D2 receptor antagonist, haloperidol. Cocaine and (+)-methamphetamine engendered full stimulus generalization to MDPV with minimal effects on response rate. LSD produced partial substitution, whereas MDMA and 4-MMC produced complete substitution, and all these serotonergic compounds produced dose-dependent response suppression. (S)-MDPV and α-PVP engendered full substitution with similar potency to the racemate, while (R)-MDPV failed to substitute up to 5 mg/kg. Both Sch 23390 and haloperidol attenuated the discrimination of low MDPV doses and essentially shifted the dose-response curve to the right but failed to block discrimination of the training dose. These findings are generally consistent with previous reports based exclusively on male rodents. Moreover, they confirm the contribution of dopaminergic mechanisms but do not rule out the possible contribution of other neurotransmitter actions to the interoceptive stimulus effects of MDPV.

Re-evaluation of the discriminative stimulus effects of lysergic acid diethylamide with male and female Sprague-Dawley rats.

Recent discoveries from clinical trials with psychedelic-assisted therapy have led to a resurgence of interest in the psychopharmacology of lysergic acid diethylamide (LSD). Preclinical drug discrimination is an invaluable tool to investigate the neurochemical mechanisms underlying subjective drug effects. The current study extends previous drug discrimination research by including both sexes. Adult female (n = 8) and male (n = 8) Sprague-Dawley rats were trained to discriminate 0.08 mg/kg LSD from saline under a fixed ratio 20 schedule of food reinforcement. Substitution tests were conducted with several substances, including other serotonergic hallucinogens, psychostimulants, mixed psychedelic-stimulants and synthetic cathinones. Stimulus antagonist tests were conducted with selected serotonin and dopamine antagonists. LSD-substitution with serotonergic hallucinogens was comparable between sexes. Modest but intriguing differences were observed between male and female rats in the extent of partial substitution by 3,4-methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine enantiomers and the synthetic cathinones, 3,4-methylenedioxypyrovalerone and 4-methylmethcathinone. Dopamine antagonists failed to block the LSD cue in both sexes and exerted stronger rate suppressant effects in male rats. The 5-hydroxytryptamine antagonist, (R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol (MDL 100 907) blocked LSD discrimination in both sexes, although complete blockade was evident at lower doses in male rats. These results support previous findings regarding the prominent role of serotonergic activities underlying LSDs discriminative stimulus effects in male rats and generalize these findings to female rats. In consideration of the rising popularity in psychedelic-assisted psychotherapy, further research may be warranted to evaluate possible sex differences in the behavioral and subjective effects of LSD.

Combined effects of mephedrone and cocaine on locomotor activity and conditioned place preference in male Sprague-Dawley rats.

Mephedrone (MEPH) is one of several synthetic cathinone derivatives and a common constituent of illicit 'bath salts'. Concomitant use of MEPH with other psychostimulants is common among recreational users, but their combined effects have not been evaluated rigorously. In experiment 1, 56 male Sprague-Dawley rats were administered saline, MEPH (1 or 5 mg/kg), COC (5 mg/kg), or a mixture of MEPH (1 or 5 mg/kg) + COC (5 mg/kg) for seven consecutive days. Following a 10-day drug washout, rats were given a challenge injection of COC (5 mg/kg). Locomotor activity was recorded for 60 minutes immediately before and for 60 minutes immediately after injections on days 1, 7, and 17. In experiment 2, an unbiased conditioned place preference procedure was implemented over a 10-day period with a separate group of 66 male Sprague-Dawley rats randomly assigned to similar drug treatments used in experiment. Results of experiment 1 indicated significant increases in horizontal activity after repeated treatment with MEPH+COC mixtures, but not with either drug alone. Additionally, rats pretreated with MEPH + COC mixtures exhibited an augmented response to cocaine following drug abstinence. Evidence for CPP was established in rats treated with 5 mg/kg MEPH, 5 mg/kg COC and the 5 mg/kg MEPH + 5 mg/kg COC mixture. In conclusion, cocaine and mephedrone may have additive locomotor stimulant effects, although further assessment with a wider range of dose combinations must be evaluated. As a precautionary note, concurrent use of these substances may pose an enhanced risk for abuse.

Locomotor sensitization in male Sprague-Dawley rats following repeated concurrent treatment with 4-methylmethcathinone and 3,4-methylenedioxymethamphetamine.

