scholarly journals Methotrexate Toxicity: Molecular Mechanisms and Management

Author(s):  
Riyadh S. Almalki ◽  
Hala Eweis ◽  
Fatemah Kamal ◽  
Dina Kutbi

Methotrexate (MTX) is the most widely used drug in cancer chemotherapy and is considered to be the first-line drug for the treatment of a number of rheumatic and non-rheumatic disorders. The pulmonary toxicity, hepatotoxicity of MTX are two of its major side effects. Other toxicities such as endocrinological toxicity, GI toxicity, cutaneous toxicity, hematological toxicity, fatal malfunction or loss, and malignancy can also occur, but at a significantly lower rate of prevalence. This review aims to provide a comprehensive understanding of the molecular mechanisms of methotrexate toxic effects and Lastly, we discussed the management of this toxicity.

2019 ◽  
Vol 20 (20) ◽  
pp. 5023 ◽  
Author(s):  
Yosra Bedoui ◽  
Xavier Guillot ◽  
Jimmy Sélambarom ◽  
Pascale Guiraud ◽  
Claude Giry ◽  
...  

Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses—including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus—have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients’ immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.


2018 ◽  
Vol 9 (2) ◽  
pp. 128-135 ◽  
Author(s):  
Rashmi Kumari ◽  
Bhawesh Chandra Saha ◽  
Bibhuti Prasanna Sinha ◽  
Nilesh Mohan

Introduction: The aim of the study was to evaluate and compare the efficacy, side effects and recurrence rate of vernal kerato conjunctivitis (VKC) with 0.03% tacrolimus and 0.05% cyclosporin.Material and method: A prospective randomised double blinded comparative study was conducted at a tertiary eye center. 46 Patients of VKC between March 2015- August 2015 were randomly divided into two groups and treated for 6weeks with either Tacrolimus(0.03%) eye ointment BD or Cyclosporine (0.05%) eyedrops QID.The main outcome measures were scoring and comparison of Total subjective symptom scores (TSSS) and Total objective ocular sign scores (TOSS) within and between the Groups at each follow up.Thirty two patients, sixteen from each group, with comparable baseline characters were analysed.Results: With treatment both TSSS and TOSS decreased consistently in both groups without any adverse effects but an increase in scores was noticed within two weeks after drug withdrawal.Conclusion: Both drugs are equally effective and safe in VKC but with short lasting effect.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4786-4786
Author(s):  
Joseph Feliciano ◽  
Kerstin Mueller ◽  
Ellen E Korol ◽  
Zhouqin He ◽  
Niloufer Khan ◽  
...  

Abstract Introduction: The standard of care for previously untreated classical Hodgkin lymphoma (HL) in the United States has been combination chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or with radiotherapy depending on clinical characteristics. Other treatment programs exist, including intensified chemotherapy regimens, and substitution of brentuximab vedotin for bleomycin recently received FDA approval as first-line therapy for advance stage HL. The objective of this study was to understand how specific treatment attributes impact preferences among patients and physicians for choice of first-line treatment of HL. Methods: An online survey including a discrete choice experiment (DCE) was administered both to oncologists who manage patients with HL and to patients diagnosed within HL within the last two years in the United States. Participants were identified via online research panels. The attributes and levels of the hypothetical treatments presented in the DCE were informed by targeted literature review and physician and patient interviews. For physicians, six attributes were included: two-year overall survival (OS); two-year progression free survival (PFS); risk of side effects requiring hospitalization; risk of peripheral neuropathy (PN); risk of pulmonary toxicity; and patient out-of-pocket cost. The patient DCE included four attributes: OS, PFS, risk of PN and risk of pulmonary toxicity. DCE scenarios were developed using a d-efficient design. Participants reviewed 10 scenarios, and selected their preference between two hypothetical treatments. Patients considered themselves when selecting their preference; physicians considered four different advanced HL patient profiles that differed in age (30 or 65 years), smoking status, and the presence of baseline PN. The DCE data were analyzed using a mixed logit model (MXL). The relative importance of each attribute was calculated by determining the differences between the maximum and minimum coefficients of each attribute. These were then normalized and presented as percentages. Results: A total of 200 physicians and 141 patients were included in the analysis. Physicians had a mean of 15 years' experience and 71% practiced in a community setting. Patients had a median age of 35 years (range 19 to 69), 60% were male, and 34% were diagnosed with advanced stage HL. In the DCE, the most important attributes to both patients and physicians were OS and PFS. Based on the coefficients from the MXL model, a 1% increase in OS was more important to both groups than a 1% increase in PFS. The coefficients and level ranges for each attribute were used to calculate preference weights (see methods). Based on preference weights, PFS was the most important attribute for patients, followed by OS, risk of pulmonary toxicity, and risk of PN (Table 1). Compared to male patients, there was a trend for female patients to have a lower preference for a 1% decrease in risk of progression (p=0.077). Patients above the median age of 35 years had a significant preference (p=0.048) for a lower risk of pulmonary toxicity, and a trend for a higher preference for a 1% increase in OS (p=0.059) was observed. OS was also marginally more important to patients diagnosed with advanced stage HL versus those diagnosed in earlier stages. For physicians, preferences for treatment attributes differed based on the patient profile presented. PFS outweighed OS for a healthy 35 year-old patient (Table 2), whereas OS had a higher relative preference weight for a 35 year old smoker and older patients. For smokers, physicians ranked pulmonary toxicity as the most important attribute. Among older patients, side effects requiring hospitalization were more important to physicians' preferences than both OS and PFS. There were no major differences in preferences between academic and community oncologists. Conclusion: Patients are willing to accept treatments with worse short and long-term side effects in exchange for improved OS or PFS. Physicians' treatment preferences are patient-specific, with age and comorbidities impacting both the relative weight of OS and PFS attributes and the importance of pulmonary toxicity and short-term side effects. These results underscore the importance of assessing and sharing patient and physician preferences in creating a treatment plan for the management of newly diagnosed Hodgkin lymphoma. Disclosures Feliciano: Seattle Genetics: Employment, Equity Ownership. Mueller:ICON plc: Employment. Korol:ICON plc: Employment. He:ICON plc: Employment. Matasar:Seattle Genetics: Honoraria.


