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Drugs
Journal Prestige (SJR): 1.547  Citation Impact (citeScore): 5 Number of Followers: 143  Subscription journalISSN (Print) 0012-6667 - ISSN (Online) 1179-1950 Published by Adis  [21 journals]
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- Immune Mechanisms in Epileptogenesis: Update on Diagnosis and Treatment of
Autoimmune Epilepsy Syndromes-
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Abstract: Abstract Seizures and epilepsy can result from various aetiologies, yet the underlying cause of several epileptic syndromes remains unclear. In that regard, autoimmune-mediated pathophysiological mechanisms have been gaining attention in the past years and were included as one of the six aetiologies of seizures in the most recent classification of the International League Against Epilepsy. The increasing number of anti-neuronal antibodies identified in patients with encephalitic disorders has contributed to the establishment of an immune-mediated pathophysiology in many cases of unclear aetiology of epileptic syndromes. Yet only a small number of patients with autoimmune encephalitis develop epilepsy in the proper sense where the brain transforms into a state where it will acquire the enduring propensity to produce seizures if it is not hindered by interventions. Hence, the term autoimmune epilepsy is often wrongfully used in the context of autoimmune encephalitis since most of the seizures are acute encephalitis-associated and will abate as soon as the encephalitis is in remission. Given the overlapping clinical presentation of immune-mediated seizures originating from different aetiologies, a clear distinction among the aetiological entities is crucial when it comes to discussing pathophysiological mechanisms, therapeutic options, and long-term prognosis of patients. Moreover, a rapid and accurate identification of patients with immune-mediated epilepsy syndromes is required to ensure an early targeted treatment and, thereby, improve clinical outcome. In this article, we review our current understanding of pathogenesis and critically discuss current and potential novel treatment options for seizures and epilepsy syndromes of underlying or suspected immune-mediated origin. We further outline the challenges in proper terminology.
PubDate: 2023-01-25
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- Risk of COVID-19 Diagnosis and Hospitalisation in Patients with
Osteoarthritis or Back Pain Treated with Ibuprofen Compared to Other
NSAIDs or Paracetamol: A Network Cohort Study-
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Abstract: Objective We aimed to investigate whether ibuprofen use, compared with other non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), cyclooxygenase-2 inhibitors (COX-2i) or paracetamol, increases the risk of coronavirus disease 2019 (COVID-19) diagnosis or hospitalisation. Design A prevalent user and active comparator cohort study. Setting Two US claims databases (Open Claims and PharMetrics Plus) mapped to the Observational Medical Outcomes Partnership Common Data Model. Participants Insured patients with a history of osteoarthritis or back pain and receiving ibuprofen, other ns-NSAIDs, COX-2i or paracetamol between 1 November, 2019 and 31 January, 2020 (study enrolment window 1) or between 1 February, 2020 and 31 October, 2020 (study enrolment window 2). Main Outcome Measures Large-scale propensity score matching and empirical calibration were used to minimise confounding. Incidence and hazard ratios of COVID-19 diagnosis and hospitalisation according to drug/s use were estimated and pooled in the same study period across data sources using a fixed-effects meta-analysis. Index treatment episode was the primary risk evaluation window, censored at the time of discontinuation. Results A total of 633,562 and 1,063,960 participants were included in periods 1 and 2, respectively, for the ibuprofen versus ns-NSAIDs comparison, 311,669 and 524,470 for ibuprofen versus COX-2i, and 492,002 and 878,598 for ibuprofen versus paracetamol. Meta-analyses of empirically calibrated hazard ratios revealed no significantly differential risk of COVID-19 outcomes in users of ibuprofen versus any of the other studied analgesic classes: hazard ratios were 1.13 (0.96–1.33) for the ibuprofen-ns-NSAIDs comparison, 1.03 (0.83–1.28) for the ibuprofen-COX-2i comparison and 1.13 (0.74–1.73) for ibuprofen-paracetamol comparison on COVID-19 diagnosis in the February 2020–October 2020 window. Similar hazard ratios were found on COVID-19 hospitalisation and across both study periods. Conclusions In patients with osteoarthritis or back pain, we found no differential risks of incident COVID-19 diagnosis or COVID-19 hospitalisation for ibuprofen users compared with other ns-NSAIDs, COX-2i or paracetamol. Our findings support regulatory recommendations that NSAIDs, including ibuprofen, should be prescribed as indicated in the same way as before the COVID-19 pandemic, especially for those who rely on ibuprofen or NSAIDs to manage chronic arthritis or musculoskeletal pain symptoms. Graphical abstract
PubDate: 2023-01-24
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- Mirvetuximab Soravtansine: First Approval
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Abstract: Abstract Mirvetuximab soravtansine (mirvetuximab soravtansine-gynx; Elahere™) is an antibody-drug conjugate (ADC), which is comprised of a folate receptor α (FRα) directed antibody conjugated to a microtubule inhibitor via a cleavable linker. The ADC is being developed by ImmunoGen for the treatment of FRα expressing cancers. In November 2022, mirvetuximab soravtansine was approved in the USA for the treatment of adult patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received 1–3 prior systemic treatment regimens. This article summarizes the milestones in the development of mirvetuximab soravtansine leading to this first approval.
