Impact of changes to the delivery of opioid agonist treatment, introduced during the COVID-19 pandemic, on treatment access and dropout in Ireland: An interrupted time series analysis.

BACKGROUND: Following the emergence of COVID-19, Ireland introduced national contingency guidelines to ensure rapid and uninterrupted access to opioid agonist treatment (OAT). This study aims to assess the impact of changes introduced to the delivery of OAT on the number of people accessing treatment and treatment dropout. METHODS: The study conducted interrupted time series analyses, with separate segmented regression models (March 2019-February 2020) vs (April 2020-March 2021), for (A) total number of people accessing OAT, (B) the number initiating treatment, and (C) the number dropping out of treatment, using data from the National OAT treatment register. The study examined immediate (change in level or intercept: ß2) and long-term impacts (change in slope; i.e., the difference between the slope before and after the intervention: ß3). We performed total and stratified analyses by gender, age group (<40/≥40 years), and OAT drug (methadone or buprenorphine). RESULTS: A total of 10,251 people accessed OAT in Ireland in March 2019 (2 % buprenorphine, n = 178), increasing to 11,441 (4 % buprenorphine, n = 471) in March 2021. The study observed an immediate (ß2 = 504.3, p < 0.001) and continued (ß3 = 31.9, p < 0.001) increase of people accessing treatment following the introduction of the OAT contingency guidelines. In contrast, observed changes in level and slope were not significant for treatment initiation or dropout. The study did find, however, a modest reduction in dropout among those receiving buprenorphine (ß3 = -0.6, p = 0.036). CONCLUSIONS: Changes introduced to the delivery of OAT, under the COVID-19 contingency guidelines, are associated with increased access to OAT in Ireland, with no evidence of increase in treatment dropout. Whether these effects will be maintained over time remains to be seen.

Consensus recommendations for opioid agonist treatment following the introduction of emergency clinical guidelines in Ireland during the COVID-19 pandemic: A national Delphi study.

BACKGROUND: Emergency contingency guidelines for opioid agonist treatment (OAT) were introduced in Ireland in March 2020, to ensure rapid and uninterrupted access to treatment while mitigating COVID-19 risk. The contingency guidelines deviated, across multiple clinical domains, from pre-pandemic clinical guidelines published in 2016. The objectives of this study are to (1) identify changes introduced to OAT clinical guidelines in Ireland during the pandemic; and (2) develop consensus on whether the new recommendations should be retained beyond the pandemic, using a national Delphi consensus methodology. METHODS: Clinical guidance recommendations ('statements') were generated by comparing the newly established contingency guidelines with the national 2016 Clinical Guidelines for OAT. Over two rounds of on-line Delphi testing, a panel of experts (people currently accessing OAT, psychiatrists, general practitioners, community pharmacists, a nurse, a psychologist and support/key workers) independently rated their agreement with each statement and provided comments. Statements with a median score of 4 or 5 and a lower quartile of ≥4 were classified as having reached consensus. RESULTS: Forty-eight panel members were recruited, with a high participation level at Round 2 (90%, n=43). Consensus was achieved for 12 of the 19 statements at Round 1. The 7 remaining statements were revised, with 2 new statements, resulting in 9 statements at Round 2. Four statements reached consensus at Round 2. The final list includes 16 clinical guidance statements; 9 relating to assessment, 3 to OAT drug choice and dosing, 1 to take-away doses, 2 to overdose prevention and 1 to the continuation of e-prescriptions. CONCLUSIONS: A wide range of stakeholders involved in the delivery and receipt of OAT agreed on 16 clinical guidance statements for inclusion in OAT clinical guidelines as we move beyond the pandemic, rather than reverting to pre-pandemic guidelines. The agreed statements relate to facilitating safe access to OAT with minimal waiting time, supporting patient-centred care to promote health and well-being, and preventing drug overdose. Notably, consensus was not achieved for OAT drug dosage and frequency of urine testing during the stabilisation and maintenance phase of care.

An audit of the cervical screening programme in the National Drug Treatment Centre (NDTC).

