An anchor-tether 'hindered' HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model.

BACKGROUND: Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood-brain barrier. METHODS: In silico molecular dynamics simulation, in vitro electrophysiology, and in vivo rat spared nerve injury methods were used to test whether 'hindered' variants of 26DTB-P (wherein a hydrophilic 'anchor' is attached in the para-position of 26DTB-P via an acyl chain 'tether') had the desired properties. RESULTS: Molecular dynamics simulation showed that membrane penetration of hindered 26DTB-Ps is controlled by a tethered diol anchor without elimination of head group rotational freedom. In vitro and in vivo analysis showed that BP4L-18:1:1, a variant wherein a diol anchor is attached to 26DTB-P via an 18-carbon tether, is an HCN1 inverse agonist and an orally available antihyperalgesic. With a CNS multiparameter optimisation score of 2.25, a >100-fold lower drug load in the brain vs blood, and an absence of adverse cardiovascular or CNS effects, BP4L-18:1:1 was shown to be poorly CNS penetrant and cardiac sparing. CONCLUSIONS: These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.

If we build it, will they come? Perspectives on pharmacy-based naloxone among family and friends of people who use opioids: a mixed methods study.

BACKGROUND: Expanding access to the opioid antagonist naloxone to reduce overdose mortality is a public health priority in the United States. Naloxone standing orders (NSOs) have been established in many states to increase naloxone dispensing at pharmacies, but increased pharmacy access does not ensure optimal uptake among those likely to witness an overdose. In a prior statewide purchase trial, we documented high levels of naloxone access at Massachusetts pharmacies under a statewide NSO. In this study, we characterize barriers to pharmacy-based naloxone uptake among potential opioid overdose "bystanders" (friends or family of people who use opioids) that may be amenable to intervention. METHODS: Eligible bystanders were Massachusetts residents ≥ 18 years of age, did not use illicit opioids in the past 30 days, and knew someone who currently uses illicit opioids. We used a sequential mixed methods approach, in which a series of semi-structured qualitative interviews (N = 22) were conducted April-July 2018, to inform the development of a subsequent quantitative survey (N = 260), conducted February-July 2020. RESULTS: Most survey participants (77%) reported ever obtaining naloxone but few (21%) attempted to purchase it at a pharmacy. Qualitative participants revealed that barriers to utilizing the NSO included low perceived risk of overdose, which was rooted in misconceptions regarding the risks of prescription opioid misuse, denial about their loved one's drug use, and drug use stereotypes; inaccurate beliefs about the impact of naloxone on riskier opioid use; and concerns regarding anticipated stigma and confidentiality. Many participants had engaged in mutual support groups, which served as a source of free naloxone for half (50%) of those who had ever obtained naloxone. CONCLUSIONS: Despite high levels of pharmacy naloxone access in Massachusetts, few bystanders in our study had attempted to obtain naloxone under the NSO. Low perceived risk of overdose, misinformation, stigma, and confidentiality were important barriers to pharmacy naloxone uptake, all of which are amenable to intervention. Support groups provided a setting for addressing stigma and misinformation and provided a discreet and comfortable setting for naloxone access. Where these groups do not exist and for bystanders who do not participate in such groups, pharmacies are well-positioned to fill gaps in naloxone availability.

Pharmacists' experiences with a statewide naloxone standing order program in Massachusetts: a mixed methods study.

OBJECTIVES: In a prior statewide naloxone purchase trial conducted in Massachusetts, we documented a high rate of naloxone dispensing under the state's standing order program. The purpose of this study was to understand the factors that facilitate naloxone access under the Massachusetts naloxone standing order (NSO) program and identify any remaining barriers amenable to intervention. DESIGN: Mixed methods design involving a pharmacist survey and 3 pharmacist focus groups. SETTING AND PARTICIPANTS: Focus groups were conducted at 3 separate professional conferences for pharmacists (n = 27). The survey was conducted among Massachusetts pharmacists (n = 339) working at a stratified random sample chain and independent retail pharmacies across Massachusetts. All data were collected between September 2018 and November 2019. OUTCOME MEASURES: Facilitators and barriers to NSO implementation and naloxone dispensing and pharmacists' attitudes and beliefs regarding naloxone and opioid use. RESULTS: Most pharmacists described NSO implementation as being straightforward, although differences were reported by pharmacy type in both the survey and focus groups. Facilitators included centralized implementation at chain pharmacies, access to Web-based resources, regularly stocking naloxone, and use of naloxone-specific intake forms. Barriers included patient confidentiality concerns and payment/cost issues. Only 31% of surveyed pharmacists reported always providing naloxone counseling; the most commonly cited barriers were perceived patient discomfort (21%) and time limitations (14%). Confidential space was also more of a concern for independent (vs. chain) pharmacists (18% vs. 6%, P = 0.008). A majority of pharmacists held supportive attitudes toward naloxone, although some reported having moral/ethical concerns about naloxone provision. CONCLUSION: We documented several facilitators to NSO implementation and naloxone dispensing. Areas for improvement include addressing stigma and misconceptions around opioids and naloxone use. These remain important targets for improving pharmacy-based naloxone dispensing, although our overall positive results suggest Massachusetts' experience with NSO implementation can inform other states' efforts to expand pharmacy-based naloxone access.