PubDate: 2023-01-19
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- Diagnosis and Treatment of AL Amyloidosis
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Abstract: Abstract Systemic light chain (AL) amyloidosis is caused by an usually small B cell clone that produces a toxic light chain forming amyloid deposits in tissue. The heart and kidney are the major organs affected, but all others, with the exception of the CNS, can be involved. The disease is rapidly progressive, and it is still diagnosed late. Screening programs in patients followed by hematologists for plasma cell dyscrasias should be considered. The diagnosis requires demonstration in a tissue biopsy of amyloid deposits formed by immunoglobulin light chains. The workup of patients with AL amyloidosis requires adequate technology and expertise, and patients should be referred to specialized centers whenever possible. Stagings are based on cardiac and renal biomarkers and guides the choice of treatment. The combination of daratumumab, cyclophosphamide, bortezomib and dexamethasone (dara-CyBorD) is the current standard of care. Autologous stem cell transplant is performed in eligible patients, especially those who do not attain a satisfactory response to dara-CyBorD. Passive immunotherapy targeting the amyloid deposits combined with chemo-/immune-therapy targeting the amyloid clone is currently being tested in controlled clinical trials. Response to therapy is assessed based on validated criteria. Profound hematologic response is the early goal of treatment and should be accompanied over time by deepening organ response. Many relapsed/refractory patients are also treated with daratumumab combination, but novel regimens will be needed to rescue daratumumab-exposed subjects. Immunomodulatory drugs are the current cornerstone of rescue therapy, while immunotherapy targeting B-cell maturation antigen and inhibitors of Bcl-2 are promising alternatives.
PubDate: 2023-01-18
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- Use of Levosimendan in Patients with Pulmonary Hypertension: What is the
Current Evidence'-
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Abstract: Abstract Pulmonary hypertension, defined as an increase in mean arterial pressure > 20 mmHg, is a chronic and progressive condition with high mortality and morbidity. Drug therapy of patients with pulmonary hypertension is based on the distinctive pathophysiologic aspect that characterizes the different groups. However, recently, levosimendan, a calcium-sensitizing agent with inotropic, pulmonary vasodilator, and cardioprotective properties, has been shown to be an effective and safe therapeutic strategy for patients with pulmonary arterial hypertension (in addition to specific drugs) and pulmonary hypertension associated with left heart disease (as possible treatment). This review provides a comprehensive overview of the current evidence on the use of levosimendan in patients with pulmonary hypertension.
PubDate: 2023-01-18
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- Treating Head and Neck Cancer in the Age of Immunotherapy: A 2023 Update
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Abstract: Abstract Most patients diagnosed with head and neck squamous cell carcinoma (HNSCC) will present with locally advanced disease, requiring multimodality therapy. While this approach has a curative intent, a significant subset of these patients will develop locoregional failure and/or distant metastases. The prognosis of these patients is poor, and therapeutic options other than palliative chemotherapy are urgently needed. Epidermal growth factor receptor (EGFR) overexpression is an important factor in the pathogenesis of HNSCC, and a decade ago, the EGFR targeting monoclonal antibody cetuximab was approved for the treatment of late-stage HNSCC in different settings. In 2016, the anti-programmed death-1 (PD-1) immune checkpoint inhibitors nivolumab and pembrolizumab were both approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy, and in 2019, pembrolizumab was approved for first-line treatment (either as monotherapy in PD-L1 expressing tumors, or in combination with chemotherapy). Currently, trials are ongoing to include immune checkpoint inhibition in the (neo)adjuvant treatment of HNSCC as well as in novel combinations with other drugs in the recurrent/metastatic setting to improve response rates and survival and help overcome resistance mechanisms to immune checkpoint blockade. This article provides a comprehensive review of the management of head and neck cancers in the current era of immunotherapy.
