Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy
[Display omitted] Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of...
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| Veröffentlicht in: | International journal of pharmaceutics 2015-02, Vol.479 (1), p.23-27 |
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| container_title | International journal of pharmaceutics |
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| creator | Mehta, A.M. Van den Hoven, J.M. Rosing, H. Hillebrand, M.J.X. Nuijen, B. Huitema, A.D.R. Beijnen, J.H. Verwaal, V.J. |
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Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30min to 90min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS–HIPEC procedures.
5mg of oxaliplatin was added to 50mL of various carrier solutions at 42°C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal® PD4 glucose 1.36% solution for peritoneal dialysis and 0.14M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC–UV); oxaliplatin degradation products were identified using HPLC-mass spectometry.
In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to |
| doi_str_mv | 10.1016/j.ijpharm.2014.12.025 |
| format | Article |
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Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30min to 90min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS–HIPEC procedures.
5mg of oxaliplatin was added to 50mL of various carrier solutions at 42°C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal® PD4 glucose 1.36% solution for peritoneal dialysis and 0.14M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC–UV); oxaliplatin degradation products were identified using HPLC-mass spectometry.
In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30min (the standard peritoneal perfusion time in most clinical CRS–HIPEC protocols) and <20% degradation after 120min at 42°C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2].
The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS–HIPEC procedures.</description><identifier>ISSN: 0378-5173</identifier><identifier>EISSN: 1873-3476</identifier><identifier>DOI: 10.1016/j.ijpharm.2014.12.025</identifier><identifier>PMID: 25535649</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Antineoplastic Agents - chemistry ; Antineoplastic Agents - therapeutic use ; Carrier solutions ; Chlorides - chemistry ; Cytoreduction Surgical Procedures ; Degradation ; Drug Stability ; Hyperthermia, Induced ; Hyperthermic intraperitoneal chemotherapy ; Organoplatinum Compounds - chemistry ; Organoplatinum Compounds - therapeutic use ; Oxaliplatin ; Peritoneal Neoplasms - drug therapy ; Peritoneal Neoplasms - surgery ; Peritoneal Neoplasms - therapy ; Solutions</subject><ispartof>International journal of pharmaceutics, 2015-02, Vol.479 (1), p.23-27</ispartof><rights>2014 Elsevier B.V.</rights><rights>Copyright © 2014 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c365t-5004b6526fdd29c000f3e7e02f68c33213a8afdd8f946185cd9459294b8fe21e3</citedby><cites>FETCH-LOGICAL-c365t-5004b6526fdd29c000f3e7e02f68c33213a8afdd8f946185cd9459294b8fe21e3</cites><orcidid>0000-0002-4973-3016</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0378517314009223$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25535649$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mehta, A.M.</creatorcontrib><creatorcontrib>Van den Hoven, J.M.</creatorcontrib><creatorcontrib>Rosing, H.</creatorcontrib><creatorcontrib>Hillebrand, M.J.X.</creatorcontrib><creatorcontrib>Nuijen, B.</creatorcontrib><creatorcontrib>Huitema, A.D.R.</creatorcontrib><creatorcontrib>Beijnen, J.H.</creatorcontrib><creatorcontrib>Verwaal, V.J.</creatorcontrib><title>Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy</title><title>International journal of pharmaceutics</title><addtitle>Int J Pharm</addtitle><description>[Display omitted]
Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30min to 90min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS–HIPEC procedures.
5mg of oxaliplatin was added to 50mL of various carrier solutions at 42°C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal® PD4 glucose 1.36% solution for peritoneal dialysis and 0.14M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC–UV); oxaliplatin degradation products were identified using HPLC-mass spectometry.
In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30min (the standard peritoneal perfusion time in most clinical CRS–HIPEC protocols) and <20% degradation after 120min at 42°C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2].
