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1.
Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer.
Shitara, K, Baba, E, Fujitani, K, Oki, E, Fujii, S, Yamaguchi, K
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2021;(4):780-789
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Abstract
Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.
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2.
Oral anticoagulant monitoring: Are we on the right track?
Onundarson, PT, Flygenring, B
International journal of laboratory hematology. 2019;:40-48
Abstract
Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran-related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.
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3.
Clinically Relevant Drug-Drug Interactions in Primary Care.
Carpenter, M, Berry, H, Pelletier, AL
American family physician. 2019;(9):558-564
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Abstract
Drug interactions are common in the primary care setting and are usually predictable. Identifying the most important and clinically relevant drug interactions in primary care is essential to patient safety. Strategies for reducing the risk of drug-drug interactions include minimizing the number of drugs prescribed, re-evaluating therapy on a regular basis, considering nonpharmacologic options, monitoring for signs and symptoms of toxicity or effectiveness, adjusting dosages of medications when indicated, and adjusting administration times. Inhibition or induction of cytochrome P450 drug metabolizing isoenzymes is the most common mechanism by which clinically important drug interactions occur. The antimicrobials most likely to affect the international normalized ratio significantly in patients receiving warfarin are trimethoprim/sulfamethoxazole, metronidazole, and fluconazole. An empiric warfarin dosage reduction of 30% to 50% upon initiation of amiodarone therapy is recommended. In patients receiving amiodarone, limit dosages of simvastatin to 20 mg per day and lovastatin to 40 mg per day. Beta blockers should be tapered and discontinued several days before clonidine withdrawal to reduce the risk of rebound hypertension. Spironolactone dosages should be limited to 25 mg daily when coadministered with potassium supplements. Avoid prescribing opioid cough medicines for patients receiving benzodiazepines or other central nervous system depressants, including alcohol. Physicians should consider consultation with a clinical pharmacist when clinical circumstances require the use of drugs with interaction potential.
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4.
Monitoring recommendations for oral azathioprine, methotrexate and cyclosporin in a paediatric dermatology clinic and literature review.
Yee, J, Orchard, D
The Australasian journal of dermatology. 2018;(1):31-40
Abstract
BACKGROUND/OBJECTIVES Systemic oral immunomodulators azathioprine, methotrexate and cyclosporin are widely used in paediatric dermatology. Routine blood tests are performed to minimise drug-related adverse events. However, the frequency of monitoring tests may lead to significant fearful experiences for patients. We reviewed haematological abnormalities and clinical side-effects in a paediatric clinic population commencing immunomodulators for dermatological conditions, where haematological profiles are monitored less frequently than in current recommendations. METHODS A retrospective chart review of children started on azathioprine, methotrexate or cyclosporin for a dermatological condition between 2001-2015 from a primarily paediatric, private dermatology practice was performed. Blood tests were done at baseline, 1 month, 2 months and then 3-monthly for children on azathioprine. Children on methotrexate and cyclosporin had tests done at baseline, after 1 month and then 3-monthly. RESULTS In total, 242 children were included in this study. Azathioprine, methotrexate and cyclosporin cohorts had 95, 97 and 50 patients treated for a mean duration of 656, 758 and 313 days, respectively. Isolated abnormal blood tests indicated the cessation of azathioprine in 3/95 (3%), methotrexate in 5/97 (5%) and cyclosporin in 2/50 (4%) of patients. Abnormal blood test results were not associated with any reported clinical side-effects in the azathioprine (P = 0.726), methotrexate (P = 0.06) or cyclosporin groups (P = 0.250). CONCLUSION In our experience, less frequent monitoring did not result in any significant adverse events over a 15-year period. We suggest that haematological monitoring during immunosuppressants use can be safely reduced from current recommendations.
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Use of (1→3)-β-d-glucan for diagnosis and management of invasive mycoses in HIV-infected patients.
Farhour, Z, Mehraj, V, Chen, J, Ramendra, R, Lu, H, Routy, JP
Mycoses. 2018;(10):718-722
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Abstract
People living with HIV (PLHIV) are highly vulnerable to invasive fungal infections (IFIs) due to their immune dysfunction. Diagnosis and treatment of IFIs remain challenging due to the requirement of deep tissue sampling to visualise and culture fungi before initiating treatment. Such techniques are less practical in resource-limited settings due to their cost and requirement of relatively invasive procedures. Hence, identification of surrogate markers for the early diagnosis and therapeutic monitoring of IFIs is required. Recent studies have shown that (1→3)-β-d-glucan (BDG), a major fungal cell wall antigen, represents a promising soluble marker for the presumptive diagnosis and therapeutic monitoring of IFIs in HIV-infected patients. Herein, we review findings on the merits of BDG assays in the diagnosis of IFIs and monitoring of antifungal therapies for PLHIV. Conversely to other types of immunocompromised patients, HIV infection is associated with gut damage and subsequent bacterial and fungal translocation leading to elevated BDG plasma levels.
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Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease.
