Abstract Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary therapeutic activity profile of CHR-2797 (tosedostat), a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases with antiproliferative and antiangiogenic activity in vitro. Experimental Design: A phase I study of accelerated titration design that escalated through nine doses (10-320 mg) in patients (Eastern Cooperative Oncology Group performance status, ≤2) with advanced solid tumors. CHR-2797 was administered once daily. Results: Forty patients (median age, 60 years; range, 24-80 years; male, 27; female, 13) were treated in 12 cohorts with once daily doses (10-320 mg). Dose-limiting toxicities were thrombocytopenia, dizziness, and visual abnormalities in one patient, and anemia, blurred vision, and vomiting in a second patient at 320 mg, resulting in an inability to complete 28 days of study drug. The most commonly observed toxicities were fatigue, diarrhea, peripheral edema, nausea, dizziness, and constipation. One patient had a partial response (renal cell carcinoma) and four patients had stable disease for >6 months. CHR-2797 and its active metabolite, CHR-79888, show dose-proportional increases in plasma AUC and Cmax. The terminal half-life for CHR-2797 is ∼1 to 3.5 hours and between 6 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to CHR-79888 is consistent with intracellular levels that proved to be efficacious in xenograft models. Conclusion: CHR-2797 is well tolerated and can be safely administered at doses that result in intracellular levels of CHR-79888 that are associated with activity in preclinical models. The recommended dose for single agent therapy in solid tumors is 240 mg/d.
Summary Objective TSH receptor antibodies (TRAb) are responsible for autoimmune hyperthyroid disease (Graves’ disease; GD) with TRAb levels tending to decrease following treatment. Measurement of TRAb activity during follow‐up could prove valuable to better understand treatment effectiveness. Study design TRAb concentration and stimulating (TSAb) and blocking (TSBAb) activity of patient serum were assessed following different treatment modalities and follow‐up length. Methods Sixty‐six subjects were recruited following treatment with carbimazole (n = 26), radioiodine (n = 27) or surgery (n = 13). TRAb, TPOAb, TgAb and GADAb were measured at a follow‐up visit as well as bioassays of TSAb and TSBAb activity. Results Forty‐five per cent of all patients remained TRAb‐positive for more than one year and 23% for more than 5 years after diagnosis, irrespective of treatment method. Overall, TRAb concentration fell from a median (IQR) of 6.25 (3.9‐12.7) to 0.65 (0.38‐3.2) U/L. Surgery conferred the largest fall in TRAb concentration from 11.4 (6.7‐29) to 0.58 (0.4‐1.4) U/L. Seventy per cent of TRAb‐positive patients were positive for TSAb, and one patient (3%) was positive for TSBAb. TRAb and TSAb correlated well ( r = 0.83). In addition, 38/66 patients were TgAb‐positive, 47/66 were TPOAb‐positive and 6/66 were GADAb‐positive at follow‐up. Conclusions TRAb levels generally decreased after treatment but persisted for over 5 years in some patients. TRAb activity was predominantly stimulatory, with only one patient demonstrating TSBAb. A large proportion of patients were TgAb/TPOAb‐positive at follow‐up. All treatment modalities reduced TRAb concentrations; however, surgery was most effective.
Over the past 30 years, many researchers have demonstrated the critical role of zinc (Zn), a group IIb metal, in diverse physiological processes, such as growth and development, maintenance and priming of the immune system, and tissue repair. This review will discuss aspects of Zn physiology and its possible beneficial role in the respiratory epithelium. Here we have detailed the mechanisms by which Zn diversely acts as: (i) an anti‐oxidant; (ii) an organelle stabilizer; (iii) an anti‐apopototic agent; (iv) an important cofactor for DNA synthesis; (v) a vital component for wound healing; and (vi) an anti‐inflammatory agent. This paper will also review studies from the authors’ laboratory concerning the first attempts to map Zn in the respiratory epithelium and to elucidate its role in regulating caspase‐3 activated apoptosis. We propose that Zn, being a major dietary anti‐oxidant has a protective role for the airway epithelium against oxyradicals and other noxious agents. Zn may therefore have important implications for asthma and other inflammatory diseases where the physical barrier is vulnerable and compromised.