Recreational abuse of illicit synthetic cathinones is an ongoing public health concern. Recent studies indicate that the methcathinone derivative 4-methylmethcathinone (4-MMC) produces behavioral and neurochemical effects similar to the entactogen 3,4-methylenedioxymethamphetamine (MDMA). Whereas polysubstance abuse is common, most preclinical studies of drug abuse liability only evaluate the effects of single drugs. Utilizing the locomotor sensitization paradigm, the present study assessed the combined locomotor stimulant effects of 4-MMC and MDMA for induction of sensitization following repeated administration and for expression of sensitization to a challenge dose of either substance alone after a 10-day period of drug abstinence. Male Sprague-Dawley rats received once daily intraperitoneal injections of saline, 4-MMC (1.0 mg/kg or 5.0 mg/kg), MDMA (3.0 mg/kg), or a mixture containing 4-MMC (1.0 mg/kg or 5.0 mg/kg) + MDMA (3.0 mg/kg) for 7 consecutive days. Following a 10-day drug-free period, rats were given a single intraperitoneal injection of either saline, 4-MMC (1.0 or 5.0 mg/kg), or 3.0 mg/kg MDMA. Activity was recorded for 1 h immediately before and 1 h immediately after injections on days 1, 7, and 17. 4-MMC treatment failed to induce locomotor sensitization, but, when combined with MDMA, sensitization was induced to a greater extent than with MDMA alone. Furthermore, the expression of sensitization to a subsequent challenge dose of MDMA was observed only in animals previously exposed to MDMA or a 5.0 mg/kg 4-MMC + MDMA mixture. In consideration of these findings along with the fact that 4-MMC has similar neurochemical actions to MDMA, further research may be warranted to determine the abuse liability of drug mixtures including 4-MMC and MDMA.

Characterization of the discriminative stimulus effects of 3,4-methylenedioxypyrovalerone in male Sprague-Dawley rats.

Recreational use of 3,4-methylenedioxypyrovalerone (MDPV) in the early 2000s prompted numerous scientific investigations of its behavioral and neurochemical effects. The purpose of this study was to further characterize the interoceptive stimulus effects of MDPV using a validated in-vivo drug-detection assay. Male Sprague-Dawley rats were trained to discriminate 0.3 mg/kg MDPV from saline under a fixed ratio 20 (FR 20) schedule of food reinforcement. After stimulus control was established with MDPV (∼35 training sessions), substitution tests were commenced with drugs from several chemical classes, including drugs with predominantly dopaminergic actions [MDPV, D-amphetamine, (+)-methamphetamine, (-)-cocaine], drugs with predominantly serotonergic actions [(+)-lysergic acid diethylamide, (+)-fenfluramine], and drugs with both serotonergic and dopaminergic actions (3,4-methylenedioxymethamphetamine, 4-methylmethcathinone). Full substitution for the 0.3 mg/kg MDPV cue was observed with D-amphetamine, (+)-methamphetamine, and (-)-cocaine. Surprisingly, the 5-HT releaser (+)-fenfluramine fully substituted in half the subjects, but completely suppressed responding in the remaining subjects. 3,4-Methylenedioxymethamphetamine, 4-methylmethcathinone, and (+)-lysergic acid diethylamide failed to fully substitute for MDPV. These results indicate that the MDPV cue is similar to cues produced by drugs with predominantly dopamine-increasing effects and perhaps serotonin-releasing effects among individual subjects. Given these findings, further research is warranted to directly assess the contributions of dopamine and serotonin receptor isoforms to the discriminative stimulus functions of MDPV.

Effects of D1 and D2 receptor antagonists on the discriminative stimulus effects of methylendioxypyrovalerone and mephedrone in male Sprague-Dawley rats trained to discriminate D-amphetamine.

Psychopharmacology research has amassed substantial evidence for similarities between synthetic cathinones and other commonly abused psychostimulants. Few studies have utilized drug discrimination methods to investigate synthetic cathinones, and the precise neurochemical substrates underlying their interoceptive effects have not been examined. The present study assessed the involvement of D1 and D2 dopaminergic receptors in the stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and mephedrone (MEPH) in rats trained to discriminate D-amphetamine. Eight male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg D-amphetamine (AMPH) from saline. Dose-response curves were then generated with AMPH (0.0-1.0 mg/kg), MDPV (0.0-1.0 mg/kg), and MEPH (0.0-2.0 mg/kg). Subsequently, Sch 39166 (0.3 mg/kg) and haloperidol (0.5 mg/kg) were administered in combination with select doses of MDPV and MEPH. Both MDPV and MEPH produced full substitution for AMPH. Sch 39166 produced a downward shift in the MDPV and MEPH dose-response curves and haloperidol produced similar results with MDPV. These preliminary findings indicate that MDPV and MEPH produce interoceptive stimuli that are similar to those produced by AMPH and that D1 and D2 dopamine receptors contribute to these effects. Additional studies are warranted to investigate the contribution of other receptor mechanisms involved in the interoceptive stimuli produced by synthetic cathinones.