Carman, N, Mack, DR, Benchimol, EI
Current gastroenterology reports. 2018;(5):18
Abstract
PURPOSE OF REVIEW Therapeutic drug monitoring (TDM) has emerged as a useful tool to optimize the use of drug therapies in adults with inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC), especially during the use of biological therapies, for which the pharmacokinetics and pharmacodynamics are highly variable among patients. Fewer data exist in children. This review examines the current literature on TDM in pediatric IBD. RECENT FINDINGS Drug clearance is affected by a number of patient and disease factors. For thiopurines, adjusting dosing by monitoring 6-thioguanine (6TGN) and 6-methylmercaptopurine ((6MMP) levels is demonstrated to maximize response and minimize toxicity, while monitoring metabolite levels when treating with anti-tumor necrosis factor (anti-TNF) remain controversial. While in adults the use of TDM in the setting of loss of response to anti-TNF therapy is established, in children, only a small number of studies exist, but these too have encouraging results. There are however, conflicting data regarding the optimal timing of TDM, comparing "reactive" monitoring and "proactive" monitoring. No such data exist in pediatrics. TDM is cost-effective, and dose reduction may represent a safety benefit. There are limited adult data for use of TDM for the newer biologics, vedolizumab and ustekinumab, but early results suggest similarly promising utility. The use of TDM in pediatric IBD is increasing in clinical practice, with similar efficacy to adults demonstrated in children with loss of response to anti-TNF therapy. More prospective studies are needed in children to examine proactive monitoring and utility of TDM with newer biologics.
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Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa.
Kishnani, PS, Rush, ET, Arundel, P, Bishop, N, Dahir, K, Fraser, W, Harmatz, P, Linglart, A, Munns, CF, Nunes, ME, et al
Molecular genetics and metabolism. 2017;(1-2):4-17
Abstract
Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment.
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[Use of vasopressors and inotropics in cardiogenic shock].
Lemm, H, Dietz, S, Janusch, M, Buerke, M
Herz. 2017;(1):3-10
Abstract
Vasoactive drugs and inotropic agents are important for the hemodynamic management of cardiogenic shock. In this article the use of different vasoactive and ionotropic drugs in cardiogenic shock is presented. Hemodynamic management during cardiogenic shock occurs after initial moderate volume delivery by dobutamine to increase inotropism. If adequate perfusion pressures are not achieved norepinephrine is administered. If a sufficient increase in cardiac performance can still not be achieved by the treatment, administration of levosimendan or phosphodiesterase (PDE) inhibitors may be necessary. Levosimendan is superior to PDE inhibitors for patients in cardiogenic shock. The aim of hemodynamic management in cardiogenic shock is to allow the transient use of inotropics and vasopressors in the lowest necessary dose and only as long as necessary. The daily question is whether the dose can be reduced or in the case of deterioration whether the use of an extracorporeal circulatory support system should be considered. There are currently no available data on mortality that demonstrate the benefit of hemodynamic monitoring using target criteria. The advantage, however, results from the economic use of inotropics and vasopressors by certain target criteria.
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Successful treatment of Aspergillus ventriculitis through voriconazole adaptive pharmacotherapy, immunomodulation, and therapeutic monitoring of cerebrospinal fluid (1→3)-β-D-glucan.
Chen, TK, Groncy, PK, Javahery, R, Chai, RY, Nagpala, P, Finkelman, M, Petraitiene, R, Walsh, TJ
Medical mycology. 2017;(1):109-117
Abstract
Aspergillus ventriculitis is an uncommon but often fatal form of invasive aspergillosis of the central nervous system (CNS). As little is known about the diagnosis, treatment, and outcome of this potentially lethal infection, we report the strategies used to successfully treat Aspergillus ventriculitis complicating a pineal and pituitary germinoma with emphasis on the critical role of adaptive pharmacotherapy of voriconazole and serial monitoring of (1→3)-β-D-glucan in cerebrospinal fluid. We describe several rationally based therapeutic modalities, including adaptive pharmacotherapy, combination therapy, sargramostim-based immunomodulation, and biomarker-based therapeutic monitoring of the CNS compartment. Through these strategies, our patient remains in remission from both his germinoma and Aspergillus ventriculitis making him one of the few survivors of Aspergillus ventriculitis.
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10.
Pharmacometabonomics Technique to Identify Warfarin Response Using Nuclear Magnetic Resonance Spectroscopy.
Bawadikji, AA, Teh, CH, Kader, MABSA, Sulaiman, SAS, Ibrahim, B
Current pharmaceutical biotechnology. 2017;(9):740-747
Abstract
BACKGROUND Warfarin, an anticoagulant medication, is prescribed regularly despite of its bleeding tendency for the prevention and/or treatment of various thromboembolic conditions, such as deep vein thrombosis, and complications associated with atrial fibrillation, and myocardial infarction, but because of its narrow therapeutic window, it has a lot of interactions with drugs and diet. METHODS Warfarin relies on regular monitoring of International Normalized Ratio which is a standardized test to measure prothrombin time and appropriate dose adjustment. Pharmacometabonomics is a novel scientific field which deals with identification and quantification of the metabolites present in the metabolome using spectroscopic techniques such as Nuclear Magnetic Resonance (NMR). Pharmacometabonomics helps to indicate perturbation in the levels of metabolites in the cells and tissues due to drug or ingestion of any substance. NMR is one of the most widely-used spectroscopic techniques in metabolomics because of its reproducibility and speed. RESULTS There are many factors that influence the metabolism of warfarin, making changes in drug dosage common, and clinical factors like drug-drug interactions, dietary interactions and age explain for the most part the variability in warfarin dosing. Some studies have showed that pharmacogenetic testing for warfarin dosing does not improve health outcomes, and around 26% of the variation in warfarin dose requirements remains unexplained yet. CONCLUSION Many recent pharmacometabonomics studies have been conducted to identify novel biomarkers of drug therapies such as paracetamol, aspirin and simvastatin. Thus, a technique such as NMR based pharmacometabonomics to find novel biomarkers in plasma and urine might be useful to predict warfarin outcome.