Intranasal Oxytocin for Stimulant Use Disorder Among Male Veterans Enrolled in an Opioid Treatment Program: A Randomized Controlled Trial

The increasing prevalence of illicit stimulant use among those in opioid treatment programs poses a significant risk to public health, stimulant users have the lowest rate of retention and poorest outcomes among those in addiction treatment, and current treatment options are limited. Oxytocin administration has shown promise in reducing addiction-related behavior and enhancing salience to social cues. We conducted a randomized, double-blind, placebo-controlled clinical trial of intranasal oxytocin administered twice daily for 6 weeks to male Veterans with stimulant use disorder who were also receiving opioid agonist therapy and counseling (n = 42). There was no significant effect of oxytocin on stimulant use, stimulant craving, or therapeutic alliance over 6 weeks. However, participants receiving oxytocin (vs. placebo) attended significantly more daily opioid agonist therapy dispensing visits. This replicated previous work suggesting that oxytocin may enhance treatment engagement among individuals with stimulant and opioid use disorders, which would address a significant barrier to effective care.

Managing Opioid Agonist Therapy in the Post-Soviet Limbo

According to Dante, “Limbo” is the first circle of Hell located at its edge. Unlike other residents of Hell, the Limbo population suffers no torment other than their lack of hope. We argue that a lack of hope in post-Soviet Ukraine is expressed by a lack of conditions for a better future since the past is overrepresented in the present. Therefore, every movement transforms under the past’s pressure, changing its course in order to reproduce and perpetuate ghosts of what is long gone. We argue that the current state of Ukraine can be framed as “post-Soviet limbo.” If the great stability of the Soviet regime was a result of overregulation and extensive control, or of “uncertainty avoidance,” then a post-Soviet limbo is a result of “managing uncertainty” simultaneously influenced by Soviet legacies and neoliberal promises of growth, calculability, and deregulation on the part of the State. “Soviet legacies” are dominant and represent a mix of formal overregulation explicitly presented through laws and policies and informality which, according to some authors, became even more widespread in the post-Soviet period than it used to be under the Soviet rule. We do not aim to consider the past legacies as being opposite to neoliberal features and futures, but negotiate the way the two are interrelated and mutually reinforced in the present to produce the post-Soviet limbo. Ukraine’s performance of Opioid Agonist Therapy (OAT) coverage is consistently estimated as insufficient and needing further improvement. However, we argue that that there are two modes of OAT implementation in Ukraine: state-funded (formal) and privately-funded (informal). The latter’s size does not fall into official estimates since the national reports on OAT performance never include the numbers of patients involved in informal treatment. We suggest, that the informal mode of OAT implementation appeared as a result of contrasting efforts towards intensive regulation and extensive growth. To understand how these two modes are produced in the context of post-Soviet narcology, how they differ and where their paths cross, we analyze two types of texts: legal and policy documents regulating substance use disorder (SUD) treatment, mainly OAT; and qualitative data, including interviews with OAT patients and field notes reflecting the environment of OAT programs. Finally, the presented article seeks to answer how the state’s contrasting efforts to manage the uncertainty of SUD treatment through OAT regulation and implementation reproduce the post-Soviet limbo and, thus, people with SUD as “patients of the state” who are frozen in a hopeless wait for changes.

Long-acting injectable buprenorphine – ‘best practice’ opioid agonist therapy for Australian prisoners

Objective To consider opioid agonist therapy in prisons. Conclusions Given the substantial risks of substance misuse by prisoners, long-acting injectable buprenorphine should be adopted as ‘best practice’ treatment in Australian prison populations.

The role of beta-agonist therapy for chronic obstructive airway disease in patients with coexistent atrial fibrillation

Background: New advances have been made in medicine, but the incidence and prevalence of chronic obstructive pulmonary disease (COPD) are evident, and it is established as the fourth cause of death in the United States representing a high cost for the healthcare system. This condition has been related to atrial fibrillation due to the changes in the lungs and vasculature. Based on this history, we seek to evaluate the outcome of AF in the patients with COPD and its relationship with medical therapy utilized to treat this pulmonary condition with the objective of establishing the relationship between the use of beta-agonist therapy for obstructive airway disease in patients with AF. Discussion: Cell receptors participate in multiple reactions and the sympathetic response is received via the alpha- and betareceptors are related to the hemodynamic of the vasculature of the lungs and cardiovascular system. The beta-blockade agents are one of the most common medication classes used for rate control in cardiac arrhythmias, but the side effect could be COPD exacerbation; on the other hand, beta-adrenergic or beta-agonist as a therapy for this pulmonary condition could increase the heart rate leading to AF decompensation. There is a clear dilemma in our patients who have airway disease and AF since the treatment for one might worsen the other. The clear benefit in morbidity and mortality of beta-blocker therapy, especially beta1- selective, outweighs the potential for any pulmonary side-effects related to ex-acerbation of COPD or airway disease. Conclusion: There is clear data showing the evidence of the potential paradoxical side-effect between COPD and AF therapies, given the exacerbation of one due to treatment of the other, benefits versus risks should be discussed and the medical decision should be made based on them. The deteriorated cardiac condition can rapidly predispose to critical complications leading to death, which is why the use of beta-blockade agents will be chosen over possible complications with pulmonary disease. In other words, the benefit should outweigh the risk based on the best outcome for the patient.