'I don't think I'd be frightened if the statins went': a phenomenological qualitative study exploring medicines use in palliative care patients, carers and healthcare professionals.

BACKGROUND: There is a growing body of evidence suggesting patients with life-limiting illness use medicines inappropriately and unnecessarily. In this context, the perspective of patients, their carers and the healthcare professionals responsible for prescribing and monitoring their medication is important for developing deprescribing strategies. The aim of this study was to explore the lived experience of patients, carers and healthcare professionals in the context of medication use in life-limiting illness. METHODS: In-depth interviews, using a phenomenological approach: methods of transcendental phenomenology were used for the patient and carer interviews, while hermeneutic phenomenology was used for the healthcare professional interviews. RESULTS: The study highlighted that medication formed a significant part of a patient's day-to-day routine; this was also apparent for their carers who took on an active role-as a gatekeeper of care-in managing medication. Patients described the experience of a point in which, in their disease journey, they placed less importance on taking certain medications; healthcare professionals also recognize this and refer it as a 'transition'. This point appeared to occur when the patient became accepting of their illness and associated life expectancy. There was also willingness by patients, carers and healthcare professionals to review and alter the medication used by patients in the context of life-limiting illness. CONCLUSIONS: There is a need to develop deprescribing strategies for patients with life-limiting illness. Such strategies should seek to establish patient expectations, consider the timing of the discussion about ceasing treatment and encourage the involvement of other stakeholders in the decision-making progress.

The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats.

This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 µg/kg atrazine, 10mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning.

Behavioral sensitization following concurrent exposure to mephedrone and D-amphetamine in female mice.

Recreational use of illicit methcathinone derivatives is a public health concern in the USA and Europe. Recent reports indicate that mephedrone (MEPH) produces neurochemical and behavioral effects comparable with amphetamines. The present study investigated the effects of a mixture of MEPH and D-amphetamine (AMPH) on the induction and expression of behavioral sensitization. Thirty female CD-1 mice received seven subcutaneous injections of saline, AMPH (1.0 mg/kg), MEPH (3.0 mg/kg), or AMPH (1.0 mg/kg)+MEPH (3.0 mg/kg) over an 8-day period with 48 h between the first and second injection and 24 h between subsequent injections. Activity was assessed immediately following the first and seventh dose. After a 10-day washout, 1.0 mg/kg AMPH was administered to all animals and activity was assessed in a similar manner. Compared with mice treated with AMPH or MEPH, those treated with AMPH+MEPH displayed stronger indices of behavioral sensitization after the seventh dose and in response to AMPH after the washout period. These results suggest that MEPH may enhance sensitivity to the behavioral effects of AMPH. Considered in light of findings that MEPH has comparable neurochemical actions to the amphetamines and is commonly used with other stimulants, further research on the abuse liability of drug mixtures with methcathinones and other psychostimulants is warranted.

Disaster preparedness and families of children with special needs: a geographic comparison.

Over eleven million children in the United States have special health care needs. These unique needs can burden community and emergency responders after a disaster, complicating rescue and recovery efforts and generating reunification needs. Family disaster preparedness can help to moderate the extent that community resources are utilized by preparing families to be self-sustaining after a disaster and streamline access to medical care when needed. This study explored differences in two populations of families of children with special health care needs to determine if geographic differences exist in preparedness levels and whether a brief education intervention would prove successful in increasing baseline preparedness levels across both populations. A brief education intervention was delivered by trained community health educators to 210 families of children with special health care needs. A quasiexperimental pre-posttest design was used to compare baseline preparedness levels and 1 month follow-up levels. Although there was no difference in preparedness levels based on geographic location, both populations demonstrated a statistically significant increase in preparedness levels post-intervention. This study provides additional evidence that a brief education intervention helps to increase preparedness levels among families of children with special health care needs.

A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.

Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the Km for ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 µM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.

Preparing families of children with special health care needs for disasters: an education intervention.

