ABSTRACT
BACKGROUND: Icodextrin (IDX) is an antiadhesive polymer that can be used as a carrier solution for intraperitoneal (IP) delivery of chemotherapeutic drugs. METHODS: We investigated the suitability of IDX solution as a carrier of Cisplatin and Doxorubicin for delivery as pressurized intraperitoneal aerosol chemotherapy (PIPAC). We examined the sprayability of IDX, the aerosol characteristics, the stability of the molecule after aerosolization, the effects of IDX on the adhesion of MKN45 human gastric cancer cells, the synergistic effect of aerosolized IDX with Cisplatin and Doxorubicin, and the chemical stability of IDX, Cisplatin, and Doxorubicin in combination. RESULTS: Delivery of IDX as PIPAC is feasible with no particular restrictions. The median droplet size of 35.7 µm did not change at increasing concentrations. IDX withstood the shear forces applied by the nebulizer and remained stable after aerosolization (ANOVA, p = 0.97). IDX did not impair the cytotoxic effects of Cisplatin and Doxorubicin (ns). IDX had a significant antiadhesive impact alone (p < 0.03) and in combination with Cisplatin and Doxorubicin (p < 0.02). IDX as a carrier for Cisplatin and Doxorubicin remained stable at 4 °C for three months and did not cause degradation of those two substances. CONCLUSION: The proposed combination takes advantage of the antiadhesive properties of IDX, the cytotoxic effect of Cisplatin and Doxorubicin, and an advanced drug delivery system.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cell Adhesion/drug effects , Cell Proliferation/drug effects , Dialysis Solutions/administration & dosage , Icodextrin/administration & dosage , Aerosols , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Line, Tumor , Cisplatin/administration & dosage , Cisplatin/chemistry , Dialysis Solutions/chemistry , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Drug Stability , Humans , Icodextrin/chemistry , Icodextrin/pharmacology , Peritoneum , PressureABSTRACT
PURPOSE: To investigate the amount of pyridine generated from degradation of ceftazidime in icodextrin peritoneal dialysis (PD) solutions. METHODS: PD solutions that contained 1 and 1.5 g of ceftazidime were stored at 25 °C for 12 hours and then at 37 °C for 14 hours. An aliquot was withdrawn at predefined time points and analyzed for the concentrations of ceftazidime and pyridine. FINDINGS: The amount of pyridine generated was >225% and 400% of its maximum recommended daily exposure in the 1- and 1.5-g ceftazidime-PD admixtures, respectively. IMPLICATIONS: Until these results are confirmed with appropriate in vivo studies, intermittent intraperitoneal dosing of ceftazidime admixed with icodextrin should be used with caution and appropriate clinical monitoring or a suitable alternative antibiotic should be used.
Subject(s)
Anti-Bacterial Agents/chemistry , Ceftazidime/chemistry , Dialysis Solutions/chemistry , Icodextrin/chemistry , Pyridines/chemistry , Drug Combinations , Drug Stability , Peritoneal Dialysis/adverse effects , Peritonitis/drug therapy , Peritonitis/etiologyABSTRACT
The authors report the first case of successful peritoneal dialysis (PD) in a developing country performed about a 13-year-old adolescent followed-up for stage V chronic kidney disease (CKD) with anuria. After 3 months of hemodialysis, the parents opted for continuous ambulatory peritoneal dialysis (CAPD) as they wished to return home located 121km from Dakar. After PD catheter insertion, the plan proposed to the patient consisted 3-4 hours stasis of isotonic dialysate during the day and a night stasis of 8 hours of icodextrin for an injection volume of 1L per session. The patient and his mother were trained and assessed on the PD technique. After dialysis adequacy was tested while hospitalised, they were able to return home and continued the sessions following the same plan prescribed and while keeping in touch, by telephone, with the medical team. The technique assessment at the day hospital every 2 weeks revealed dialysis adequacy and satisfactory tolerance of PD at home after 04 months of observation. It was the first case of successful CAPD in the pediatrics unit in this context. Scaling this technique is a challenge for the pediatric nephrologist in developing countries like Senegal.
Subject(s)
Hemodialysis, Home/methods , Peritoneal Dialysis, Continuous Ambulatory/methods , Renal Insufficiency, Chronic/therapy , Adolescent , Developing Countries , Dialysis Solutions/chemistry , Humans , Icodextrin/chemistry , Male , Renal Dialysis , SenegalABSTRACT
Autotaxin is an extracellular phospholipase D that catalyzes the hydrolysis of lysophosphatidyl choline (LPC) to generate the bioactive lipid lysophosphatidic acid (LPA). Autotaxin has been implicated in many pathological processes relevant to cancer. Intraperitoneal administration of an autotaxin inhibitor may benefit patients with ovarian cancer; however, low molecular mass compounds are known to be rapidly cleared from the peritoneal cavity. Icodextrin is a polymer that is already in clinical use because it is slowly eliminated from the peritoneal cavity. Herein we report conjugation of the autotaxin inhibitor HA155 to icodextrin. The conjugate inhibits autotaxin activity (IC50 = 0.86 ± 0.13 µg mL-1) and reduces cell migration. Conjugation of the inhibitor increased its solubility, decreased its membrane permeability, and improved its intraperitoneal retention in mice. These observations demonstrate the first application of icodextrin as a covalently-bonded drug delivery platform with potential use in the treatment of ovarian cancer.
