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Perioperative and anaesthetic care
Published in Tom Cecil, John Bunni, Akash Mehta, A Practical Guide to Peritoneal Malignancy, 2019
Nina Ashraf-Kashani, John Bell
Intra-operative euvolaemia is a specific intra-operative target. Low cardiac output and poor kidney perfusion increase the risk of AKI and should be avoided [28]. Goal-directed fluid therapy using cardiac output monitoring to target administration of fluid to specific circulatory parameters is associated with improved outcomes in CRS with HIPEC [14]. Amifostine is a cytoprotective agent that has been used in the prevention of toxicity caused by platinum-based chemotherapy agents [29]. It is an organic thiophosphate involved in free radical scavenging and promotion of DNA repair mechanisms [30]. There is some evidence to suggest a potential reduction in AKI following cisplatin HIPEC [31]; however, its administration is associated with a risk of profound hypotension. In the setting of major fluid shifts, the potential for haemorrhage and a systemic inflammatory response may not be tolerated by some patients. It is not used routinely in PMI Basingstoke. Administration of a single specific agent is unlikely to result in significant reductions in renal deterioration postoperatively without additional preventative and supportive measures. These form the mainstay of the approach to the prevention of renal injury during the perioperative period.
Stimulus-Secretion Coupling: Intracellular Proteins and Nucleotides
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
The phosphorylation and thiophosphorylation of saponin-permeabilized bovine chromaffin cells was examined by Brooks and Brooks (1987a). The rationale for using ATP-thiophosphate was that it could fix phosphorylation-dependent reactions in the thiophosphorylated state because the resultant thiophosphoproteins were resistant to the action of cell phosphatases. Thiophosphate is incorporated primarily into two cellular proteins, 54 kDa and 47 kDa. Calcium enhanced thiophosphorylation of the 47 kDa but not the 54 kDa protein. They found different electrophoretic banding patterns for thiophosphorylation and phosphorylation. This is likely due to the irreversibility of the thiophosphorylation reaction and the reversibility of the phosphorylation reaction. Brooks and Brooks (1987a) suggested that the inability to turn over thiophosphate groups in association with changes in secretion may permit identification of phosphoproteins that are putatively involved in secretion.
Three-Dimensional Structure of p21 and Its Implications
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
The fact that the overall structure of the G domain of GNB proteins is similar does not mean, however, that the details of the structure are similar too. Several studies dealing with the specificity of binding of thiophosphate analogs of GTP and GDP have appeared.74 They showed that all of the proteins investigated have a low affinity for GTPβS, which is not surprising on the basis of the three-dimensional structure results. There are characteristic differences in the affinities for the Rp and Sp isomers of GTPβS. This has, in fact, been used to selectively activate calcium signaling in mast cells without affecting another G protein, which mediates degranulation.75 Similar experiments have shown that the active site is somewhat different between transducin on one side and p21 and EF-Tu on the other.14 It has also been reported that Gα proteins can be induced by GDP together with AIF4 or BeF3 to adopt a GTP-like conformation.76,77 It is thought that A1F4- and BeF3 on those complexes occupy the terminal phosphate position. Similar experiments with EF-Tu and p21 show that these proteins behave differently.79 (F. Wittinghofer et al., unpublished observations).
Nanotechnology-enabled gene delivery for cancer and other genetic diseases
Published in Expert Opinion on Drug Delivery, 2023
Tong Jiang, Karina Marie Gonzalez, Leyla Estrella Cordova, Jianqin Lu
The human reticuloendothelial system, especially the liver and spleen, can identify and remove exogenous substances in the blood quickly [16]. At the same time, kidney filtration function presents a further challenge to the function of nucleic acid drugs in the blood [17]. Glomerular filtration typically removes molecules below 50 kDa and naked low molecular weight nucleic acids (about 10–30 kDa) are easily released by the kidney. Administered systematically, nucleic acid drugs accumulate in the kidneys with a fortyfold accumulation rate than other organs preferentially and then are excreted during 1 h by glomerulus and kidney tubules [18]. Kidney or liver toxicity may be induced as some patients presented with proteinuria and increased liver transaminase after the treatment of thiophosphate modified oligonucleotides therapy. These side effects also are influenced by dosage strength and can dissipate with dosage reduction or suspension [19].
Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mateusz Daśko, Sebastian Demkowicz, Karol Biernacki, Olga Ciupak, Witold Kozak, Maciej Masłyk, Janusz Rachon
Recently, Kozak et al. have synthesised new tricyclic coumarin derivatives containing phosphoric acid residues, dimethyl- and diethylphosphate groups as well as phosphoroamidates and phosphorodiamidates that were able to inhibit STS activity in the micromolar range78. The most active derivative 33 (Table 3) inhibited STS with the IC50 value of 21.5 µM in an enzymatic assay. Although the mechanism of inhibition is unknown, docking studies suggest the possibility of a phosphate group transfer to fGly75 during the inactivation process. Further development led to the synthesis of thiophosphate analogues with slightly improved inhibitory potencies79. The highest activity (in an assay with an isolated enzyme) was exhibited by compound 34 (Table 3), which contained a chlorothiophosphate group (IC50 value of 13.3 µM).
Effect of intraoperative dexmedetomidine on renal function after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a randomized, placebo-controlled trial
Published in International Journal of Hyperthermia, 2019
Young Song, Do-Hyeong Kim, Tae Dong Kwon, Dong Woo Han, Seung Hyuk Baik, Hwan Ho Jung, Ji Young Kim
Despite the fact that renal compromise is the major complication of CRS and HIPEC, few studies have suggested protective strategies. Amifostine, an organic thiophosphate prodrug, showed positive results in a phase I study nearly 2 decades ago, but there were no follow-up next-phase trials [33]. Sodium thiosulfate, a well-known cytoprotective adjuvant in chemotherapy or high-volume hydration combined with magnesium supplementation [34] has also been used empirically but never been tested in clinical trials on this surgery. Moreover, the protective mechanisms of these agents are mainly associated with cisplatin-induced nephrotoxicity. In contrast, dexmedetomidine has an experimental background and clinical experience upon the IR injury, inflammation and sympathetic excitation [17–25].