The impact of relaxation of methadone take-home protocols on treatment outcomes in the COVID-19 era.

BACKGROUND: Background: In response to the COVID-19 pandemic, the US Substance Abuse and Mental Health Services Administration (SAMHSA) allowed for an increase in methadone take-home doses for the treatment of Opioid Use Disorder (OUD) in March 2020. OBJECTIVE: To evaluate the effects of the SAMSHA exemption on methadone adherence and OUD-related outcomes. METHODS: A convenience sample of 183 clients (58% female) were recruited from a methadone clinic in the fall of 2019 for a cross-sectional survey. Survey data was linked to clinical records, including urine drug testing (UDT) results for methadone and emergency department (ED) visits at the local hospital. Participants were on stable methadone dosing for 9 months prior to and following March 2020. Methadone adherence was assessed by UDTs; OUD-related outcomes were assessed by overdose events and ED visits. Logistic regression was used to assess the association between change in take-home methadone doses and outcomes. RESULTS: Mean take-home doses increased nearly 200% (11.4 doses/30 days pre-COVID-19 vs. 22.3 post-SAMHSA exemption). ED visits dropped from 74 (40.4%) pre-COVID-19 to 56 (30.6%) post-SAMHSA exemption (p = <0.001). No significant changes were observed in either the number of clients experiencing overdose or those who experienced one or more methadone negative UDTs in the post-SAMHSA exemption period. Adjusted models did not show a significant association between changes in take-home doses and associated outcomes. CONCLUSIONS: Despite a near-doubling of take-home methadone doses during the COVID-19 exemption period, the increase in take-home doses was not associated with negative treatment outcomes in methadone-adherent clients.

Spatial access to opioid treatment program and alcohol and cannabis outlets: analysis of missed doses of methadone during the first, second, and third 90 days of treatment.

Background: The burden of access to opioid treatment programs (OTPs) may change as clients become eligible for take-home privileges. Our previous study showed clients who lived more than 10-miles away from an OTP were more likely to miss methadone doses during the first 30 days of treatment. Proximity to alcohol and cannabis outlets may also negatively influence treatment adherence.Objective: To examine the association between access to this OTP, alcohol and cannabis outlets, and the number of missed methadone doses during the first, second, and third 90 days of treatment.Methods: The number of missed methadone doses was calculated for 752, 689, and 584 clients who remained in treatment, respectively, for at least 3, 6, and 9 months (50% female). Distance between client's home and the OTP, alcohol, and cannabis outlets was measured. Generalized linear models were employed.Results: Shorter distance from a client's residence to the OTP was associated with a decreased number of missed methadone doses during the first 90 days of treatment. Shorter distance to the closest cannabis retail outlet was associated with an increased number of missed methadone doses during the first and second 90 days of treatment. Shorter distance to the closest off-premise alcohol outlet was associated with an increased number of missed methadone doses during the third 90 days of treatment.Conclusions: Improving spatial accessibility of OTPs are essential to ensure treatment opportunities are available for individuals so affected. Exploring to what extent residing in areas that facilitate alcohol and cannabis availability can influence treatment adherence is warranted.

Three-year retention in methadone opioid agonist treatment: A survival analysis of clients by dose, area deprivation, and availability of alcohol and cannabis outlets.

OBJECTIVE: To determine the effect of clinical, socio-demographic, and contextual characteristics on treatment retention in an opioid treatment program (OTP). METHODS: A retrospective longitudinal review of 851 clients who received methadone at the only state-funded OTP in Spokane County, Washington between 2015 and 2017. A time variable (the number of days in treatment) and a status indicator (to distinguish between clients who dropped out or censored) worked together to define retention in treatment. Our hypothesized covariates included: area deprivation, distance to the OTP, availability of cannabis retail outlets, availability of on-premise and off-premise alcohol outlets, methadone dosage, age, gender, race, and years on treatment. Cox regression within the family of survival analysis was used to model time-to-event data in the presence of censored cases. RESULTS: The median duration of retention was 394 (95%CI = 324-464) days. In the multivariable Cox regression, factors predicting treatment retention were area deprivation (HR = 1.79, 95%CI = 1.02-3.15, p = 0.04), age (HR=0.99, 95%CI=0.98-.99, p = 0.008), dosage of methadone (HR=0.98, 95%CI=0.98-0.98, p < 0.001), and the number of years on treatment (HR=1.12, 95%CI=1.06-1.18, p < 0.001). CONCLUSIONS: The findings of this study showed age and methadone dosage were protective factors and area deprivation and years on treatment were risk factors for treatment retention. After dichotomizing methadone dosage, a unique finding of this study was that higher dosage of methadone did not lead to increasingly smaller HRs for dropping out of treatment. Considering that opioid use disorder is a chronic condition, efforts need to be made to target factors associated with retention.

