Drugs

Chalhoub, Reda M.; Kalivas, Peter W.

doi: 10.1007/s40265-020-01373-1pmid: 32776315

Opioid use disorder (OUD) represents a major public health problem that affects millions of people in the USA and worldwide. The relapsing and recurring aspect of OUD, driven by lasting neurobiological adaptations at different reward centres in the brain, represents a major obstacle towards successful long-term remission from opioid use. Currently, three drugs that modulate the function of the opioidergic receptors, methadone, buprenorphine and naltrexone have been approved by the US Food and Drug Administration (FDA) to treat OUD. In this review, we discuss the limitations and challenges associated with the current maintenance and medication-assisted withdrawal strategies commonly used to treat OUD. We further explore the involvement of glutamatergic, endocannabinoid and orexin signaling systems in the development, maintenance and expression of addiction-like behaviours in animal models of opioid addiction, and as potential and novel targets to expand therapeutic options to treat OUD. Despite a growing preclinical literature highlighting the role of these potential targets in animal models of opioid addiction, clinical and translational studies for novel treatments of OUD remain limited and inconclusive. Further preclinical and clinical investigations are needed to expand the arsenal of primary treatment options and adjuncts to maximise efficacy and prevent relapse.

Onstad, Michaela; Coleman, Robert L.; Westin, Shannon N.

doi: 10.1007/s40265-020-01382-0pmid: 32852746

The use of poly (ADP-ribose) polymerase (PARP) inhibitors in the front-line management of advanced ovarian cancer has recently emerged as an exciting strategy with the potential to improve outcomes for patients with advanced ovarian cancer. In this article, we review the results of four recently published Phase III randomised controlled trials evaluating the use of PARP inhibitors in the primary treatment of ovarian cancer (SOLO1, PRIMA, PAOLA-1, and VELIA). Collectively, the studies suggest that PARP maintenance in the upfront setting is most beneficial among patients with BRCA-associated ovarian cancers (hazard ratios range from 0.31 to 0.44), followed by patients with tumours that harbour homologous recombination deficiencies (hazard ratios range from 0.33 to 0.57). All three studies that included an all-comer population were able to demonstrate benefit of PARP inhibitors, regardless of biomarker status. The FDA has approved olaparib for front-line maintenance therapy among patients with BRCA-associated ovarian cancers, and niraparib for all patients, regardless of biomarker status. In determining which patients should be offered front-line maintenance PARP inhibitors, and which agent to use, there are multiple factors to consider, including FDA indication, dosing preference, toxicity, risks versus benefits for each patient population, and cost. There are ongoing studies further exploring the front-line use of PARP inhibitors, including the potential downstream effects of PARP-inhibitor resistance in the recurrent setting, combining PARP-inhibitors with other anti-angiogenic drugs, immunotherapeutic agents, and inhibitors of pathways implicated in PARP inhibitor resistance.

Fuggle, N. R.; Cooper, C.; Harvey, N. C.; Al-Daghri, N.; Brandi, M.-L.; Bruyere, O.; Cano, A.; Dennison, E. M.; Diez-Perez, A.; Kaufman, J.-M.; Palacios, S.; Prieto-Alhambra, D.; Rozenberg, S.; Thomas, T.; Tremollieres, F.; Rizzoli, R.; Kanis, J. A.; Reginster, J. Y.

doi: 10.1007/s40265-020-01364-2

Hajra, Adrija; Mathai, Sheetal Vasundara; Ball, Somedeb; Bandyopadhyay, Dhrubajyoti; Veyseh, Maedeh; Chakraborty, Sandipan; Lavie, Carl J.; Aronow, Wilbert S.

doi: 10.1007/s40265-020-01377-xpmid: 32803670

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2), is now a global pandemic. This virus primarily affects the respiratory tract and causes lung injury characterized by acute respiratory distress syndrome. Although the pathophysiology of COVID-19 is not yet clear, the most widely accepted mechanism is systemic inflammation. A clinically significant effect of the inflammation is coagulopathy. As a result of this effect, patients are found to have a high risk of venous thromboembolism. Studies have reported a high incidence of thrombotic complications in critically ill patients with COVID-19. In this review, we discuss the most updated evidence on the pathophysiology, diagnosis, and treatment of the coagulopathy of COVID-19. Prophylactic anticoagulation is recommended for all in-patients with COVID-19. Those with a higher risk of developing thromboembolic events or who have already developed venous thromboembolism should be treated with therapeutic anticoagulation. We also discuss post-discharge prophylaxis for high-risk patients and some newly proposed treatments for the hypercoagulability that could improve the outcomes of the affected patients.