Pharmacy naloxone codispensing: A mixed methods study of practices and perspectives under a statewide standing order program.

BACKGROUND: In a previous statewide naloxone purchase trial conducted in Massachusetts, we documented high levels of naloxone accessibility, upon patient request, under the state's naloxone standing order (NSO) program. Equally important for reducing overdose mortality rates is expanding naloxone access via codispensing alongside opioid prescription and syringe purchases at pharmacies. OBJECTIVE: To understand naloxone codispensing from the perspective of pharmacists under the Massachusetts NSO program. METHODS: The study used a mixed methods design involving 3 focus groups and a quantitative survey. Participants in both the focus groups (N = 27) and survey (N = 339) were licensed Massachusetts pharmacists. Focus groups were conducted at 3 separate professional conferences for pharmacists. The survey was conducted using a stratified random sample of 400 chain and independent retail pharmacies across Massachusetts. All data were collected between September 2018 and November 2019. Quantitative and qualitative analyses examined current policies, practices, and attitudes regarding naloxone codispensing for patients at risk of opioid overdose. RESULTS: Most pharmacists (69%) reported that they, their pharmacy, or both promoted codispensing alongside opioid prescriptions. A majority promoting naloxone codispensing did so for patients prescribed high opioid dosages (80%); fewer promoted codispensing for patients also prescribed benzodiazepines (20%). Facilitators to codispensing were pre-existing relationships between pharmacists and prescribers, mandatory pharmacist consultation, and universal naloxone promotion to all patients meeting certain criteria. Barriers to codispensing were pharmacists' concerns about offending patients by initiating a conversation about naloxone, insufficient technician training, workflow and resource constraints, and misconceptions surrounding naloxone. We found no substantive differences in outcomes between chain and independent pharmacies. CONCLUSION: We documented several facilitators and barriers to naloxone codispensing in Massachusetts pharmacies. Areas amenable to intervention include increased training for front-line pharmacy technicians, mandatory pharmacist consultation for opioid-prescribed patients, workflow reorganization, and addressing stigma concerns on the pharmacist end.

Assessing pharmacy-based naloxone access using an innovative purchase trial methodology.

OBJECTIVES: Massachusetts was among the first states to allow standing orders to facilitate pharmacy-based naloxone purchases and reduce opioid overdose deaths. We conducted a unique purchase trial to establish a valid measure of standing order naloxone in Massachusetts, using purchasers from 2 high priority populations to determine whether naloxone is less accessible to those who use illicit opioids than other potential purchasers. DESIGN: Purchase trial. SETTING AND PARTICIPANTS: The study used a stratified random sample of 200 chain and independent retail pharmacies across Massachusetts. Each pharmacy underwent 2 purchase attempts-1 by a person who used illicit opioids (PWUIO) and 1 by a potential bystander who did not use illicit opioids but had a relationship with someone at risk of opioid overdose. OUTCOME MEASURE: Successful or unsuccessful naloxone purchase attempt. RESULTS: Overall, 322 of 397 purchase attempts (81%) were successful, with no statistically significant difference between PWUIO and bystanders (P = 0.221). Most purchases (93%) resulted in the acquisition of single-step nasal naloxone (Narcan; median cost $133.38). Forty percent of the purchases included state-mandated verbal counseling, and PWUIO were significantly less likely to receive counseling than bystanders (30% vs. 51%, P < 0.001). Common reasons for failed purchase were not stocking naloxone (47%), price > $150 (25%), and requiring a prescription (15%). Chain pharmacies were significantly more likely to sell naloxone than independent pharmacies (86% vs. 53%, P < 0.001). CONCLUSION: We documented high levels of naloxone access for both PWUIO and bystanders, suggesting Massachusetts could serve as a model for states seeking to improve pharmacy-based naloxone access. Additional implementation efforts should focus on expanding availability at independent pharmacies and supporting pharmacies in proactively offering naloxone to PWUIO and other high-risk individuals.

