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ISSN (Print) 0012-6667 - ISSN (Online) 1179-1950
Published by Adis Homepage  [21 journals]
  • Clinical Considerations When Initiating and Titrating Insulin
           Degludec/Liraglutide (IDegLira) in People with Type 2 Diabetes
    • Abstract: Abstract Therapeutic inertia is a substantial obstacle to the initiation of insulin therapy in people with uncontrolled type 2 diabetes (T2D). This effect has in part been perpetuated by concerns over the impact of a burdensome regimen and the increased risk of hypoglycemia and body weight gain often associated with insulin use. An effective, yet simple, less burdensome regimen with a lower risk of body weight gain and hypoglycemia compared with an insulin-only regimen, may help to address these concerns more effectively. We review the available clinical and real-world data on IDegLira, a once-daily, injectable, fixed-ratio combination of insulin degludec (degludec) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide, in people with T2D. Evidence from the comprehensive DUAL clinical trial program suggests an advantage of IDegLira over traditional insulin therapies in a number of clinical outcomes, including maintenance of glycemic control, achievement of glycemic targets, reducing the risk of hypoglycemia, and body weight loss. These findings were demonstrated in participants with T2D irrespective of prior GLP-1RA and insulin use. Furthermore, the individual components of IDegLira have confirmed safety (degludec) or significant benefit in terms of improvement of cardiovascular risk (liraglutide). As an injectable therapy that is simple to titrate, IDegLira has the potential to optimize the ability to achieve relevant glycemic targets, and offers a suitable treatment option for people with T2D requiring insulin therapy who are at risk of hypoglycemia or weight gain.
      PubDate: 2020-01-20
  • Novel Therapeutics for Recurrent Cervical Cancer: Moving Towards
           Personalized Therapy
    • Abstract: Abstract While screening programs and HPV vaccination have decreased the incidence of cervical cancer, still over 13,000 cases occur in the USA annually. Early-stage cervical cancer has an excellent long-term prognosis, with 5-year survival for localized disease being > 90%. Survival decreases markedly for both locally advanced and metastatic disease, and both are associated with a higher risk of recurrence. Few effective treatment options exist for persistent, recurrent, or metastatic cervical cancer. In 2014, the anti-VEGF antibody bevacizumab was approved in combination with chemotherapy based on the results of the Phase III GOG-240 study. As the majority of cervical cancers have a viral etiology, which impairs the immune system, immunotherapy using checkpoint inhibitors and other agents, appears to be a promising approach. In June 2018, the US FDA approved the anti-PD1 antibody pembrolizumab for recurrent or metastatic cervical cancer with PD-L1 expression that progressed after one or more lines of chemotherapy. Another anti-PD1 antibody, cemiplimab also shows potential in this setting, either as monotherapy or combined with radiotherapy, and it is currently being evaluated in a Phase III trial. Additional checkpoint inhibitors including nivolumab, durvalumab, atezolizumab, and camrelizumab are in different stages of clinical development for the disease. Finally, an additional targeted approach being pursued involves PARP inhibitors (rucaparib and olaparib are both in Phase II) based on earlier study results.
      PubDate: 2020-01-14
  • Luspatercept: First Approval
    • Abstract: Abstract Luspatercept (REBLOZYL®) is an erythroid maturation agent developed by Acceleron Pharma and Celgene Corporation for the treatment of anaemia associated with myelodysplastic syndromes, myelofibrosis and beta-thalassaemia. Based primarily on the results of the phase III BELIEVE trial, subcutaneous luspatercept was recently approved in the USA for the treatment of anaemia associated with beta-thalassaemia. This article summarizes the milestones in the development of luspatercept leading to this first approval.