Children with special health care needs pose a special challenge in post-disaster response. Current research suggests that the general population is not adequately prepared for a major disaster event, with members of vulnerable populations even less prepared. The purpose of this study was to determine the short-term effectiveness of a brief patient education intervention aimed at increasing levels of disaster preparedness among families of special health care needs children. One hundred twenty-one families were randomly assigned to either intervention or intervention plus incentive group. Families were surveyed prior to the intervention using a previously published instrument on family preparedness, and at 30-45 days post-intervention. A Preparedness Score was assigned to each family based on the number of items completed on the preparedness instrument. Significant differences were found between pre- and posttest scores for families that received the intervention, regardless of whether or not an incentive item was provided. Posttest scores were significantly higher than pretest scores, suggesting that the intervention was successful in increasing short-term overall levels of family preparedness in this population.

Norepinephrine pressor infusion withdrawal in a National Health Service hospice.

Norepinephrine (NE) is a peripheral vasoconstrictor used as an emergency measure to restore blood pressure secondary to acute hypotension. NE must be administered centrally as a continuous infusion and requires intensive monitoring. Consequently, its use is restricted to critical care environments. We discuss the withdrawal of NE in a hospice for a patient with advanced malignancy and profound hypotension from sepsis. The patient was admitted to intensive care but chose to stop active treatment and insisted on being discharged. Due to concerns about withdrawing NE in the community, he was transferred to a local hospice. We describe various challenges, including the administration and monitoring of NE outside of intensive care, the withdrawal process and concerns that profound hypotension might compromise subcutaneous medications absorption.

Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.

Objectives: Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab. Methods: Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed. Results: Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9. Conclusion: Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.

PAC-FragmentDEL - photoactivated covalent capture of DNA-encoded fragments for hit discovery.

We describe a novel approach for screening fragments against a protein that combines the sensitivity of DNA-encoded library technology with the ability of fragments to explore what will bind. Each of the members of the library consists of a fragment which is linked to a photoactivatable diazirine moiety. Split and pool synthesis combines each fragment with a set of linkers with the version of the library reported here containing some 70k different compounds, each with an individual DNA code. Incubation of the library with a protein sample is followed by photoactivation, washing and subsequent PCR and sequencing which allows the individual fragment hits to be identified. We illustrate how the approach allows successful hit fragment identification using only microgram quantities of material for two targets. PAK4 is a kinase for which conventional fragment screening has generated many advance leads. The as yet undrugged target, 2-epimerase, presents a more challenging active site for identification of hit compounds. In both cases, PAC-FragmentDEL identified fragments validated as hits by ligand-observed NMR measurements and crystal structure determination of off-DNA sample binding to the proteins.

Salvinorin B derivatives, EOM-Sal B and MOM-Sal B, produce stimulus generalization in male Sprague-Dawley rats trained to discriminate salvinorin A.

Salvinorin A, the main active component of Salvia divinorum, is a potent and selective κ opioid receptor agonist. Synthetic derivatives of this substance may be useful in the development of medicinal treatments for pain, mood disorders, and drug dependence. Such developments require extensive preclinical screening of these compounds. The drug discrimination assay is a valuable method for exploring potential similarities between novel compounds and known drugs of abuse with respect to their interoceptive stimulus properties, and can be used to investigate the potency of salvinorin A and its derivatives in vivo. This study used drug discrimination methods to compare two synthetic derivatives of salvinorin B, the ethoxymethyl ether (EOM-Sal B) and methoxymethyl ether (MOM-Sal B) with salvinorin A. Male Sprague-Dawley rats were trained to discriminate 2.0 mg/kg of salvinorin A from its vehicle (75% dimethylsulfoxide/25% water) in a fixed ratio 20 food-reinforced drug discrimination procedure, and were tested for stimulus generalization with EOM-Sal B and MOM-Sal B. For comparison, substitution tests were also conducted with a µ agonist, morphine, a dissociative hallucinogen, ketamine, and two serotonergic hallucinogens, D-lysergic diethylamide (LSD) and 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane. Time-course tests were also conducted with salvinorin A and EOM-Sal B. Both EOM-Sal B and MOM-Sal B substituted fully for salvinorin A and displayed greater potency than salvinorin A. EOM-Sal B was discriminated at longer postinjection intervals than salvinorin A. Morphine and 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane failed to substitute for salvinorin A, although ketamine and LSD produced significant drug-appropriate responding. The current findings are consistent with previous reports that salvinorin A produces detectable stimulus effects that are distinct from those of other drug classes and, for the first time, establish that synthetic derivatives of this substance produce similar discriminative stimulus effects. The unexpected partial substitution with LSD and ketamine indicate that further preclinical studies of these novel κ opioid receptor agonists may be warranted.