The role of beta-agonist therapy for chronic obstructive airway disease in patients with coexistent atrial fibrillation: Literature review

Background: New advances have been made in medicine, but the incidence and prevalence of Chronic Obstructive Pulmonary Disease (COPD) are evident, and it is established as the fourth cause of death in the United States representing a high cost for the healthcare system. This condition has been related to atrial fibrillation due to the changes in the lungs and vasculature. Based on this history, we seek to evaluate the outcome of AF in the patients with COPD and its relationship with medical therapy utilized to treat this pulmonary condition with the objective of establishing the relationship between the use of beta-agonist therapy for obstructive airway disease in patients with AF. Discussion: Cell receptors participate in multiple reactions and the sympathetic response is received via the alpha- and beta-receptors are related to the hemodynamic of the vasculature of the lungs and cardiovascular system. The beta-blockade agents are one of the most common medication classes used for rate control in cardiac arrhythmias, but the side effect could be COPD exacerbation; on the other hand, beta-adrenergic or beta-agonist as a therapy for this pulmonary condition could increase the heart rate leading to AF decompensation. There is a clear dilemma in our patients who have airway disease and AF since the treatment for one might worsen the other. The clear benefit in morbidity and mortality of beta-blocker therapy, especially beta1-selective, outweighs the potential for any pulmonary side-effects related to ex-acerbation of COPD or airway disease. Conclusion: There is clear data showing the evidence of the potential paradoxical side-effect between COPD and AF therapies, given the exacerbation of one due to treatment of the other, benefits versus risks should be discussed and the medical decision should be made based on them. The deteriorated cardiac condition can rapidly predispose to critical complications leading to death, which is why the use of beta-blockade agents will be chosen over possible complications with pulmonary disease. In other words, the benefit should outweigh the risk based on the best outcome for the patient. Keywords: atrial fibrillation; pulmonary disease; obstructive pulmonary disease; chronic obstructive pulmonary disease (COPD); B-Agonist; B-Block (selective; non-selective); digitalis; other antiarrhythmic.

730 Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy

BackgroundThe majority of patients with pancreatic ductal adenocarcinoma (PDAC) fail to derive any durable responses from single agent immune checkpoint blockade therapy. This refractory state originates from PDAC's unique tumor microenvironment that is densely populated by immunosuppressive myeloid cells while excluding most antitumor CD8 T cells.1 In addition, PDAC is highly hypoxic and exhibits poor vascularity, both qualities which further limit antitumor immunity.2 3 We showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) potentiates immunotherapy responses.4 Mechanistically, TH-302 decreases intratumoral hypoxia and initiates normalization of the tumor vasculature. While TH-302 facilitates a cellular remodeling process that diminishes tumor hypoxia, the nature of the vascular remodeling involved remains unknown, as do the downstream consequences for the composition of the tumor microenvironment and responsiveness to immunotherapy. We hypothesized that anti-angiogenic therapy and Evofosfamide might cooperate to normalize tumor vasculature and diminish hypoxia.MethodsTH-302 and a vascular endothelial growth factor receptor-2 (VEGFR-2) blocking antibody were used to treat several syngeneic murine models, including orthotopic pancreatic cancer and a transplantable model of prostate cancer. Immunofluorescence and flow cytometry were used to assess intratumoral hypoxia, vessel normalization, and tumor immune infiltrate.ResultsWe find that anti-VEGFR-2 (DC101) in combination with TH-302 demonstrates a cooperative benefit to combat both orthotopically implanted pancreatic cancer and transplantable prostate cancer. Combination therapy reduces intratumoral hypoxia, leads to pruning of the tumor vasculature, and increases the infiltration of endothelial cells into hypoxic regions. Across models, the combination of DC101 and TH-302 significantly enhance CD8 T cell function and limits their exhausted state. At the same time, tumor associated macrophages exhibit decreased expression of M2-like features. Similar to other anti-angiogenic therapies, combination DC101 and TH-302 leads to an increased frequency of PD-L1 expressing cells. Concurrent anti-PD-1 failed to provide any additional therapeutic benefit, which in part may be due poor CD8 T cell infiltration. Instead, we find that CD40 agonist therapy is improved when combined with TH-302 and DC101.ConclusionsTH-302 and DC101 utilize unique yet complementary mechanisms to improve the survival of mice challenged with pancreatic or prostate tumors. This combination relieves hypoxia and simultaneously reinvigorates T cell function and reduces macrophage mediated immunosuppression. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted hypoxia reduction with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC.ReferencesBear AS, Vonderheide RH, O'Hara MH. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell. 2020;38(6):788–802. doi: 10.1016/j.ccell.2020.08.004. Epub 2020 Sep 17. PMID: 32946773; PMCID: PMC7738380.Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000;48(4):919–22. doi: 10.1016/s0360-3016(00)00803-8. PMID: 11072146.Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324(5933):1457–61. doi: 10.1126/science.1171362. Epub 2009 May 21. PMID: 19460966; PMCID: PMC2998180.Jayaprakash P, Ai M, Liu A, Budhani P, Bartkowiak T, Sheng J, Ager C, Nicholas C, Jaiswal AR, Sun Y, Shah K, Balasubramanyam S, Li N, Wang G, Ning J, Zal A, Zal T, Curran MA. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest 2018;128(11):5137–5149. doi: 10.1172/JCI96268. Epub 2018 Oct 15. PMID: 30188869; PMCID: PMC6205399.