BACKGROUND: Women diagnosed with substance use disorders (SUDs) have higher rates of major medical conditions compared to women without SUDs. Cervical cancer is the second leading cause of cancer death in women aged 20-39 years worldwide and women with SUDs have an increased risk of cervical cancer compared to women without SUD. The National Drug Treatment Centre (NDTC) cervical screening programme, derived from the national CervicalCheck programme, offers free cervical screening to patients attending for treatment of SUDs. AIMS: This study aimed to audit adherence to the NDTC Cervical Screening guidelines before and after the implementation of an awareness-raising educational intervention. METHODS: The electronic clinical records of women aged between 25 and 60 years attending the lead consultant's (M.S.) outpatient clinic were reviewed for documentary evidence indicating that information about the cervical screening programme had been discussed. This was completed before and one month after the implementation of an awareness-raising educational intervention. RESULTS: All women (n = 46, mean age 36.3 (SD = 6.5) years) had an opioid use disorder; 85% had a benzodiazepine use disorder, and 24% had an alcohol use disorder. Of these, 80% had at least one chronic medical condition, 76% had a psychiatric disorder, and 59% were homeless. Adherence to the NDTC cervical screening guideline, as indicated by documentary evidence in clinical records, was 33% (14/43) at baseline, and rose to 88% (36/41) (p < 0.0001) one month after the intervention. CONCLUSIONS: This completed audit cycle shows that an awareness-raising educational intervention can significantly improve adherence to a cervical screening programme in women with SUDs.

ADAM-15 disintegrin-like domain structure and function.

The ADAM (a disintegrin-like and metalloproteinase) proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD) in its disintegrin-like domain. This motif is also found in most snake venom disintegrins and other disintegrin-like proteins. This unique RGD motif within ADAM-15 serves as an integrin ligand binding site, through which it plays a pivotal role in interacting with integrin receptors, a large family of heterodimeric transmembrane glycoproteins. This manuscript will present a review of the RGD-containing disintegrin-like domain structures and the structural features responsible for their activity as antagonists of integrin function in relation to the canonical RGD template.

ADAM proteins - therapeutic potential in cancer.

The A Disintegrin And Metalloprotease (ADAM) proteins belong to the metzincin-superfamily of Zn-dependent metalloproteinases that shed the extracellular domains of membrane-bound growth factors, cytokines and their receptors. The latter play a central role in cell signaling and contribute a potential target in cancer therapy. Of particular interest are the ErBB/HER family of growth factor receptors associated with elevated intrinsic tyrosine kinase activity. Overexpression of ADAMs and cell signaling components have also been implicated in the development and progression of a variety of tumor types. Emerging evidence has suggested that the ADAM proteins are involved in tumour cell proliferation, in angiogenesis as well as metastasis. Therefore, strategies targeting ADAMs may constitute an important target for the design of cancer drugs. The review will focus on current understanding of the role of ADAM in the physiological and pathological functions associated with cancer. It is the intention of the review to provide insights which may assist in the development of ADAM-based approaches for the treatment of human cancers.

The role of integrins in cancer and the development of anti-integrin therapeutic agents for cancer therapy.

Integrins have been reported to mediate cell survival, proliferation, differentiation, and migration programs. For this reason, the past few years have seen an increased interest in the implications of integrin receptors in cancer biology and tumor cell aggression. This review considers the potential role of integrins in cancer and also addresses why integrins are present attractive targets for drug design. It discusses of the several properties of the integrin-based chemotherapeutic agents currently under consideration clinically and provides an insight into cancer drug development using integrin as a target.

Integrin binding characteristics of the disintegrin-like domain of ADAM-15.

Although discovered as potent inhibitors of a (IIb) ss (3) -mediated platelet aggregation, snake venom disintegrins are now known to bind to other integrins according to different degrees of potency and specificity. More recently, homologues of the disintegrinlike loop have been found as a discrete domain in the ADAM family, yet the potency and specificity of each of these domains in terms of integrin binding is relatively unknown. In this present study, we have selected the disintegrin-like domain (dd) of ADAM-15 (designated as ddADAM-15), the only RGD containing domain in the ADAM family, for a structure/function study. Experimentally, the ddADAM-15 and a number of mutants in which the RGD-containing loop was substituted by cognate regions from ADAM-2, -12 and -19 were tested in terms of integrin-binding activity. For comparison with ADAM-15, an additional mutant (dd (den) ADAM-15) was designed based upon the RGD-containing loop of snake venom dendroaspin, a disintegrin-like integrin antagonist. The results showed that ddADAM-15 is an inhibitor of platelet aggregation, though with less potency than dd (den) ADAM-15. None of the other mutants exhibited significant inhibition of platelet aggregation. ddADAM-15 was found to have higher binding ability for a (2) ss (1) and a (9) ss (1) than the ADAM-2 derived mutant which appeared to be more selective for a (V) ss (3) and a (4) ss (1) than either ddADAM-15 or its ADAM-19 based mutant. The integrin-binding properties of ddADAM-15 were completely abolished by point mutation within the RGD motif (R (64) GD ? A (64) GD). These results suggest a more subtle contribution of this loop sequence to defining the functionality of the ADAMs compared to dendroaspin.

The effect of the single substitution of arginine within the RGD tripeptide motif of a modified neurotoxin dendroaspin on its activity of platelet aggregation and cell adhesion.