      PubDate: 2020-01-14
  • Crizanlizumab: First Approval
    • Abstract: Abstract Crizanlizumab (Adakveo®; crizanlizumab-tmca) is an intravenously administered monoclonal antibody developed by Novartis Pharmaceuticals for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease. Crizanlizumab binds to P-selectin, thereby blocking its interaction with P-selectin glycoprotein ligand-1. In November 2019, crizanlizumab received its first global approval in the USA, where it is indicated to reduce the frequency of VOCs in adults and paediatric patients aged ≥ 16 years with sickle cell disease. The drug is also under regulatory review in the EU for the prevention of VOCs in patients with sickle cell disease. The use of crizanlizumab (in combination with ruxolitinib) in myelofibrosis is also being evaluated in Australia, Spain, Germany and Hungary. This article summarizes the milestones in the development of crizanlizumab leading to this first approval for the reduction of VOCs in patients with sickle cell disease.
      PubDate: 2020-01-13
  • Zanubrutinib: First Approval
    • Abstract: Abstract Zanubrutinib (Brukinsa®), an orally-administered Bruton tyrosine kinase (BTK) inhibitor, is being developed by BeiGene for the treatment of B-cell malignancies. Zanubrutinib received accelerated approval in the USA on 14 November 2019 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, based on overall response rate (ORR) seen in phase II and I/II clinical trials. This article summarizes the milestones in the development of zanubrutinib leading to this first approval for the treatment of MCL.
      PubDate: 2020-01-13
  • Cenobamate: First Approval
    • Abstract: Abstract Cenobamate (XCOPRI®) is an oral, small molecule neurotherapeutic azole compound that is being developed by SK Life Science Inc. and Arvelle Therapeutics for the treatment of epilepsy. Based on results of two pivotal phase 2 trials, cenobamate was recently approved in the USA for use in the treatment of partial-onset seizures in adult patients. This article summarizes the milestones in the development of cenobamate leading to this first approval.
      PubDate: 2020-01-13
  • Apremilast: A Review in Oral Ulcers of Behçet’s Disease
    • Abstract: Abstract The oral phosphodiesterase 4 inhibitor apremilast (Otezla®) is indicated for the treatment of oral ulcers associated with Behçet’s disease in some countries, including the USA (where it is the first agent approved for the disease) and Japan. In phase 2 and 3 trials in adults with this chronic and debilitating disorder, 12 weeks of treatment with apremilast 30 mg twice daily reduced the number and pain of oral ulcers and disease activity relative to placebo, with these clinical benefits being accompanied by improvements in health-related quality of life (HR-QOL). Benefits of apremilast were seen regardless of baseline patient/disease characteristics and in Japanese patients, and were sustained over up to 64 weeks of treatment. Apremilast was generally well tolerated, with gastrointestinal adverse events being among the most common tolerability issues. Emerging real-world data also support the drug’s use in this setting. Thus, for patients with oral ulcers associated with Behçet’s disease, apremilast provides an effective and generally well tolerated approved treatment option.
      PubDate: 2020-01-13
  • Kratom ( Mitragyna Speciosa ) Liver Injury: A Comprehensive Review
    • Abstract: Kratom (Mitragyna speciosa) leaves contain the mu opioid Kupferschmidt,partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a ‘drug of concern’, and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2–49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24–10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.
      PubDate: 2020-01-09
  • Potential of Lipoprotein(a)-Lowering Strategies in Treating Coronary
           Artery Disease
    • Abstract: Abstract High levels of lipoprotein(a) [Lp(a)] are considered causal risk factor of cardiovascular disease (CVD), including aortic stenosis. The 2019 ESC/EAC guidelines for the management of dyslipidaemias recommend to measure Lp(a) at least once in each adult person’s lifetime to identify those with inherited Lp(a) levels > 180 mg/dL (> 430 nmol/L) who may have a cardiovascular risk similar to heterozygous familial hypercholesterolaemia or in selected patients with a family history of premature CVD and for reclassification in people who are borderline between moderate- and high-risk. Some lipid-lowering agents not specific for Lp(a) have shown to reduce Lp(a) levels (niacin, PCSK9 inhibitors and CETP inhibitors). Prespecified analyses from the FOURIER trial have shown that participants who had reduction in Lp(a) levels with PCSK9 levels had a decreased risk of cardiovascular events. To lower Lp(a), two antisense oligonucleotides are under development targeting apolipoprotein B and apolipoprotein (a). Mipomersen is an oligonucleotide that targets apolipoprotein B, with a potential benefit in reducing Lp(a) by 20–50%. AKCEA-APO(a)-LRX is another antisense oligonucleotide targeting Lp(a) and reducing Lp(a) by 50–80%. A Phase III study with AKCEA-APO(a)-LRX will start in order to evaluate the effect on cardiovascular outcomes.