Size-exclusion chromatographic NMR of polymer mixtures.

The use of chromatographic stationary phases or solvent modifiers to modulate diffusion properties in NMR experiments is now well established. Their use can be to improve resolution in the diffusion domain or to provide an insight into analyte-modifier interactions and, hence, the chromatography process. Here, we extend previous work using size-exclusion chromatographic stationary phases to the investigation of polymer mixtures. We demonstrate that similar diffusion modulation behaviour is observed with a size-exclusion chromatographic stationary phase that can be understood in terms of size-exclusion behaviour.

Probucol is anti-hyperalgesic in a mouse peripheral nerve injury model of neuropathic pain.

2,6-di-tert-butylphenol (2,6-DTBP) ameliorates mechanical allodynia and thermal hyperalgesia produced by partial sciatic nerve ligation in mice, and selectively inhibits HCN1 channel gating. We hypothesized that the clinically utilized non-anesthetic dimerized congener of 2,6-DTBP, probucol (2,6-di-tert-butyl-4-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)sulfanylpropan-2-ylsulfanyl]phenol), would relieve the neuropathic phenotype that results from peripheral nerve damage, and that the anti-hyperalgesic efficacy in vivo would correlate with HCN1 channel inhibition in vitro. A single oral dose of probucol (800 mg/kg) relieved mechanical allodynia and thermal hyperalgesia in a mouse spared-nerve injury neuropathic pain model. While the low aqueous solubility of probucol precluded assessment of its possible interaction with HCN1 channels, our results, in conjunction with recent data demonstrating that probucol reduces lipopolysaccharide-induced mechanical allodynia and thermal hyperalgesia, support the testing/development of probucol as a non-opioid, oral antihyperalgesic albeit one of unknown mechanistic action.

Limited access to pharmacy-based naloxone in West Virginia: Results from a statewide purchase trial.

BACKGROUND: West Virginia (WV) has the highest overdose mortality rate in the United States and expanding naloxone access is crucial for reducing opioid overdose deaths. We conducted a purchase trial to establish an objective measure of naloxone access under WV's naloxone standing order (NSO) program. METHODS: A stratified random sample of 200 chain and independent retail pharmacies across WV were included. Each pharmacy underwent two purchase attempts-one by a person who used illicit opioids (PWUIO) and one by a potential bystander who did not use illicit opioids but had a relationship with a PWUIO. We used matched-pairs analysis to identify differences in outcomes by purchaser type (PWUIO vs bystander). Chi-square and independent-samples t-tests were used to compare outcomes by pharmacy type (chain vs independent). RESULTS: Overall, 29% of purchase attempts were successful, with no significant difference between PWUIO and bystanders (p = 0.798). Fewer than half (44%) of successful purchases included verbal counseling, and bystanders were more likely to receive counseling than PWUIO (33% vs 4%, p = 0.018). Common reasons for failed purchases were naloxone not being in stock (41%), requiring a naloxone prescription (35%), and/or requiring formal identification (23%). Chain pharmacies were more likely to sell naloxone than independents (35% vs 19%, p = 0.001). CONCLUSIONS: We documented limited naloxone access under the WV NSO. These findings indicate that simply establishing an NSO program is insufficient to expand access. Implementation efforts should ensure adequate naloxone stocks, pro-active delivery of NSO-related information and pharmacist training, and avoidance of recordkeeping requirements that may impede access.

Reported care quality in federal Ryan White HIV/AIDS Program supported networks of HIV/AIDS care.

Since 1991, the US Government has funded medical and support services for people living with HIV and AIDS (PLWHA) through the Ryan White HIV/AIDS Program. The Ryan White Program supports networks of care which include medical care providers and support services for PLWHA in 51 Eligible Metropolitan Areas (EMAs). In the 2000 reauthorization of the Ryan White Program, quality management programs were required for all sites receiving funding. To facilitate quality management and improvement activities in EMAs, we developed a set of surveys to measure characteristics of care networks and the quality, accessibility, and coordination of services from the perspective of case management and medical providers, administrators and consumers. The surveys measured quality management and support activities of the entire network, as well as reported quality of services at individual care sites. They were administered in 42 EMAs from a total of 43 who had not participated in earlier pilot testing and were located in the continental US. The care networks were rated highly on access, quality, and coordination between case management and primary care providers. However, there were frequently differences in ratings of quality and barriers by type of respondent (consumer representatives, Grantees, and providers). There were also substantial variations across EMAs in network characteristics, perceived effectiveness, performance measurement, and quality improvement activities. The results indicate that the Ryan White Program has been successful in some areas of developing networks of care, but additional support is needed to strengthen the comprehensiveness and coordination of care. Additional work also is needed to better define and measure the essential characteristics of coordinated and integrated networks of care and assess whether those characteristics are related to access and quality of care and services.