The Arg-Gly-Asp (RGD) tripeptide unit is a cell-cell and cell-extracellular matrix recognition sequence of some integrins that is found within several extracellular matrix glycoproteins and dendroaspin, a disintegrin-like venom protein isolated from the snake venom of the Dendroaspis jamsonii. In the present study, the RGD motif in dendroaspin was substituted by Lys-Gly-Asp (KGD), His-Gly-Asp (HGD), Gln-Gly-Asp (QGD) and Ala-Gly-Asp (AGD) denoted as KGD-den, HGD-den, QGD-den and AGD-den, respectively. Each of the mutants exhibited activity as inhibitor of ADP-induced platelet aggregation with IC50 values of 0.26, 2.5, 6, and 17 microM for KGD-den, HGD-den, QGD-den, and AGD-den, respectively, as compared with RGD-den (IC50 = 0.18 microM). Interestingly, HGD-den was approx. two-fold more potent and a more selective inhibitor than either the KGD-den or QGD-den counterpart at blocking A375-SM human melanoma cell adhesion to fibrinogen (beta3-mediated). KGD-den, HGD-den, and QGD-den were preferentially antagonists of A375-SM human melanoma cell adhesion to fibrinogen rather than to fibronectin (alpha5beta1-, beta3-mediated). Both HGD-den and KGD-den were equipotent as inhibitors of human erythroleukaemia (HEL) cell adhesion to fibrinogen (IC50 = 0.15 microM) and also preferential inhibitors of HEL cell adhesion to fibrinogen (beta3 and beta1-mediated) rather than to fibronectin. These findings show that the presence of the arginine within the RGD motif of dendroaspin is not obligatory and substitution of this residue can modulate inhibitory potency and integrin binding selectivity.

Specialized drug liaison midwife services for pregnant opioid dependent women in Dublin, Ireland.

The health needs of pregnant opioid dependent women are increasingly being recognized by health care professionals. These women generally receive limited antenatal care. Maternal and neonatal outcomes are also poorer compared to non-drug using women. The number of pregnant opioid dependent women accessing drug treatment services in the Irish Republic has increased. A specialist Drug Liaison Midwife service was created in March 1999 to liaise between the three Dublin Maternity hospitals and the Drug Treatment Services. This paper surveys the first year of operation of one of these posts. It documents sociodemographic background, substance use, and medical histories of these women in addition to maternal and neonatal outcomes. Higher maternal methadone dose was associated with an increased risk of neonatal withdrawals among these women. The experience of this specialist liaison service indicates that it is possible to build effective working relationships between opioid dependent pregnant women and the Obstetric and Drug services involved in their care. This has resulted in benefit to these women, their children and the Irish Health Care system.

Risk factors and coagulation parameters in relationship to phlebographic response and clinical outcome in the treatment of acute deep vein thrombosis.

Possible correlation of the effects of pharmacotherapy on the inhibition of the in-vivo generation of thrombin and on the prevention of thrombus extension in patients with deep vein thrombosis (DVT) could help to define patients at higher risk. Patients with symptomatic deep vein thrombosis confirmed by phlebography were randomised to intravenous unfractionated heparin (UFH), or a subcutaneous low-molecular-weight heparin (reviparin) twice daily for one week, or a subcutaneous reviparin once daily for four weeks. The patients were treated with oral anticoagulants for at least 3 months. Main endpoints were regression of thrombus on phlebography on Day 21 and recurrent symptomatic venous thromboembolism up to 3 months. Coagulation parameters, markers of in-vivo thrombin generation, and TFPI-release were determined at randomisation, weeks 1 and 3. Four hundred sixty six responders (reduction of at least 30 per cent in Marder score) and 419 non-responders (Marder score unchanged or changed less than +/-30%) showed no significantly different baseline characteristics. The non-responder group had a higher median Marder score at baseline and after one and three weeks of treatment, and had significantly higher fibrinogen levels, TAT complexes and F1+2 values than responders. There were no significant differences in coagulation parameters between non-responders and patients with asymptomatic + symptomatic VTE with the exception of higher TAT complexes at baseline. Significant differences in Marder score and coagulation parameters at baseline were found between responders and nonresponders. Non-responders have a higher risk tosuffer recurrent VTE and may need intensified treatment.

Pre-thrombotic state and impaired fibrinolytic potential in coronary heart disease patients with left ventricular dysfunction.