The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS–HIPEC procedures.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Carrier solutions</subject><subject>Chlorides - chemistry</subject><subject>Cytoreduction Surgical Procedures</subject><subject>Degradation</subject><subject>Drug Stability</subject><subject>Hyperthermia, Induced</subject><subject>Hyperthermic intraperitoneal chemotherapy</subject><subject>Organoplatinum Compounds - chemistry</subject><subject>Organoplatinum Compounds - therapeutic use</subject><subject>Oxaliplatin</subject><subject>Peritoneal Neoplasms - drug therapy</subject><subject>Peritoneal Neoplasms - surgery</subject><subject>Peritoneal Neoplasms - therapy</subject><subject>Solutions</subject><issn>0378-5173</issn><issn>1873-3476</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1P3DAQhi1EBQvlJ7TKkUuCP2InOaEK0YKExKHt2fI6E3ZWThxsp-r-e7zahSvSSKPRvPPOzEPIN0YrRpm62Va4nTcmjBWnrK4YryiXJ2TF2kaUom7UKVlR0bSlZI04JxcxbimlijNxRs65lEKquluR-DuZNTpMu8IPhf9vHM7OJJyKHHbjfMAeSuunZHDC6aWwJgSEUETvloR-isUSod-rN7sZQtpAGNHmOgWTa0x-AuOyFYx-3zTz7iv5MhgX4eqYL8nfn_d_7h7Kp-dfj3c_nkorlEylpLReK8nV0Pe8s_n6QUADlA-qtULkT0xrcq8dulqxVtq-q2XHu3rdDsAZiEtyffCdg39dICY9YrTgnJnAL1GzbF6zlgqVpfIgtcHHGGDQc8DRhJ1mVO95660-8tZ73ppxnXnnue_HFct6hP5j6h1wFtweBJAf_ZfB6WgRJgs9BrBJ9x4_WfEGCnyXIg</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>Mehta, A.M.</creator><creator>Van den Hoven, J.M.</creator><creator>Rosing, H.</creator><creator>Hillebrand, M.J.X.</creator><creator>Nuijen, B.</creator><creator>Huitema, A.D.R.</creator><creator>Beijnen, J.H.</creator><creator>Verwaal, V.J.</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4973-3016</orcidid></search><sort><creationdate>20150201</creationdate><title>Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy</title><author>Mehta, A.M. ; Van den Hoven, J.M. ; Rosing, H. ; Hillebrand, M.J.X. ; Nuijen, B. ; Huitema, A.D.R. ; Beijnen, J.H. ; Verwaal, V.J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c365t-5004b6526fdd29c000f3e7e02f68c33213a8afdd8f946185cd9459294b8fe21e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Carrier solutions</topic><topic>Chlorides - chemistry</topic><topic>Cytoreduction Surgical Procedures</topic><topic>Degradation</topic><topic>Drug Stability</topic><topic>Hyperthermia, Induced</topic><topic>Hyperthermic intraperitoneal chemotherapy</topic><topic>Organoplatinum Compounds - chemistry</topic><topic>Organoplatinum Compounds - therapeutic use</topic><topic>Oxaliplatin</topic><topic>Peritoneal Neoplasms - drug therapy</topic><topic>Peritoneal Neoplasms - surgery</topic><topic>Peritoneal Neoplasms - therapy</topic><topic>Solutions</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mehta, A.M.</creatorcontrib><creatorcontrib>Van den Hoven, J.M.</creatorcontrib><creatorcontrib>Rosing, H.</creatorcontrib><creatorcontrib>Hillebrand, M.J.X.</creatorcontrib><creatorcontrib>Nuijen, B.</creatorcontrib><creatorcontrib>Huitema, A.D.R.</creatorcontrib><creatorcontrib>Beijnen, J.H.</creatorcontrib><creatorcontrib>Verwaal, V.J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of pharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mehta, A.M.</au><au>Van den Hoven, J.M.</au><au>Rosing, H.</au><au>Hillebrand, M.J.X.</au><au>Nuijen, B.</au><au>Huitema, A.D.R.</au><au>Beijnen, J.H.</au><au>Verwaal, V.J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy</atitle><jtitle>International journal of pharmaceutics</jtitle><addtitle>Int J Pharm</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>479</volume><issue>1</issue><spage>23</spage><epage>27</epage><pages>23-27</pages><issn>0378-5173</issn><eissn>1873-3476</eissn><abstract>[Display omitted]
Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30min to 90min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS–HIPEC procedures.
5mg of oxaliplatin was added to 50mL of various carrier solutions at 42°C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal® PD4 glucose 1.36% solution for peritoneal dialysis and 0.14M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC–UV); oxaliplatin degradation products were identified using HPLC-mass spectometry.
In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30min (the standard peritoneal perfusion time in most clinical CRS–HIPEC protocols) and <20% degradation after 120min at 42°C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2].
The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS–HIPEC procedures.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>25535649</pmid><doi>10.1016/j.ijpharm.2014.12.025</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0002-4973-3016</orcidid></addata></record> |
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| subjects | Antineoplastic Agents - chemistry Antineoplastic Agents - therapeutic use Carrier solutions Chlorides - chemistry Cytoreduction Surgical Procedures Degradation Drug Stability Hyperthermia, Induced Hyperthermic intraperitoneal chemotherapy Organoplatinum Compounds - chemistry Organoplatinum Compounds - therapeutic use Oxaliplatin Peritoneal Neoplasms - drug therapy Peritoneal Neoplasms - surgery Peritoneal Neoplasms - therapy Solutions |
| title | Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy |
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