      PubDate: 2020-01-09
  • In Search of the Long-Desired ‘Copernican Therapeutic Revolution’ in
           Small-Cell Lung Cancer
    • Abstract: Abstract Small-cell lung cancer has defied our scientific community for decades. Chemotherapy has been the mainstay treatment for small-cell lung cancer (SCLC) and unlike its counterpart, non-small cell lung cancer, no significant therapeutic breakthroughs have been made since the 1970s. Among the reasons for this slow-paced therapeutic development, one that stands out is the distinctive and almost universal loss of function of the tumour suppressor genes TP53 and RB1 in this disease, for which pharmacological activation has yet to be achieved, despite having been highly sought after. Although no molecularly targeted approach has been approved for clinical practice thus far, several strategies are currently exploring the potential to drug the tumour’s “Achilles heel” that stems from essential pathways regulating DNA-damage response. Most recently, we have witnessed newfound reasons to hope, as the combination of immunotherapy and systemic chemotherapy has improved survival outcomes, representing the first landmark achievement in decades and a new standard of care for patients with extensive disease SCLC. However, continuous efforts are still needed towards a better understanding of the molecular pathways that singularise this tumour to eventually identify the predictive biomarkers that might result in the development of a more rational therapeutic approach, including the use of immunotherapy combinations. In this review we aim to uncover critical aspects of the immune microenvironment and biology of SCLC and provide an overview of the current and future landscape of promising therapeutic opportunities. The challenge still stands, but regardless, we are living in exciting times to finally check SCLC off the ”bucket list” of our scientific community.
      PubDate: 2020-01-08
  • 24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release
           Implant (Bimatoprost SR) in Glaucoma Patients
    • Abstract: Objective The objective of this study was to evaluate the safety and intraocular pressure (IOP)-lowering effects over 24 months of biodegradable bimatoprost sustained-release implant (Bimatoprost SR) administration versus topical bimatoprost 0.03% in patients with open-angle glaucoma (OAG). Methods This was a phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. At baseline following washout, adult patients with OAG (N = 75) received Bimatoprost SR (6, 10, 15, or 20 µg) intracamerally in the study eye; the fellow eye received topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or single repeat administration with implant was permitted. The primary endpoint was IOP change from baseline. Safety measures included adverse events (AEs). Results At month 24, mean IOP reduction from baseline was 7.5, 7.3, 7.3, and 8.9 mmHg in eyes treated with Bimatoprost SR 6, 10, 15, and 20 µg, respectively, versus 8.2 mmHg in pooled fellow eyes; 68, 40, and 28% of pooled study eyes had not been rescued/retreated at months 6, 12, and 24, respectively. AEs in study eyes that occurred ≤ 2 days post-procedure typically were transient. After 2 days post-procedure, overall AE incidence was similar between study and fellow eyes, with some events typically associated with topical prostaglandin analogs having lower incidence in study eyes. Conclusions Bimatoprost SR showed favorable efficacy and safety profiles up to 24 months, with all evaluated dose strengths demonstrating overall IOP-reducing effects comparable to those of topical bimatoprost. Targeted and sustained delivery of bimatoprost resulted in protracted IOP lowering, suggesting that Bimatoprost SR may represent a transformational new approach to glaucoma therapy. identifier: NCT01157364
      PubDate: 2019-12-28
  • Dolutegravir/Lamivudine Single-Tablet Regimen: A Review in HIV-1 Infection