Phase II evaluation of phenoxodiol in combination with cisplatin or paclitaxel in women with platinum/taxane-refractory/resistant epithelial ovarian, fallopian tube, or primary peritoneal cancers.

INTRODUCTION: Chemoresistance is a major limitation in the treatment of ovarian cancer. Phenoxodiol is a novel biomodulator capable of reversing chemoresistance in vitro and in vivo. In this study, we determined the safety and efficacy of intravenous phenoxodiol in combination with cisplatin or paclitaxel in women with platinum/taxane-refractory/resistant ovarian cancers. METHODS: Thirty-two patients were randomized to 1 of 2 treatment arms according to their previous responses: (1) platinum refractory/resistant, cisplatin (40 mg/m intravenous) weekly on day 2 + phenoxodiol (3 mg/kg) weekly on days 1 and 2 and (2) taxane refractory/resistant, paclitaxel (80 mg/m IV) weekly on day 2 and phenoxodiol (3 mg/kg) weekly on days 1 and 2. Patients continued on treatment until complete response, disease progression, unacceptable toxicity, or voluntary withdrawal. RESULTS: There were no treatment-related deaths. There was only one treatment-related hospitalization and 2 grade 4 toxicities. In the cisplatin arm, there were 3 partial responses, 9 patients (56%) achieved stable disease, 4 (25%) progressed, and the overall best response rate was 19%. In the paclitaxel arm, there was one complete response and 2 partial responses, 8 patients (53%) achieved stable disease, 4 patients (27%) progressed, and the overall best response rate was 20%. DISCUSSION: The combination of IV phenoxodiol with cisplatin or paclitaxel was well tolerated in this study. Cisplatin-phenoxodiol was particularly active and warrants further study in patients with platinum-resistant ovarian cancer.

Establishing Clinical Swallowing Assessment Services via Telepractice: A Multisite Implementation Evaluation.

Purpose While research has confirmed the feasibility and validity of delivering clinical swallowing evaluations (CSEs) via telepractice, challenges exist for clinical implementation. Using an implementation framework, strategies that supported implementation of CSE services via telepractice within 18 regional/rural sites across five health services were examined. Method A coordinated implementation strategy involving remote training and support was provided to 18 sites across five health services (five hub and spoke services) that had identified a need to implement CSEs via telepractice. Experiences of all 10 speech-language pathologists involved at the hub sites were examined via interviews 1 year post implementation. Interview content was coded using the Consolidated Framework for Implementation Research (CFIR) and constructs were rated for strength and direction of influence, using published CFIR coding conventions. Results Services were established and are ongoing at all sites. Although there were site-specific differences, 10 CFIR constructs were positive influencing factors at all five sites. The telepractice model was perceived to provide clear advantages for the service, and clinicians were motivated by positive patient response. Strategies used to support implementation, including having a well-organized implementation resource and an external facilitator who worked closely with the local champions, were highly valued. Two CFIR constructs, Structural Characteristics and Available Resources, were challenges for all sites. Conclusions A complex interplay of factors influenced service implementation at each site. A strong local commitment to improving patient care, and the assistance of targeted strategies to support local implementation were viewed as central to enabling implementation.

Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration.

The microtubule (MT) cytoskeleton plays a critical role in axon growth and guidance. Here, we identify the MT-severing enzyme fidgetin-like 2 (FL2) as a negative regulator of axon regeneration and a therapeutic target for promoting nerve regeneration after injury. Genetic knockout of FL2 in cultured adult dorsal root ganglion neurons resulted in longer axons and attenuated growth cone retraction in response to inhibitory molecules. Given the axonal growth-promoting effects of FL2 depletion in vitro, we tested whether FL2 could be targeted to promote regeneration in a rodent model of cavernous nerve (CN) injury. The CNs are parasympathetic nerves that regulate blood flow to the penis, which are commonly damaged during radical prostatectomy (RP), resulting in erectile dysfunction (ED). Application of FL2-siRNA after CN injury significantly enhanced functional nerve recovery. Remarkably, following bilateral nerve transection, visible and functional nerve regeneration was observed in 7 out of 8 animals treated with FL2-siRNA, while no control-treated animals exhibited regeneration. These studies identify FL2 as a promising therapeutic target for enhancing regeneration after peripheral nerve injury and for mitigating neurogenic ED after RP - a condition for which, at present, only poor treatment options exist.