Αναζήτηση αυτού του ιστολογίου

Δευτέρα 19 Σεπτεμβρίου 2022

Anti‐SARS‐CoV‐2 Activity of Targeted Kinase Inhibitors: Repurposing Clinically Available Drugs for COVID‐19 Therapy

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Purpose

Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis.

Methods

We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 varian ts.

Results

Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment.

Conclusions

This work supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response.

This article is protected by copyright. All r ights reserved.
View on Web
στις Δεν υπάρχουν σχόλια:

14‐day famciclovir treatment significantly reduces the incidence of postherpetic neuralgia in elderly patients with herpes zoster

alexandrossfakianakis shared this article with you from Inoreader
14-day famciclovir treatment significantly reduces the incidence of postherpetic neuralgia in elderly patients with herpes zoster

(Left) For elderly patients with herpes zoster, the NRS in the 14-day FCV group was significantly lower than that of the 7-day FCV group on the 14th and 21st days after starting treatment. (Right) The incidence of PHN was 25.4% in the 7-day FCV group and 7.6% in the 14-day FCV group. With moderate or severe initial pain, the incidence of PHN was significantly lower in patients treated with 14-day FCV therapy than in those treated with 7-day FCV therapy.


Abstract

What is known and objective

Pain is the main symptom of herpes zoster (HZ), whilst postherpetic neuralgia (PHN) is a long-term unbearable pain, which seriously affects the quality of life of patients and is also the most intractable problem for clinicians. Early antiviral treatment is considered as a key measure to reduce acute pain and PHN. Nevertheless, most patients still have long-term pain after 7 days of antiviral treatment, and some patients will develop PHN. This study aimed to investigate whether prolonged duration of antiviral therapy could reduce HZ acute pain and the occurrence of PHN.

Methods

The outpatient data of HZ patients over 50 years old who visited the Dermatology Department from January 2016 to May 2018 were retrospectively analysed. According to the different courses of treatment of famciclovir (FCV), the patients were divided into 7-day FCV group and 14-day FCV group. The numerical rating scale (NRS) score at the first visit and on the 7th, 14th and 21st days after the start of treatment, the adverse drug reactions and the incidence of PHN were compared between the two groups.

Results

A total of 219 patients were involved in the analysis. For acute pain control, the 14-day FCV group was better than the 7-day FCV group. For patients with mild initial pain, there was no significant difference in NRS between the two treatments. For patients with moderate-to-severe initial pain, the NRS in the 14-day FCV group was significantly lower than that of the 7-day FCV group on the 14th and 21st days after starting treatment. PHN occurred in patients with moderate-to-severe initial pain, and the incidence was significantly lower in the 14-day FCV group than in the 7-day FCV group. There was no significant difference in the number of adverse reactions between the two groups.

What is new and conclusion

Compared with the traditional 7-day antiviral therapy, the 14-day course of FCV can reduce the acute pain and the incidence of PHN in elderly patients with HZ, especially in patients with moderate to severe initial pain. Prolonging the course of medication did not increase the side effects.
View on Web
στις Δεν υπάρχουν σχόλια:

EGFR, the Lazarus target for precision oncology in glioblastoma

alexandrossfakianakis shared this article with you from Inoreader
Abstract
The Lazarus effect is a rare condition that happens when someone seemingly dead shows signs of life. The epidermal growth factor receptor (EGFR) represents a target in the fatal neoplasm glioblastoma (GBM) that through a series of negative clinical trials has prompted a vocal subset of the neuro-oncology community to declare this target dead. However, an argument can be made that the core tenets of precision oncology were overlooked in the initial clinical enthusiasm over EGFR as a therapeutic target in GBM. Namely, the wrong drugs were tested on the wrong patients at the wrong time. Furthermore, new insights into the biology of EGFR in GBM vis-à-vis other EGFR-driven neoplasms, such as non-small cell lung cancer, and development of novel GBM-specific EGFR therapeutics resurrects this target for future studies. Here, we will examine the distinct EGFR biology in GBM, how it exacerbates the challenge of treating a CNS neoplasm, how these unique ch allenges have influenced past and present EGFR-targeted therapeutic design and clinical trials, and what adjustments are needed to therapeutically exploit EGFR in this devastating disease.
View on Web
στις Δεν υπάρχουν σχόλια:

Κυριακή 18 Σεπτεμβρίου 2022

The T‐shaped FST pharyngoplasty step‐by‐step closure technique

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Pharyngocutaneous fistula is one of the most common and serious complications associated with total laryngectomy. Numerous studies tried to evaluate causative and predisposing factors associated with this complication, but data are considerably variable and there is still no international consensus. Incidence rate varies considerably between studies, with reported rates from 3% to 65%. This 4K video presents our T-shaped four-step technique (FST) for closing the pharyngeal mucosa after total laryngectomy in a step-by-step manner. All sutures were performed by braided absorbable 3/0 26 mm 1/2c (Vicryl plus 3.0; Ethicon, Somerville, NJ, USA). Recordings were performed using a Karl Storz 4K 3D VITOM® exoscope (Karl Storz SE & Co. KG, Tuttlingen, Germany). We have been described this technique through a high-definition video, showing each step, and tips from the authors. Our T-shaped pharyngoplasty closure technique can be divided into four steps: 1. "Key Stitches"; 2. "A rea Refinement Stitches"; 3. "Modified Connell Suture"; 4. "Modified Purse String Suture." Our T-shaped FST closure technique proved to be an effective and reproducible method, which we feel could be the preferred choice for primary pharyngoplasty closure.
View on Web
στις Δεν υπάρχουν σχόλια:

Systemic conditions associated with increased risk to develop oral squamous cell carcinoma: Systematic review and meta‐analysis

alexandrossfakianakis shared this article with you from Inoreader

Abstract

This study aimed to map systemic alterations predisposing to oral squamous cell carcinoma (OSCC) onset. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Five databases were used to access (1) reports of OSCC co-occurring in patients with systemic conditions, (2) prevalence of OSCC among these patients, and (3) clinicopathological profiles. Data from more than 1 million patients worldwide showed that Fanconi's anemia, xeroderma pigmentosum, dyskeratosis congenital, chronic fatigue syndrome, and patients post bone marrow transplantation (BMT) present increased risk for OSCC development. The overall prevalence of OSCC in syndromic patients and post-BMT were 0.65% (95% CI = 0.13–3.11, p < 0.01) and 5.83% (95% CI = 0.00–30.90, p < 0.01), respectively. The certainty of the evidence was moderate. This study demonstrated that some systemic conditions predispose to OSCC. These results present an impact on the screening of OSCC in systemically compromised patients.
View on Web
στις Δεν υπάρχουν σχόλια:

Development of the remote 100 ml water swallow test versus clinical assessment in patients with head and neck cancer: Do they agree?

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

The 100 ml water swallow test (WST) is a validated swallow assessment used in head and neck cancer (HNC). We aimed to determine the level of agreement when completing the 100 ml WST via clinician-graded video-testing or patient self-testing compared to standard face-to-face assessment (FTF).

Methods

Convenience sampling from four UK centers. Inclusion criteria: patients with HNC treated with any modality prior to, or within 5 years of treatment. Participants were recruited to complete the 100 ml WST by video-testing or self-testing and compared with FTF.

Results

Sixty-three patients were recruited; 1 was unable to perform the task; 30 in video-testing; and 32 in self-testing. There was no difference in swallow capacity (p = 0.424) and volume (p = 0.363) for the video-testing or the self-testing swallow capacity (p = 0.777) and volume (p = 0.445).

Conclusions

This study demonstrates that video-testing and self-testing are reliable methods of completing the 100 ml WST for this sample of patients with HNC.
View on Web
στις Δεν υπάρχουν σχόλια:

Response assessment in pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively. Magnetic resonance imaging (MRI) is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by two-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response of solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated fu nctional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. Craniopharyngioma is a common pediatric CNS tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.
View on Web
στις Δεν υπάρχουν σχόλια:

Hyperkalaemia and potassium binders: Retrospective observational analysis looking at the efficacy and cost effectiveness of calcium polystyrene sulfonate and sodium zirconium cyclosilicate

alexandrossfakianakis shared this article with you from Inoreader
Hyperkalaemia and potassium binders: Retrospective observational analysis looking at the efficacy and cost effectiveness of calcium polystyrene sulfonate and sodium zirconium cyclosilicate

Both CPS and SZC are equally effective at lowering acutely raised potassium concentrations with a cost analysis that favours CPS. Any claims of benefits of newer agents over established medications need to be explored in randomized trials.