    • Abstract: Abstract The oral once-daily, fixed-dose single-tablet regimen (STR) of dolutegravir/lamivudine (Dovato®), combining a second generation integrase single-strand transfer inhibitor (INSTI) and a nucleoside reverse transcriptase inhibitor (NRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents (> 12 years of age weighing at least 40 kg) with no known or suspected resistance to the INSTI class or lamivudine. In GEMINI trials in antiretroviral therapy (ART)-naïve HIV-1-infected adults, treatment with dolutegravir plus lamivudine provided rapid and sustained virological suppression and was noninferior to dolutegravir plus tenofovir disoproxil fumarate/emtricitabine at 48 weeks, irrespective of baseline patient or disease characteristics. Virological suppression was sustained at 96 weeks in these ongoing trials. In patients with HIV-1 with sustained virological suppression on their current tenofovir alafenamide (AF)-based ART regimen (≥ 3 drugs), switching to treatment with dolutegravir/lamivudine was noninferior to continuing on a tenofovir AF-based regimen at 48 weeks in the ongoing TANGO trial. No resistance mutations to dolutegravir or lamivudine were detected in patients who met criteria for confirmed virological withdrawal in GEMINI and TANGO trials. Hence, the dolutegravir/lamivudine STR is an effective, generally well tolerated and convenient initial and subsequent ART option for adolescents and adults with HIV-1 infection with no known or suspected resistance to the INSTI class or lamivudine.
      PubDate: 2019-12-21
  • Poly (ADP-ribose) Polymerase Inhibition in Patients with Breast Cancer and
           BRCA 1 and 2 Mutations
    • Abstract: Abstract The poly-(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib, have recently been approved for use in patients with metastatic breast cancer (BC) and germline BRCA 1 or 2 mutations due to improved progression-free survival compared to chemotherapy. An increasing number of clinical trials are evaluating the role of PARP inhibitors (PARPi) in BC, alone and in combination with other therapies (including immunotherapy), as well as in earlier stages of the disease. This review describes the unique mechanism of action of these drugs and puts into clinical context the results of pivotal clinical trials. We also discuss the future development of PARPi in BC, their potential combination with other strategies, including chemotherapy and immune-checkpoint inhibitors, and the impact of these treatments in current genetic counselling.
      PubDate: 2019-12-10
  • Clinical Overview of Enfortumab Vedotin in the Management of Locally
           Advanced or Metastatic Urothelial Carcinoma
    • Abstract: Abstract The treatment landscape for locally advanced or metastatic urothelial carcinoma has broadened significantly over recent years. New therapeutic options include immunotherapy with checkpoint inhibitors and targeted therapy with erdafitinib. Despite these advances, gaps remain in the selection and sequencing of optimal therapies. Treatment decisions are often influenced by several patient-specific factors such as tolerability and biomarker expression. Following progression while receiving front- and second-line therapies, there is no widely accepted standard of care for patients. Enrollment into a clinical trial is recommended in all lines of therapy for advanced disease. Antibody–drug conjugates have recently emerged as novel therapeutics allowing for targeted delivery of chemotherapeutic agents. Enfortumab vedotin, a nectin-4-targeted antibody conjugated with monomethyl auristatin E, is the first-in-class therapeutic option and has demonstrated unprecedented response rates following progression on chemotherapy and immunotherapy for advanced disease with a tolerable safety profile. As a result, a biologics license application was submitted to the US FDA in July 2019. Ongoing clinical trials are aiming to further establish the role of enfortumab vedotin in urothelial carcinoma. In this article, we highlight the safety and efficacy of enfortumab vedotin for patients with advanced bladder cancer, ongoing clinical trials, clinical pharmacology, and pharmacokinetics.