PubDate: 2023-01-16
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- Emerging Options for the Prevention and Management of Clostridioides
difficile Infection-
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Abstract: Abstract Agents in development for the prevention or treatment of Clostridioides difficile infection can be split into three broad categories: antibiotics, microbiome restoration, and vaccines. Given the extensive list of agents currently in development, this narrative review will focus on agents that have progressed into late-stage clinical trials, defined as having a Phase III clinical trial registered on ClinicalTrials.gov. These agents include one antibiotic (ridinilazole), three live biotherapeutic products (LBPs) (CP101, RBX2660, and SER109), and two toxoid vaccines (PF06425090 and a second toxoid vaccine). As new prevention and treatment strategies enter the market, clinicians and administrators will need knowledge of these products to make rational decisions on how best to adopt them into clinical practice.
PubDate: 2023-01-16
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- Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface
Malignancies-
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Abstract: Abstract Malignancies of the peritoneal cavity are associated with a dismal prognosis. Systemic chemotherapy is the gold standard for patients with unresectable peritoneal disease, but its intraperitoneal effect is hampered by the peritoneal-plasma barrier. Intraperitoneal chemotherapy, which is administered repeatedly into the peritoneal cavity through a peritoneal implanted port, could provide a novel treatment modality for this patient population. This review provides a systematic overview of intraperitoneal used drugs, the performed clinical studies so far, and the complications of the peritoneal implemental ports. Several anticancer drugs have been studied for intraperitoneal application, with the taxanes paclitaxel and docetaxel as the most commonly used drug. Repeated intraperitoneal chemotherapy, mostly in combination with systemic chemotherapy, has shown promising results in Phase I and Phase II studies for several tumor types, such as gastric cancer, ovarian cancer, colorectal cancer, and pancreatic cancer. Two Phase III studies for intraperitoneal chemotherapy in gastric cancer have been performed so far, but the results regarding the superiority over standard systemic chemotherapy alone, are contradictory. Pressurized intraperitoneal administration, known as PIPAC, is an alternative way of administering intraperitoneal chemotherapy, and the first prospective studies have shown a tolerable safety profile. Although intraperitoneal chemotherapy might be a standard treatment option for patients with unresectable peritoneal disease, more Phase II and Phase III studies focusing on tolerability profiles, survival rates, and quality of life are warranted in order to establish optimal treatment schedules and to establish a potential role for intraperitoneal chemotherapy in the approach to unresectable peritoneal disease.
PubDate: 2023-01-12
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- Rezvilutamide: First Approval
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Abstract: Abstract Rezvilutamide (艾瑞恩®) is an oral, second-generation androgen receptor antagonist being developed by Jiangsu Hengrui Medicine Co., Ltd for the treatment of prostate cancer. In June 2022, rezvilutamide was approved in China for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC) with high tumour burden. This article summarizes the milestones in the development of rezvilutamide leading to this first approval for patients with prostate cancer.
PubDate: 2023-01-11
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- TKI Treatment Sequencing in Advanced Gastrointestinal Stromal Tumors
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Abstract: Abstract Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.
PubDate: 2023-01-06
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- An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral
Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy
Volunteers-
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Abstract: Background Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. Objective This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Methods Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. Results A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2–80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2–59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥ 0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. Conclusions For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.
PubDate: 2023-01-06
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- Nirsevimab: First Approval
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Abstract: Abstract Nirsevimab (Beyfortus®), a long-acting intramuscular recombinant neutralising human IgG1ĸ monoclonal antibody to the prefusion conformation of the respiratory syncytial virus (RSV) F protein that has been modified with a triple amino acid substitution in the Fc region to extend the serum half-life, is being jointly developed by AstraZeneca and Sanofi for the prevention of RSV disease. The extended serum half-life allows administration of nirsevimab as a single dose to cover the RSV season. Nirsevimab was approved in the EU on 3 November 2022 and in the UK on 7 November 2022 for the prevention of RSV lower respiratory tract disease in neonates and infants during their first RSV season. This article summarizes the milestones in the development of nirsevimab leading to this first approval for the prevention of RSV disease in all infants.