Mathieson, Stephanie; Maher, Christopher G.; Ferreira, Giovanni E.; Hamilton, Melanie; Jansen, Jesse; McLachlan, Andrew J.; Underwood, Martin; Lin, Chung-Wei Christine

doi: 10.1007/s40265-020-01368-ypmid: 32737739

BackgroundDeprescribing, the process of reducing or discontinuing unnecessary or harmful medicines is an essential part of clinical practice.ObjectiveTo evaluate the efficacy of interventions designed to deprescribe opioid analgesics for pain relief in patients with chronic non-cancer pain.MethodsWe searched electronic databases, including clinical trial registries, from database inception to 13th January 2020 without restrictions, and conducted citation tracking. Our systematic review included randomised controlled trials (RCTs) evaluating interventions reducing the prescription, or use of opioid analgesics in patients with chronic pain versus control. Inventions could be aimed at the patient, clinician, or both. We excluded trials enrolling patients with cancer or illicit drug use. Two authors independently screened and extracted data. Outcome follow-up timepoints were short (≤ 3 months), intermediate (> 3 but < 12 months) or long (≥ 12 months) term. Primary outcome was the reduction in opioid dose [morphine milligram equivalent (MME) mg/day]. Methodological quality was assessed using the Cochrane Risk of Bias Tool.ResultsWe included ten patient-focused RCT interventions (n = 835; median 37 participants) and 2 testing clinician-focused interventions (n = 291 clinicians); none at low risk of bias. Patient-focused interventions did not reduce opioid dose in the intermediate term [e.g. dose reduction protocol, mean difference (MD) − 19.9 MME, 95% CI − 107.5 to 67.7], nor did they increase the number of participants who ceased their dose, or increase the risk of serious adverse events or adverse events. One clinician intervention of education plus decision tools versus decision tools alone reduced the number of opioid prescriptions (risk difference (RD) − 0.1, 95% CI − 0.2 to − 0.1), dose (MD − 5.3 MME, 95% CI − 6.2 to − 4.5) and use (RD − 0.1, 95% CI − 0.1 to − 0.0) in the long term.LimitationsStudy heterogeneity prevented meta-analysis.ConclusionThe small number of studies and heterogeneity prevented firm conclusions to recommend any one opioid-analgesic-deprescribing strategy in patients with chronic pain.Systematic review registration numberPROSPERO CRD42017068422.

Mathieson, Stephanie; Maher, Christopher G.; Ferreira, Giovanni E.; Hamilton, Melanie; Jansen, Jesse; McLachlan, Andrew J.; Underwood, Martin; Lin, Chung-Wei Christine

doi: 10.1007/s40265-020-01416-7pmid: 32990940

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Hoy, Sheridan M.

doi: 10.1007/s40265-020-01401-0pmid: 32930958

Apalutamide (Erleada®) is an oral selective androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. It is approved in the EU and the USA for the treatment of adult men with metastatic castration-sensitive prostate cancer (mCSPC). In a multinational, phase III study (TITAN) in this patient population, the addition of apalutamide (240 mg once daily) to androgen deprivation therapy (ADT) significantly improved median radiographic progression-free survival (rPFS), median overall survival (OS) and the median time to cytotoxic chemotherapy, while maintaining health-related quality of life (HR-QOL) and not substantially differing from placebo plus ADT in safety. Although mature OS data are awaited with interest, the addition of apalutamide to ADT extends the treatment options available for standard of care in adult men with mCSPC.

Frampton, James E.

doi: 10.1007/s40265-020-01398-6pmid: 32990939

Atezolizumab (Tecentriq®), a fully humanized, monoclonal anti-programmed cell death ligand-1 (PD-L1) antibody, is the first immune checkpoint inhibitor to be approved, in combination with carboplatin and etoposide, for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). Approval was based on primary data from the multinational phase I/III IMpower133 trial in PD-L1-unselected patients with previously untreated ES-SCLC. In this trial, induction therapy with atezolizumab plus carboplatin and etoposide followed by maintenance therapy with atezolizumab alone significantly prolonged overall survival (OS) and progression-free survival (PFS) compared with carboplatin and etoposide alone. The addition of atezolizumab to chemotherapy was generally well tolerated, with no new safety signals being identified beyond those previously reported for the individual agents. The most common grade 3–4 treatment-related adverse events with this regimen were haematological; the most common immune-related adverse events included rash and hypothyroidism. Importantly, the addition of atezolizumab to chemotherapy improved survival outcomes without adversely impacting patient-reported health-related quality of life (HRQOL). Thus, atezolizumab in combination with carboplatin plus etoposide has emerged as a valuable option for the first-line treatment of ES-SCLC and is being accepted as a standard of care in this setting.

Shirley, Matt

doi: 10.1007/s40265-020-01399-5pmid: 32897506

Triheptanoin (Dojolvi™), a synthetic medium-chain triglyceride, is being developed by Ultragenyx Pharmaceutical as a pharmaceutical-grade anaplerotic compound for use in the treatment of inherited metabolic disorders. In June 2020, triheptanoin received its first regulatory approval, in the USA, for use as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). Triheptanoin has also been investigated for use as a treatment in a range of other metabolic disorders or other diseases where energy deficiency is implicated. This article summarizes the milestones in the development of triheptanoin leading to this first regulatory approval for use in the treatment of pediatric and adult patients with LC-FAOD.

Kang, Connie; Syed, Yahiya Y.

doi: 10.1007/s40265-020-01400-1pmid: 32926353

Bulevirtide (Hepcludex®), a first-in-class entry inhibitor, is being developed by MYR GmbH for the treatment of chronic hepatitis delta virus (HDV) and chronic hepatitis B virus (HBV) infections. Bulevirtide was recently approved in the European Union (EU) for the treatment of chronic HDV infection in HDV RNA positive adult patients with compensated liver disease. This article summarizes the milestones in the development of bulevirtide leading to this first approval for chronic HDV.