      PubDate: 2019-12-10
  • Emerging Challenges to the Safe and Effective Use of Methadone for
           Cancer-Related Pain in Paediatric and Adult Patient Populations
    • Abstract: Abstract Methadone continues to be an important medication for the treatment of paediatric and adult cancer-related pain. Appropriate patient selection to ensure safe and effective treatment by a team of clinicians who appreciate and are familiar with methadone and its unique pharmacology is crucial. Unlike morphine and other more common opioids, methadone is purported to have involvement with delta-opioid receptor and higher affinity as an N-methyl-d-aspartate-receptor antagonist. Clinically this gives it the advantage of being effective for both nociceptive and neuropathic pain, but also may be useful in the setting of tolerance to other opioids. Methadone also comes in multiple available formulations that can be administrated through a variety of routes beyond the oral route. Challenges with methadone in treating cancer-related pain include drug interactions specifically as it relates to new targeted cancer therapies. Recent guidelines recommend electrocardiogram monitoring with methadone and there is potential for additive cardiac toxicity in the oncology setting. Appropriate dosing of methadone for pain management given age, organ dysfunction, and patients who are on methadone maintenance therapy are also key factors. This article aims to provide clinicians with evidence and clinical practice guidelines for safe and appropriate use of methadone including indication, initiation, and monitoring given its complexity for management of pain in the dynamic oncology setting.
      PubDate: 2019-12-09
  • Management of Opioid-Tolerant Patients with Acute Pain: Approaching the
    • Abstract: Abstract For over two decades, dramatic increases in opioid prescriptions in the developed world, especially for long-term management of chronic noncancer pain, were accompanied by increases in patient harm. In recent years in the USA, opioid-related deaths rates have continued to increase despite falls in prescribing rates and deaths associated with prescription opioids. In large part, this is attributed to the growing availability of illicitly manufactured fentanyl. Increased opioid use, for medical and nonmedical reasons, has led to more opioid-tolerant patients requiring management of acute pain. The potential harms associated with long-term opioid use are now well known. What may be less well understood is that preoperative long-term opioid use is associated with increased perioperative complications including infection, readmissions, and greater healthcare utilisation and costs. Minimizing opioid use prior to surgery is a modifiable risk factor that could benefit both patient and healthcare system. Management of acute pain should include simple analgesics and adjuvants, with short-term opioid dose increases if needed and use of non-pharmacological strategies. Reported pain intensities may be high and titration of analgesia to function rather than pain scores is appropriate. Importantly, compared with opioid-naïve patients, opioid-tolerant patients may be at higher risk of opioid-induced ventilatory impairment when additional opioids are administered to manage new acute pain. For some patients, perioperative care may be best coordinated by a perioperative or post-discharge service with referral to multidisciplinary pain and addiction medicine services as indicated. Carefully planned and communicated discharge prescribing, with a weaning plan for additional opioids, is essential.
      PubDate: 2019-12-02
  • Correction to: Once-Daily versus Twice Daily Tacrolimus in Kidney
           Transplantation: A Systematic Review and Meta-analysis of Observational
    • Abstract: The row for study Jelassi et al. (2011) [28], where the Observational Period for ER-Tac reads June 2007–March 2010a and for IR-Tac reads N/A.
      PubDate: 2019-11-26
  • Correction to: Dapagliflozin: A Review in Type 1 Diabetes
    • Abstract: The article Dapagliflozin: A Review in Type 1 Diabetes, written by Julia Paik and Hannah A. Blair, was originally published Online First without Open Access.
      PubDate: 2019-11-26
  • Correction to: Dapagliflozin: A Review in Type 2 Diabetes
    • Abstract: The article Dapagliflozin: A Review in Type 2 Diabetes, written by Sohita Dhillon
      PubDate: 2019-11-26
  • Correction to: Cell-Based Quadrivalent Inactivated Influenza Virus Vaccine
           (Flucelvax ® Tetra/Flucelvax Quadrivalent ® ): A Review in the
           Prevention of Influenza
    • Abstract: The article Cell-Based Quadrivalent Inactivated Influenza Virus Vaccine.
      PubDate: 2019-11-25
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