Angiogenesis, a process that enables the growth of blood vessels from a pre-existing vasculature and is common to all solid tumours greater than 1 mm3 in size (Gacche and Meshram, 2014). The angiogenic process is heavily promoted by vascular endothelial growth factor (VEGF). Compounds able to inhibit VEGF signalling have been shown to reduce cancer mass (Arjaans et al., 2016). However, VEGF receptor tyrosine kinase inhibitors (RTKIs), a class of anti-VEGF treatment, have been shown to cause cardio-toxicity, with hypertension being a commonly reported, and often severe, side effect (Eskens and Verweij, 2006; Widakowich et al., 2007; Abi Aad et al., 2015). Depending on the nature of the study, the incidence of hypertension in the VEGF RTKI patient population ranges from 23% to 90% (Hamberg et al., 2010; La Vine et al., 2010; Aparicio-Gallego et al., 2011; Bible et al., 2014). Due to the increasing incidence and seriousness of hypertension observed in oncology clinics, it is clear that there are important cardiovascular issues relating to the use of RTKIs, particularly those that target VEGF, that require further exploration. This body of work set out to determine the in vitro potencies of vandetanib, pazopanib, cediranib and sorafenib at VEGFR2, alongside the in vivo cardiovascular haemodynamic and vasoactive profile of vandetanib and pazopanib, two VEGF RTKIs shown to cause hypertension in approximately 32% (Wells et al., 2012) and 33%-40% of the patient population, respectively (Bible et al., 2014).
In NFAT luciferase assays cediranib, sorafenib, pazopanib and vandetanib were shown to inhibit, in a non-competitive fashion, VEGF165 mediated signalling in vitro. In haemodynamic studies, using Doppler flowmetry and telemetry methodologies, both vandetanib and pazopanib caused significant hypertension (P<0.05, in comparision to vehicle). Pazopanib and vandetanib lead to significant vasoconstriction of the mesenteric and hindquarter vascular beds, pazopanib also produced significant vasoconstriction in the renal vascular bed (P<0.05, in comparision to vehicle). None of the variables measured in the haemodynamic studies significantly differed between the 30 mgkg-1day-1 pazopanib and 25 mgkg-1day-1 vandetanib groups. In chronic radio-telemetric studies, vandetanib was shown to cause a significantly greater but more transient increase in mean arterial blood pressure in comparison to pazopanib (P<0.05). Vandetanib was also shown to inhibit VEGF and ACh-mediated vessel dilatation in pressure myography experiments. Finally, vandetanib and pazopanib were shown to induce vasodilatation in the presence of a vasoconstrictor (U46619), a previously unseen finding.
In conclusion, the body of work undertaken here has given novel insight into the ability of non-competative anti-VEGF RTKIs to inhibit VEGF-mediated signalling and vessel dilatation as well as produce direct effect of vessel diameter in the absence of VEGF. It has also produced a validated method of hypertension in a rat model, both in the short and long term. These models have shown that different anti-VEGF RTKIs have different regional haemodynamic and post-treatment hypertensive side effect profiles. These findings are important for understanding the mechanisms behind the therapeutic and non-therapeutic effects of VEGF RTKIs and allow for further research into the signalling mechanism involved in VEGF RKTI-mediated hypertension and the potential therapeutic treatments that could treat this.
The widespread use of medical alarms in clinical in-patient facilities and also their frequent activation disrupts patient care and raises concerns about their effectiveness. Nursing students typically encounter these alarms primarily during clinical trainings or hospital internships, making it essential to learn how to respond to them early and effectively in nursing school, despite the stress it may cause during clinical and academic experiences. Educating nursing students about medical alarms not only enhances their understanding but also improves their ability to use these devices in the clinical settings, thereby positively impacting patient safety and care. To achieve this, forty-one nursing students were initially recruited, with thirty-one participants ultimately enrolled (response rate 75.6%). The analysis of nursing student's behaviors regarding client care revealed high scores in the subscales "Being Mindful of Client's Breathing Behaviors" (M = 4.60), "Being Sensitive to Client's Safety Behaviors" (M = 4.50), and "Ensuring Client's Hygiene and Skin Integrity Behaviors" (M = 4.62). Particularly notable scores were observed in providing guidance and support for breathing comfort (Q2, M = 4.71), prioritizing response to clinical alarms (Q5, M = 4.61), and assessing hygiene and skin integrity (Q10, M = 4.68). Although the questionnaire demonstrated acceptable reliability in both groups, with α = .65 for the intervention group and α = .68 for the control group, two items had lower reliability coefficients (≤ .59), specifically related to providing guidance and support for client breathing comfort and creating a supportive environment for client breathing focus. These results suggest inconsistencies in caring behaviors among nursing students. Regarding the recognition of medical alarms, eighty percent of thirty-one participants scored 90% and above on Audio Quiz 1, while ninety-six percent scored 95% and above on Audio Quiz 2. Furthermore, 97.5% of thirty-one participants achieved a perfect score of 100% on Audio Quiz 3, indicating the effectiveness of clinical alarms education in enhancing their perception of clinical alarms. The insights from this research may contribute to the need for medical alarms education in nursing school, offering consideration for patients and the healthcare team. Keywords: alarm fatigue, alarm management, nursing education, nursing need theory, behavior change, patient safety, nursing student, perception, medical alarm DOI : 10.7176/JHMN/116-02 Publication date: May 30th 2024
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