Patients with coronary heart disease (CHD) are at considerable risk for recurrent ischaemic events. A pre-thrombotic state and/or impaired fibrinolysis might play an important role in causing recurrent ischaemic events. Two hundred and fifty-seven CHD patients underwent the dobutamine stress echocardiography test (DSE) to investigate the possible presence of inducible ischaemia; 89 patients showed evidence of stunned and/or necrotic myocardium (resting wall motion abnormalities). Factor VIII activity and fibrinogen levels were significantly higher in patients with stunned/necrotic myocardium than in CHD patients with normal resting wall motions (factor VIII activity, P = 0.004; fibrinogen, P = 0.04). Of interest, after stimulating the fibrinolytic system with the DSE test, plasminogen activator inhibitor-1 activity was significantly higher in patients with necrotic/stunned myocardium than in patients with resting normal wall motion (P = 0.03), whereas tissue-type plasminogen activator activity after the DSE test was significantly lower in patients with stunned/necrotic myocardium than in patients with normal wall motion (P = 0.001). Overall, 30 CHD patients developed induced ischaemia (new wall motion abnormalities) during the DSE test. CHD patients with stunned and/or necrotic myocardium presented decreased fibrinolytic potential and the presence of a hypercoagulable state due to increased factor VIII activity, and fibrinogen levels. Therefore, these CHD patients must be considered at high risk of re-developing coronary thrombosis and might benefit from a more aggressive anticoagulant therapy.

Randomized trial of different regimens of heparins and in vivo thrombin generation in acute deep vein thrombosis.

Low-molecular-weight and unfractionated heparins are frequently used to treat venous thromboembolism, but it is not known whether they are equally effective in inhibiting in vivo generation of thrombin. In this multicenter trial, 1048 patients were randomized to intravenous unfractionated heparin (group A), twice daily low-molecular-weight heparin (reviparin) for 1 week (group B), or once daily reviparin for 4 weeks (group C). All patients received vitamin K antagonists. Blood samples withdrawn at the baseline and at weeks 1 and 3 were analyzed using markers of in vivo thrombin generation and other coagulation parameters. During the first 3 weeks symptomatic recurrent deep vein thrombosis-pulmonary embolism (DVT/PE) occurred in 17 (4.5%) of 375 patients in group A compared with 4 (1.0%) of 388 patients in group B, and 9 (2.4%) of 374 patients in group C. Forty percent of patients in group A, 53.4% in group B, and 53.5% in group C showed 30% or greater reduction in thrombus size assessed by venography. Patients in group B had significantly greater reduction in D-dimer, prothrombin fragments 1 and 2 (F1 + 2), endogenous thrombin potential (ETP), and thrombin-antithrombin (TAT) complexes compared to groups A and C. Greater release of tissue factor pathway inhibitor (TFPI) and reduction in levels of thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen were significantly more pronounced in group C patients. Reviparin administered twice daily plus vitamin K antagonist is more effective in inhibiting in vivo thrombin generation compared to intravenous unfractionated heparin plus vitamin K antagonist, and reviparin once daily produced significantly higher TFPI release and greater reduction in TAFI and fibrinogen levels.

Low molecular weight heparin (bemiparin sodium) and the coagulation profile of patients with heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with a hypercoagulable state. PATIENTS AND METHODS: A single-center, randomized, double-blind, placebo-controlled trial was performed to test the hypothesis that a prophylactic dose of low molecular weight heparin (bemiparin sodium 3500 IU/daily subcutaneously) will modify a hypercoagulable state in CHF. This study included 100 patients with CHF (New York Heart Association classification II to IV). All patients underwent 3 blood tests, at baseline (before randomization), 24 hours after randomization, and before hospital discharge or within 10 days from randomization. RESULTS: In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 24 hours, there was a significant decrease in plasma levels of D-dimer (-13.8 ng/mL; P =.01) and prothrombin fragments 1 and 2 (-0.11 nmol/L; P =.01), whereas protein C was significantly increased (+3.5%; P =.03). In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 4 to 10 days of therapy, there were significantly decreased plasma levels for factor VII:c (-3.0%; P =.01), D-dimer (-44.0 ng/mL; P =.002), and thrombin-antithrombin complex (-0.7 microg/L; P =.0001), whereas protein C was significantly increased (+16.0%; P =.03). On the other hand, in the group of patients treated with placebo after 24 hours, a significant decrease was observed of protein C (-4.0%; P =.04). After 24 hours, the changes from baseline were significantly different for some of the hemostatic factors in comparison of bemiparin sodium 3500 IU/daily and placebo (factor VII:c: -1.7 versus 0.0%; P =.04; D-dimer: -14 versus +24.3 ng/mL; P =.009; prothrombin fragments 1 and 2: -0.11 versus +0.11 nmol/L; P =.01; protein C: +3.5 versus -4.0%; P =.01). Also at discharge, the changes from baseline were different for some of the markers in comparison of bemiparin sodium with placebo (D-dimer: -44 versus 3.8 ng/mL; P =.002; thrombin-antithrombin complex: -0.70 versus +0.14 microg/L; P =.002; protein C: +16.0 versus +0.5%; P =.02). CONCLUSION: Our findings suggest that a hypercoagulable state in heart failure can be modified with bemiparin sodium therapy.