2018 ◽  
Vol 17 (04) ◽  
pp. 488-491 ◽  
Author(s):  
Kyoko Osawa ◽  
Satoshi Ukai ◽  
Toshiyuki Kuriyama

AbstractObjectiveControlling hyperactive and mixed delirium is extremely important for the continuation of cancer treatment in palliative care. In general, oral antipsychotics are the first-line drug therapy for delirium; however, oral administration is problematic in patients presenting dysphagia. In this case report, we describe an end-stage cancer patient with aphagia who developed delirium and responded to sublingual antipsychotic asenapine for treating delirium. We also discuss the effectiveness of asenapine in hyperactive delirium as well as its usefulness for treating delirium in palliative care.MethodA cancer patient with delirium was treated with several oral antipsychotics commonly used to treat delirium but did not respond to any of them. The patient subsequently developed aphagia with progression of the disease. Sublingual asenapine was therefore given to treat delirium.ResultAsenapine was effective in treating delirium without causing any obvious side effects.Significance of resultsIn the present case, asenapine was effective in treating hyperactive delirium that did not respond to commonly used antipsychotics. Because asenapine is a sublingual tablet, it can be used in patients with dysphagia and aphagia. In addition, this drug is anticipated to diminish the burden of end-stage patients from taking oral medications. Furthermore, its management is easier compared with injections, and can therefore also be easily used in homecare patients. Based on these perspectives, asenapine may become an important option for treating delirium in palliative care.


BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S69-S70
Author(s):  
Fabrizia Cassar ◽  
Giovanni Grech ◽  
Bertha Grech ◽  
Joseph Cassar

AimsAttention Deficit Hyperactivity Disorder (ADHD) is a behavior disorder originating in childhood comprising of a constellation of features including inattention, impulsivity, and hyperactivity. The National Institute of Clinical Excellence (NICE) Guidelines 2018 recommends methylphenidate as a first line pharmacological agent for treatment of children aged 5 years and over with ADHD. Lisdexamfetamine, dexamfetamine and atomoxetine are recommended in this order if methylphenidate is not tolerated or if symptoms did not respond to separate 6-week trials. Our aim was to, assess the transition of methylphenidate to atomoxetine, the reasons for switching and its clinical outcome in order to make recommendations to current practice regarding treatment of ADHD.MethodThe study examined a total of 53 children between 0-16 years of age who were being treated for ADHD with atomoxetine at CYPS till September 2018. Data was collected from patients’ files retrospectively by using a proforma based on the NICE guidelines 2018 ADHD: diagnosis and management.ResultOut of 53 patients’ on atomoxetine in September 2018, 49 were included in the study. Results recorded side-effects as the main reason for switching from methylphenidate to atomoxetine. Unwanted side-effects were documented in 71.7% of patients of which 57.9% exhibited more than 1 side-effect with the two commonest side-effects documented being weight loss and decreased appetite. The audit highlighted the fact that the correct dose of atomoxetine was only administered in 17.2% of children with 56.9% of patient's being given a higher dose than recommended. Initial weight was not documented in 19% and hence, ideal dose could not be calculated. Overall, atomoxetine was shown to be an effective treatment. Out of the 40 patients documented to have hyperactivity this symptom was decreased in 82.5% whilst 82.9% were shown to have increased concentration. 35 patients had documented impulsivity and this was decreased in 62.9% of cases. 11 patients had documented anxiety with 72.7% being treated effectively with atomoxetine. 31% of patients’ had documented side-effects with 16% of these being tics. 20% of patient's required augmentation.ConclusionThe results indicate that the majority of doctors at CYPS in Malta adhered to the NICE guidelines 2018 and atomoxetine was proven to be efficacious as a second line drug in the treatment of ADHD. However, better adherence to NICE guidelines is required when it comes to the calculation of appropriate dosage. Our prediction is had dose recommendations according to weight been adhered to there may have been less side-effects documented.


