Editing Cisplatin (section)

==Side effects==
Cisplatin has a number of side effects that can limit its use:
* [[Nephrotoxicity]] (kidney damage) is the primary dose-limiting side effect and is of major clinical concern. Cisplatin selectively accumulates into the [[proximal tubule]] via basolateral-to-apical transport, where it disrupts mitochondrial energetics and [[endoplasmic reticulum]] Ca<sup>2+</sup> homeostasis and stimulates [[reactive oxygen species]] and pro-inflammatory [[cytokines]].<ref name="Miller">{{cite journal |journal = Toxins |date = October 2010| volume = 2|issue = 11|pages = 2490–2518 | title = Mechanisms of Cisplatin Nephrotoxicity. |vauthors = Miller RP, Tadagavadi RK, Ramesh G, Reeves WB | doi=10.3390/toxins2112490| pmid=22069563 | pmc=3153174 | doi-access=free }}</ref> Multiple mitigation strategies are being explored clinically and pre-clinically, including hydration regimens, [[amifostine]], transporter inhibitors, antioxidants, anti-inflammatories, and [[epoxyeicosatrienoic acids]] and their analogues.<ref name=Miller/><ref name="Singh">{{cite journal |journal= Chemical Research in Toxicology |date =November 2021| volume=34|issue=12|pages=2579–2591 | title= New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation. |vauthors=Singh N, Vik A, Lybrand DB, Morisseau C, Hammock BD | doi=10.1021/acs.chemrestox.1c00347|pmid =34817988|pmc =8853703}}</ref>
* [[Neurotoxicity]] (nerve damage) can be anticipated by performing [[nerve conduction studies]] before and after treatment. Common neurological side effects of cisplatin include visual perception and hearing disorder, which can occur soon after treatment begins.<ref name="Milosavljevic_2010">{{cite journal | vauthors = Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, Dimanche-Boitrel MT, Rauch C, Tauc M, Counillon L, Poët M | display-authors = 6 | title = Nongenomic effects of cisplatin: acute inhibition of mechanosensitive transporters and channels without actin remodeling | journal = Cancer Research | volume = 70 | issue = 19 | pages = 7514–22 | date = October 2010 | pmid = 20841472 | doi = 10.1158/0008-5472.CAN-10-1253 | url = https://www.sciencedaily.com/releases/2010/10/101005141117.htm | doi-access = free }}</ref> While triggering apoptosis through interfering with DNA replication remains the primary mechanism of cisplatin, this has not been found to contribute to neurological side effects. Cisplatin noncompetitively inhibits an archetypal, membrane-bound mechanosensitive sodium-hydrogen ion transporter known as [[SLC9A1|NHE-1]].<ref name="Milosavljevic_2010"/> It is primarily found on cells of the peripheral nervous system, which are aggregated in large numbers near the ocular and aural stimuli-receiving centers. This noncompetitive interaction has been linked to hydroelectrolytic imbalances and cytoskeleton alterations, both of which have been confirmed in vitro and in vivo. However, NHE-1 inhibition has been found to be both dose-dependent (half-inhibition = 30&nbsp;μg/mL) and reversible.<ref name="Milosavljevic_2010"/> Cisplatin can increase levels of [[sphingosine-1-phosphate]] in the [[central nervous system]], contributing to the development of [[post-chemotherapy cognitive impairment]].<ref name="pmid36047496">{{cite journal |vauthors=Squillace S, Niehoff ML, Doyle TM, Green M, Esposito E, Cuzzocrea S, Arnatt CK, Spiegel S, Farr SA, Salvemini D |title=Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment |journal=The Journal of Clinical Investigation |volume=132 |issue=17 |date=September 2022 |pmid=36047496 |pmc=9433103 |doi=10.1172/JCI157738}}</ref><ref>{{cite web|url= https://neurosciencenews.com/chemo-brain-drug-21353/|title=Unlocking the Mystery of "Chemo Brain" | work = Neuroscience News |date=2 September 2022}}</ref>
* [[Nausea]] and [[vomiting]]: cisplatin is one of the most emetogenic chemotherapy agents, but this symptom is managed with prophylactic antiemetics ([[ondansetron]], [[granisetron]], etc.) in combination with [[corticosteroids]]. [[Aprepitant]] combined with [[ondansetron]] and [[dexamethasone]] has been shown to be better for highly emetogenic chemotherapy than just [[ondansetron]] and [[dexamethasone]].