Abstract

What is Known and Objective

Hyperkalaemia is a common medical emergency in patients admitted to hospital. There is a limited evidence base supporting some of the commonly applied treatment strategies. Although, NICE has recommended the use of sodium zirconium cyclosilicate (SZC) (TA599) and patiromer (TA623) in both acute and chronic hyperkalaemia, there is a limited evidence base for their use in acute hyperkalaemia in the hospital setting, particularly when compared to the present standard of care calcium polystyrene sulfonate (CPS).

Methods

A retrospective review of the electronic patient record system across our hospital over a 6-month period identified 138 patients who received either SZC (65 patients) or CPS (73 patients) to manage hyperkalaemia, investigating their efficacy and cost effectiveness. Results were analysed using simple descriptive statistics. Based on the results a naïve cost comparison between the two drugs was made.

Results and Discussion

CPS and SZC both effectively reduced plasm potassium concentrations in patients with hyperkalaemia (6.07 and 6.03 mmol/L respectively) by 1.17 mmol/L and 1.24 mmol/L taking a similar amount of time to work (2.97 days vs. 3 days). The principle causes of hyperkalaemia identified were acute kidney injury, medication, and chronic kidney disease. Cost comparison analysis which took into account raw product price and time needed to dispense medications revealed that CPS has slightly better cost effectiveness compared to SZC albeit at a cost of increased staff input.

What is New and Conclusion

Both CPS and SZC were equally effective at lowering acutely raised potassium concentrations. The cost difference between the two products appears to be small. Claims regarding the benefits of newer agents over older established medications need to be properly explored in randomized trials rather than being based on small scale non-comparative studies.
View on Web
στις Δεν υπάρχουν σχόλια:

Risk Characteristics of Hydrogen Sulphide Exposure in Wastewater Collection and Treatment Related Occupations

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Objectives
Water and wastewater workers can be exposed to hydrogen sulphide (H2S), with an unpredictable exposure pattern, dominated by sharp peaks. These peaks can often be high above the ceiling value (CV) at 10 ppm.
Methods
We have analyzed self-administrated H2S exposure data among 60 wastewater workers in the Municipality of Trondheim, Norway, from 2015 till 2021. The detection range of the personal alarm equipment used was 1.6 to 100 ppm H2S. The workers were divided in four similar exposed groups (SEGs): wastewater collection net, wastewater treatment plants, wastewater pumping stations and water distribution net.
Results
We identified measurements from 7083 different workdays, approximately 10% of the workdays between 2015 and 2021. Within these, 1295 days had readings above 1.6 ppm H2S, and 424 (33%) of these days had readings that exceeded the CV of 10 ppm H2S. This percentage was similar across the SEGs. Only one workday had a time weighted average (TWA) exceeding the occupational exposure limit (OEL) of 5 ppm H2S, and only 14 days exceeded 0.5 ppm H2S, 1/10th of the OEL.
Conclusions
Wastewater workers in this study are regularly exposed to short peaks of H2S, but even high peaks do not influence the 8-h TWA values significantly. A preliminary measurement program over 3 days according to EN 689 to evaluate the need for further measurements would probably not find TWA values greater than 1/10 of OEL; the EN 689 standard is not made for evaluation to peak exposures. Exceedances of CV at 10 ppm H2S occur in 6% of workdays, and in 33% of days with exposure above 1.6 ppm. The toxicity and exposure profile of H2S makes continuous exposure monitoring necessary for alarm purposes. Reliance on the 8-h occupational exposure limit as has been the normal in Norway, will not be ade quately protective for wastewater workers. H2S alarm equipment should continue to be used.
View on Web
στις Δεν υπάρχουν σχόλια:

Extracapsular dissection with a transparotid facial nerve dissection approach versus partial superficial parotidectomy for benign tumours in the tail of the parotid gland: a single-centre retrospective study of 89 patients

alexandrossfakianakis shared this article with you from Inoreader
The aims of this study were (1) to evaluate the transparotid facial nerve dissection approach (TFND), in which the intraparotid cervicofacial or temporofacial division is identified first through a superficial lobe incision; and (2) to compare extracapsular dissection with a TFND (ECD-TFND) with partial superficial parotidectomy with a retrograde approach (PSP) for benign tumours in the tail of the parotid gland with respect to surgical outcomes. Eighty-nine patients underwent PSP or ECD-TFND for benign tumours in the tail of the parotid gland: 49 were treated surgically with PSP and 40 with ECD-TFND. (Source: International Journal of Oral and Maxillofacial Surgery)
View on Web
στις Δεν υπάρχουν σχόλια:
Εγγραφή σε: Αναρτήσεις (Atom)