2020 ◽  
Vol 13 ◽  
Author(s):  
Sajad Fakhri ◽  
Jayanta Kumar Patra ◽  
Swagat Kumar Das ◽  
Gitishree Das ◽  
Mohammad Bagher Majnooni ◽  
...  

Background: As a major cause of morbidity and mortality, cardiovascular diseases (CVDs) are globally increasing. In spite of recent development in the management of cardiovascular complications, CVDs have remained a medical challenge. Numerous conventional drugs are used to play cardioprotective roles; however, they are associated with several side effects. Considering the rich phytochemistry and fewer side effects of herbal medicines, they have gained particular attention to develop novel herbal drugs with cardioprotective potentials. Amongst natural entities, ginger is an extensively used and well-known functional food and condiment, possessing plentiful bioactivities, like antiinflammatory, antioxidant, and antimicrobial properties in several disorders management. Objective: The current review deliberated phytochemical properties as well as the ginger/ginger constituents' biological activities and health benefits in several diseases, with particular attention to cardiovascular complications. Methods: A comprehensive research was conducted using multiple databases, including Scopus, PubMed, Medline, Web of Science, national database (Irandoc and SID), and related articles in terms of the health benefits and cardioprotective effects of ginger/ginger constituents. These data were collected from inception until August 2019. Results: In recent years, several herbal medicines were used to develop new drugs with more potency and also minor side effects. Amongst natural entities, ginger is an extensively used traditional medicine in several diseases. The crude extract, along with related pungent active constituents, is mostly attributed to heart health. The cardioprotective effects of ginger are contributed to its cardiotonic, antihypertensive, anti-hyperlipidemia, and anti-platelet effects. The signaling pathways and molecular mechanisms of ginger regarding its cardioprotective effects are also clarified. Conclusion: This study revealed the biological activities, health benefits, and cardioprotective properties of ginger/ginger constituents along with related mechanisms of action, which gave new insights to show new avenue in the treatment of CVDs.


2021 ◽  
pp. 1942602X2110219
Author(s):  
Theresa A. Bingemann ◽  
Anil Nanda ◽  
Anne F. Russell

Anaphylaxis is a rapidly occurring allergic reaction that is potentially life threatening. Recognition of the early signs and prompt treatment of anaphylaxis is critical. School nurses are tasked with educating nonmedical school personnel on the recognition and treatment of anaphylaxis and emphasizing that epinephrine is the first line of treatment for anaphylaxis. Fortunately, there is now availability of multiple epinephrine administration devices. However, this also means that there are more devices that school nurses and nonmedical assistive personnel need to learn about to be able to administer in an emergency. Once epinephrine is administered, emergency medical services must be activated. Education regarding what to expect after the administration of epinephrine with respect to side effects and onset of action is also necessary. Though adjunctive medicines, such as antihistamines and inhalers, may also be administered after the injection of epinephrine, they should not be solely relied on in anaphylaxis. School nurses are uniquely situated for this role, as they understand the local environment in a school and can assess and reassess the needs of the faculty and staff.


2021 ◽  
Vol 14 (4) ◽  
pp. 361
Author(s):  
Sarentha Chetty ◽  
Tom Armstrong ◽  
Shalu Sharma Kharkwal ◽  
William C. Drewe ◽  
Cristina I. De Matteis ◽  
...  

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring activation by the enzyme KatG. Mutations in KatG have largely contributed to clinical isoniazid resistance. We aimed to design new ‘direct’ InhA inhibitors that obviate the need for activation by KatG, circumventing pre-existing resistance. In silico molecular modelling was used as part of a rational structure-based drug-design approach involving inspection of protein crystal structures of InhA:inhibitor complexes, including the broad spectrum antibiotic triclosan (TCS). One crystal structure exhibited the unusual presence of two triclosan molecules within the Mycobacterium tuberculosis InhA binding site. This became the basis of a strategy for the synthesis of novel inhibitors. A series of new, flexible ligands were designed and synthesised, expanding on the triclosan structure. Low Minimum Inhibitory Concentrations (MICs) were obtained for benzylphenyl compounds (12, 43 and 44) and di-triclosan derivative (39), against Mycobacterium bovis BCG although these may also be inhibiting other enzymes. The ether linked di-triclosan derivative (38) displayed excellent in vitro isolated enzyme inhibition results comparable with triclosan, but at a higher MIC (125 µg mL−1). These compounds offer good opportunities as leads for further optimisation.


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