* [[Ototoxicity]] and hearing loss associated with cisplatin can be severe and is considered to be a dose-limiting side effect.<ref name="pmid29051464"/> Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the [[aminoglycoside]] antibiotic class) may also cause ototoxicity, and the administration of this class of antibiotics in patients receiving cisplatin is generally avoided.  The ototoxicity of both the aminoglycosides and cisplatin may be related to their ability to bind to [[melanin]] in the [[stria vascularis]] of the inner ear or the generation of [[reactive oxygen species]]. In September 2022, the U.S. [[Food and Drug Administration]] (FDA) approved [[Sodium thiosulfate (medical use)|sodium thiosulfate]] under the brand name Pedmark to lessen the risk of ototoxicity and hearing loss in people receiving cisplatin.<ref name="pmid35489339">{{cite journal |vauthors=Orgel E, Villaluna D, Krailo MD, Esbenshade A, Sung L, Freyer DR |title=Sodium thiosulfate for prevention of cisplatin-induced hearing loss: updated survival from ACCL0431 |journal=The Lancet. Oncology |volume=23 |issue=5 |pages=570–572 |date=May 2022 |pmid=35489339 |pmc=9635495 |doi=10.1016/S1470-2045(22)00155-3}}</ref><ref name="Winstead 2022">{{cite web | vauthors = Winstead E |title=Sodium Thiosulfate Reduces Hearing Loss in Kids with Cancer |website=National Cancer Institute |date=6 October 2022 |url=https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-sodium-thiosulfate-cisplatin-hearing-loss-children |access-date=9 March 2023}}</ref><ref name="FDA 2022">{{cite web |title=FDA approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic solid tumors |publisher=Food and Drug Administration |date=20 September 2022 |url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sodium-thiosulfate-reduce-risk-ototoxicity-associated-cisplatin-pediatric-patients |archive-url=https://web.archive.org/web/20220920220037/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sodium-thiosulfate-reduce-risk-ototoxicity-associated-cisplatin-pediatric-patients |url-status=dead |archive-date=20 September 2022 |access-date=9 March 2023}}</ref> There is ongoing investigation of [[acetylcysteine]] injections as a preventative measure.<ref name="pmid29051464"/><ref>{{cite journal | vauthors = Sarafraz Z, Ahmadi A, Daneshi A | title = Transtympanic Injections of N-acetylcysteine and Dexamethasone for Prevention of Cisplatin-Induced Ototoxicity: Double Blind Randomized Clinical Trial | journal = The International Tinnitus Journal | volume = 22 | issue = 1 | pages = 40–45 | date = June 2018 | pmid = 29993216 | doi = 10.5935/0946-5448.20180007 }}</ref>
* [[Electrolyte disturbance]]: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the cisplatin.
* [[Hemolytic anemia]] can be developed after several courses of cisplatin. It is suggested that an antibody reacting with a cisplatin-red-cell membrane is responsible for [[hemolysis]].<ref name="pmid6788166">{{cite journal | vauthors = Levi JA, Aroney RS, Dalley DN | title = Haemolytic anaemia after cisplatin treatment | journal = British Medical Journal | volume = 282 | issue = 6281 | pages = 2003–4 | date = June 1981 | pmid = 6788166 | pmc = 1505958 | doi = 10.1136/bmj.282.6281.2003 }}</ref>