Antibody-maytansinoid conjugates for the treatment of myeloma.

Despite recent advances in the treatment of multiple myeloma, new agents are still needed to improve the outcome for patients. The established success of monoclonal antibodies in the treatment of some cancers has promoted interest in developing antibody-based therapies for multiple myeloma. Efforts have included the development of antibodies conjugated to potent cytotoxic moieties that combine the specificity of anti-myeloma-targeting antibodies with highly active anti-tumor compounds. Two such immunoconjugates currently in clinical development are composed of antibodies that target cell surface proteins found on multiple myeloma cells, and are coupled to cytotoxic maytansinoids. IMGN901 targets the neural cell adhesion molecule, CD56, which is expressed on the majority of myeloma cells, as well as on other cancers, while BT062 targets CD138, a primary diagnostic marker for multiple myeloma. In this review, we discuss the preclinical and early clinical data for these two promising new antibody-based anti-myeloma agents.

Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease.

PURPOSE: To develop a local drug delivery system that provides therapeutic cyclosporine levels to treat lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. METHODS: Episcleral cyclosporine implants were manufactured with a silicone-based matrix design, and in vitro release rates were determined. Preclinical evaluation included toxicology (clinical examination, serial electroretinography, and histopathology) in normal rabbits and dogs, pharmacokinetics in normal rabbits, and pharmacodynamics in a canine model of aqueous tear deficiency and keratoconjunctivitis sicca. RESULTS: The cyclosporine implants showed sustained release of drug over time with in vitro assays. Histopathology showed normal ocular tissues in both dogs and rabbits 6 months after implantation. The cyclosporine implant produced lacrimal gland drug levels 1 to 2 log units higher than those reported with a variety of topical cyclosporine formulations and oral administration. The cyclosporine implant was effective in a canine model of keratoconjunctivitis sicca, with all animals able to discontinue topical cyclosporine and maintain normal Schirmer scores over a 6-month follow-up. CONCLUSIONS: This preclinical evaluation showed that the episcleral cyclosporine implant was safe, delivered potentially therapeutic cyclosporine levels to the lacrimal gland, and showed efficacy in a clinically relevant model of keratoconjunctivitis sicca. The episcleral cyclosporine implant shows promise in reducing the morbidity associated with lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. In addition, continuous release of cyclosporine in the subconjunctival space with the episcleral implant was an effective means of delivering drug to the ocular surface and may have potential in treating other ocular inflammatory diseases.

Erythrocyte survival is promoted by plasma and suppressed by a Bak-derived BH3 peptide that interacts with membrane-associated Bcl-X(L).

Erythrocytes have a defined lifespan in vivo, and the signals that maintain their survival in circulation or trigger their death are unknown. Here, we investigated the control of erythrocyte survival and death in an in vitro culture system where erythrocytes survived for 10 days in serum-free medium in the presence or absence of bovine serum. Death of the cells in culture was correlated with increased exposure of phosphatidylserine and increased levels of intracellular calcium. Cell death could be suppressed by supplementing the medium with human plasma or serum, resulting in a doubling of the lifespan to 20 days. Freshly isolated erythrocytes and cultured erythrocytes were both found to express Bcl-X(L) and, to a lesser extent, Bak in membrane protein extracts. Treatment of the cells with a Bak-derived BH3 peptide fused to the internalization sequence of the antennapedia protein, which has previously been shown to enter cells by diffusion and antagonize Bcl-X(L), resulted in substantial cell death in erythrocyte cultures. BH3-induced death was accompanied by an immediate increase in accumulation of intracellular calcium and could be suppressed by plasma, but not by the caspase inhibitor zVAD. A BH3 peptide mutated at amino acid 78 of full-length Bak required for heterodimerization with Bcl-X(L) had no effect on cell viability or calcium levels. We conclude that the BH3 peptide accelerates erythrocyte death through antagonization of Bcl-X(L). The data suggest that erythrocyte survival is promoted by survival factors in plasma and by membrane-associated Bcl-X(L.)