760 In vivo demethylation-mediated reversal of tumor cell-intrinsic cGAS silencing improves the efficacy of STING agonist therapy

BackgroundWhile STING-activating agents have shown limited efficacy in early phase clinical trials, multiple lines of evidence suggest the importance of the so far unappreciated tumor cell-intrinsic STING function in antitumor immune responses. Accordingly, we have shown that although there is a widespread impairment of STING signaling among human melanomas, its restoration through epigenetic reprogramming can augment antigenicity and T cell recognition of melanoma cells.1 2 In this study, we determined if rescue of tumor cell-intrinsic STING signaling using a DNA methyltransferase inhibitor can improve the therapeutic efficacy of a STING agonist in mouse models of melanoma.MethodsWe subjected three distinct murine melanoma cell lines (B16-F10, B16-ISG and Yumm1.7) to treatment with 5-aza-2'-deoxycytidine (5AZADC) and evaluated their activation of STING following stimulation with the STING agonist ADU-S100. Using a B16-F10 subcutaneous model, we assessed the effect of 5AZADC treatment on the efficacy of intratumorally administered ADU-S100 in STINGgt/gt mice. Additionally, we performed mechanistic studies using T-cell depletion experiments as well as phenotypic and gene expression profiling.ResultsWe observed reconstitution of cGAS in all three 5AZADC-pretreated cell lines as well as up to a 46-fold increase in induction of IFN-beta (p < 0.001) and a 4.5-fold increase in MHC class I surface expression (p < 0.01) compared to untreated controls following stimulation with ADU-S100. In B16-F10 tumor-bearing mice, while treatment with a combination of 5AZADC plus ADU-S100 resulted in a marked increase in Ifnb1 transcripts within tumors (p < 0.001), it significantly delayed tumor growth compared to treatment with ADU-S100 alone (p = 0.0244 on day 22). Antibody-mediated depletion studies in mice receiving the combination therapy further indicated that this antitumor activity depends on the generation of functional tumor antigen-specific CD8+ T cells (p = 0.0111 on day 22); however, tumor growth remained unaltered by the depletion of CD4+ T cells.ConclusionsWe show that reversal of methylation silencing of cGAS in murine melanoma cell lines using a clinically available DNA methylation inhibitor can improve agonist-induced STING activation and type I IFN induction, which in tumor-bearing mice is capable of inducing tumor regression through a CD8+ T cell-dependent immune response. These findings not only provide mechanistic insight into how STING signaling dysfunction in tumor cells can contribute to impaired responses to STING agonist therapy, but also suggest, depending on tumor cell-intrinsic STING signaling status, its pharmacologic restoration should be considered for improving therapeutic efficacy of STING agonists in future clinical studies.AcknowledgementsFunding: NCI P50 CA168536, Cindy and Jon Gruden Fund, Chris Sullivan Fund, V Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.ReferencesFalahat R, Perez-Villarroel P, Mailloux AW, Zhu G, Pilon-Thomas S, Barber GN, Mulé JJ. STING signaling in melanoma cells shapes antigenicity and can promote antitumor T-cell activity. Cancer Immunol Res 2019;7(11):1837–48.Falahat R, Berglund A, Putney RM, Perez-Villarroel P, Aoyama S, Pilon-Thomas S, Barber GN, Mulé JJ. Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma. PNAS 2021;118(15).