Alkylphenol inverse agonists of HCN1 gating: H-bond propensity, ring saturation and adduct geometry differentially determine efficacy and potency.

BACKGROUND AND PURPOSE: In models of neuropathic pain, inhibition of HCN1 is anti-hyperalgesic. 2,6-di-iso-propyl phenol (propofol) and its non-anesthetic congener, 2,6-di-tert-butyl phenol, inhibit HCN1 channels by stabilizing closed state(s). EXPERIMENTAL APPROACH: Using in vitro electrophysiology and kinetic modeling, we systematically explore the contribution of ligand architecture to alkylphenol-channel coupling. KEY RESULTS: When corrected for changes in hydrophobicity (and propensity for intra-membrane partitioning), the decrease in potency upon 1-position substitution (NCO∼OH >> SH >>> F) mirrors the ligands' H-bond acceptor (NCO > OH > SH >>> F) but not donor profile (OH > SH >>> NCO∼F). H-bond elimination (OH to F) corresponds to a ΔΔG of ∼4.5 kCal mol-1 loss of potency with little or no disruption of efficacy. Substitution of compact alkyl groups (iso-propyl, tert-butyl) with shorter (ethyl, methyl) or more extended (sec-butyl) adducts disrupts both potency and efficacy. Ring saturation (with the obligate loss of both planarity and π electrons) primarily disrupts efficacy. CONCLUSIONS AND IMPLICATIONS: A hydrophobicity-independent decrement in potency at higher volumes suggests the alkylbenzene site has a volume of ≥800 Å3. Within this, a relatively static (with respect to ligand) H-bond donor contributes to initial binding with little involvement in generation of coupling energy. The influence of π electrons/ring planarity and alkyl adducts on efficacy reveals these aspects of the ligand present towards a face of the channel that undergoes structural changes during opening. The site's characteristics suggest it is "druggable"; introduction of other adducts on the ring may generate higher potency inverse agonists.

Disentangling neighborhood contextual associations with child body mass index, diet, and physical activity: the role of built, socioeconomic, and social environments.

Obesity prevalence among US children and adolescents has tripled in the past three decades. Consequently, dramatic increases in chronic disease incidence are expected, particularly among populations already experiencing health disparities. Recent evidence identifies characteristics of "obesogenic" neighborhood environments that affect weight and weight-related behaviors. This study aimed to examine associations between built, socioeconomic, and social characteristics of a child's residential environment on body mass index (BMI), diet, and physical activity. We focused on pre-adolescent children living in New Haven, Connecticut to better understand neighborhood environments' contribution to persistent health disparities. Participants were 1048 fifth and sixth grade students who completed school-based health surveys and physical measures in fall 2009. Student data were linked to US Census, parks, retailer, and crime data. Analyses were conducted using multilevel modeling. Property crimes and living further from a grocery store were associated with higher BMI. Students living within a 5-min walk of a fast food outlet had higher BMI, and those living in a tract with higher density of fast food outlets reported less frequent healthy eating and more frequent unhealthy eating. Students' reported perceptions of access to parks, playgrounds, and gyms were associated with more frequent healthy eating and exercise. Students living in more affluent neighborhoods reported more frequent healthy eating, less unhealthy eating, and less screen time. Neighborhood social ties were positively associated with frequency of exercise. In conclusion, distinct domains of neighborhood environment characteristics were independently related to children's BMI and health behaviors. Findings link healthy behaviors with built, social, and socioeconomic environment assets (access to parks, social ties, affluence), and unhealthy behaviors with built environment inhibitors (access to fast food outlets), suggesting neighborhood environments are an important level at which to intervene to prevent childhood obesity and its adverse consequences.

Chromatographic NMR with size exclusion chromatography stationary phases.

Chromatographic NMR describes the use of stationary phases or solvent additives, such as polymers, to modify the diffusion properties of analyte molecules and thereby improve the observed resolution in the diffusion domain. This paper demonstrates similar ideas using size exclusion chromatographic media and characterises the changes in the observed diffusion coefficient using a series of polymer molecular weight reference standards of known polydispersity. The results are interpreted in terms of a simple description of the size exclusion phenomena.