Standardized Solutions of Catecholamines in Intensive Care Medicine: Application, Safety and Economic Aspects.

Background/Objectives: Catecholamines are among those agents that are indispensable in modern intensive care medicine. The rapid availability of hygienically impeccable and correctly concentrated injectable solutions, e.g., for syringe pumps, is becoming more and more important. However, little research has been conducted regarding how the use of catecholamines is distributed in different wards and what options can be used to achieve optimal availability. Methods: In a retrospective monocentric study from 2019 to 2022, all continuously applied catecholamines in intensive care units (ICU) and intermediate care units (IMC) were investigated. The focus was on potential optimization by utilizing manufactured ready-to-administer solutions in the context of the economization of patient care. Results: Norepinephrine syringes represented 81% of all syringes administered, appearing to be the most frequently used on all wards. Production by the in-house pharmacy showed both financial advantages and an increase in patient safety compared to syringes produced at the bedside. Discussion: Increasing numbers of critically ill patients coupled with growing staff shortages and an increased awareness of safety requirements are driving the move towards ready-to-use and ready-to-administer solutions in critical care medicine. In-house manufacturing by hospital pharmacies can be a promising option to optimize processes and improve the economics of patient care. Conclusions: Individual calculations of the required catecholamine preparations with regard to possible economic advantages should be carried out in hospitals. In particular, in-house production of ready-to-use and ready-to-administer preparations could significantly increase patient safety and seems to be economically viable.

In-use stability of diluted thiamazole (methimazole) infusion solutions in prefilled 0.9% sodium chloride infusion bags for continuous infusion.

OBJECTIVE: In patients with severe hyperthyroidism unable to tolerate oral antithyroid therapy, diluted thiamazole infusion solutions (dose 120-240 mg) are administered by continuous infusion over 24 hours. Information about the type of diluent and compatibility/stability of the ready-to-administer thiamazole preparation is missing in the summary of product characteristics of the injection concentrate marketed in Germany. We studied the in-use stability of diluted infusion solutions over 24 hours. METHODS: Thiamazol 40 mg inject. Henning was diluted in prefilled polyolefin infusion bags containing 250 mL 0.9% sodium chloride (NaCl) infusion solution and kept for 24 hours at room temperature and diffuse room light. Content of the diluted infusion solutions (0.48 and 0.96 mg/mL) was analysed every 4 hours over the course of 24 hours by reversed-phase high-performance liquid chromatography. pH was measured after 0, 12 and 24 hours. The infusion bags were regularly inspected for visible particles. Subvisible particles were measured by particle counting. RESULTS: Thiamazole infusion solutions of the nominal concentrations 0.48 and 0.96 mg/mL in 0.9% NaCl diluent, kept at room temperature under diffuse room light, are physicochemically stable over a period of at least 24 hours. No evidence of colour change, particle formation or pH change was observed throughout the observation period. CONCLUSION: Dilution of 120 or 240 mg doses of licensed thiamazole injection concentrate with 0.9% NaCl infusion solution in prefilled polyolefin containers is recommendable for continuous infusion over 24 hours in the treatment of thyrotoxicosis.

The role of p53 in cancer drug resistance and targeted chemotherapy.

Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53's regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as α-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.