PubDate: 2022-12-29
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- Tremelimumab: First Approval
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Abstract: Abstract Tremelimumab (tremelimumab-actl; IMJUDO®), a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) blocking antibody, is being developed by AstraZeneca, under license from Pfizer, for the treatment of a range of malignant tumours. Tremelimumab was approved in the USA in October 2022 in combination with durvalumab for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). In addition, tremelimumab in combination with durvalumab and platinum-based chemotherapy was approved in the USA in November 2022 for the treatment of adult patients with metastatic non-small cell lung cancer (mNSCLC) with no sensitizing epidermal growth factor receptor mutation or anaplastic lymphoma kinase genomic tumour aberrations. In December 2022, tremelimumab in combination with durvalumab received a Positive Opinion from the EU Committee for Medicinal Products for Human Use for the first line treatment of adults with advanced or unresectable HCC. Tremelimumab in combination with durvalumab is under regulatory review for these indications in Japan and in other countries worldwide. This article summarizes the milestones in the development of tremelimumab leading to this first approval.
PubDate: 2022-12-26
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- Gabapentinoids for Pain: A Review of Published Comparative Effectiveness
Trials and Data Submitted to the FDA for Approval-
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Abstract: Abstract Use of the gabapentinoids for pain continues to increase. In 2018, the US Food and Drug Administration (FDA) strengthened the warnings for both gabapentin and pregabalin to emphasize the central nervous system side effects and the risk of respiratory depression, especially when combined with other centrally acting drugs. We reviewed the published comparative effectiveness literature for gabapentinoids for pain as well as all trials (published and unpublished) used by the FDA for the approval of the five pain indications for these agents (one for gabapentin, four for pregabalin). Among the findings of interest are the fact that the FDA rejected the application for gabapentin for diabetic peripheral neuropathy based on the risk versus benefit profile of that drug in the clinical trials that were submitted by the manufacturer. Additionally, both the comparative effectiveness trials as well as the studies used by the FDA tend to be short in duration and show only modest pain benefits for the gabapentinoids. The placebo response in these trials was frequently one-third to one-half as great as the pain benefit demonstrated by the gabapentinoid. Based on the available clinical trial evidence, we feel prescribers should be cautious when using gabapentinoids for pain, particularly when using these agents for a prolonged period or when combined with other, centrally acting agents.
PubDate: 2022-12-18
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- Ozoralizumab: First Approval
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Abstract: Abstract Ozoralizumab (Nanozora®), a trivalent anti-tumour necrosis factor alpha (TNFα) NANOBODYⓇ compound, has been developed by Taisho Pharmaceutical Co. Ltd (under license from Ablynx, an affiliate of Sanofi) for the treatment of rheumatoid arthritis (RA). In September 2022, ozoralizumab was approved in Japan for the treatment of RA that is inadequately managed by current available treatments. This article summarizes the milestones in the development of ozoralizumab leading to this first approval.
PubDate: 2022-12-13
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- Correction to: Spesolimab: First Approval
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PubDate: 2022-12-12
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- Should We Interfere with the Interleukin-6 Receptor During COVID-19: What
Do We Know So Far'-
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Abstract: Abstract Severe manifestations of COVID-19 consist of acute respiratory distress syndrome due to an initially local reaction leading to a systemic inflammatory response that results in hypoxia. Many therapeutic approaches have been attempted to reduce the clinical consequences of an excessive immune response to viral infection. To date, systemic corticosteroid therapy is still the most effective intervention. More recently, new hope has emerged with the use of interleukin (IL)-6 receptor inhibitors (tocilizumab and sarilumab). However, the great heterogeneity of the methodology and results of published studies obfuscate the true value of this treatment, leading to a confusing synthesis in recent meta-analyses, and the persistence of doubts in terms of patient groups and the appropriate time to treat. Moreover, their effects on the anti-infectious or pro-healing response are still poorly studied. This review aims to clarify the potential role of IL-6 receptor inhibitors in the treatment of severe forms of COVID-19.
PubDate: 2022-12-12
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- Correction: Teprotumumab: A Review in Thyroid Eye Disease
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PubDate: 2022-12-02
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- Comment on: “Global Consumption Trend of Antifungal Agents in Humans
from 2008 to 2018: Data from 65 Middle‐ and High‐Income Countries”-
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PubDate: 2022-12-01
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- Authors’ Reply to Denning: Comment on: “Global Consumption Trend of
Antifungal Agents in Humans From 2008 to 2018: Data From 65 Middle- and
High-Income Countries”-
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PubDate: 2022-12-01
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