How can cisplatin ototoxicity be prevented?

To summarize, the most suitable protocol for treating cisplatin-induced ototoxicity is intratympanic injection to be delivered 1h before each cisplatin injection, due to superior perilymph concentrations within 1 h of administration (Chandrasekhar et al., 2000; Hargunani et al., 2006).

How does cisplatin cause ototoxicity?

Current evidence indicates that cisplatin triggers the production of reactive oxygen species in target tissues in the inner ear. A variety of agents that protect against cisplatin-induced ototoxicity have been successfully tested in cell culture and animal models.

What is the mechanism of ototoxicity?

Ototoxicity refers to damage to the inner ear, specifically cochlear and vestibular structures and functions, due to exposure to pharmaceuticals, chemicals, and/or ionizing radiation. Ototoxic compounds can also damage the auditory and/or vestibular neural pathways to the brainstem, and beyond to the auditory cortex.

How can ototoxicity be prevented?

At present, medical personnel consider three ways to reduce the problem of drug-induced ototoxicity: development of efficacious ototoxic protective drugs; reversing ototoxicity-induced symptoms using neurotrophic grow factor; screening for genetic markers in patients at high risk of ototoxicity (for example, people who …

How does cisplatin cause deafness?

The stria vascularis helps maintain the positive electrical charge in inner ear fluid that certain cells need to detect sound. The research team determined that the accumulation of Cisplatin in the stria vascularis portion of the inner ear contributed to Cisplatin-related hearing loss.

Can cisplatin cause ringing in ears?

Hearing loss affects one in five patients treated with cisplatin and nearly one in five patients with carboplatin, Dr. Schink says. The drugs also are associated with tinnitus, a condition that causes noise or ringing in the ears. Hearing loss or tinnitus caused by the drugs typically doesn’t go away.

How does cisplatin induced apoptosis?

Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis.

What is the mechanism of action for 5 Fu?

The main mechanism of 5-FU activation is conversion to fluorouridine monophosphate (FUMP), either directly by orotate phosphoribosyltransferase (OPRT) with phosphoribosyl pyrophosphate (PRPP) as the cofactor, or indirectly via fluorouridine (FUR) through the sequential action of uridine phosphorylase (UP) and uridine …

How do ototoxic drugs cause hearing loss?

Ototoxic medications cause damage to the sensory cells used in hearing and balance. These sensory cells are located in the inner ear. Which medications are ototoxic? There are more than 200 medications and chemicals that are known to cause hearing and balance problems.

What are the preventive measures of hearing loss?

Increase the distance between you and the source of the noise. Reduce your time in noisy areas. Always wear hearing protection in noisy areas, and if using foam plugs, insert them correctly. If you are listening to music or something else, keep the volume at a safe level and only listen in areas that are not noisy.

How do you manage ototoxicity?

Management options include modification to the medication (drug withdrawal, dosage modification, and alternating with non-ototoxic medications to increase exposure-free durations), supporting the hearing function (prescribing hearing aids or cochlear implants), minimising the disability (assistive listening devices.

How do you reduce ototoxicity?

Prevention. Limit using drugs to those that are absolutely needed and follow the instructions carefully for those medications that are prescribed for you. If possible, avoid taking multiple types of ototoxic drugs (aspirin, quinine, loop diuretics, and aminoglycosides).

Does cisplatin cause permanent hearing loss?

But cisplatin and other similar platinum-containing drugs can damage the cochlea, leaving 40%–80% of adults, and at least 50% of children, with significant permanent hearing loss, a condition that can greatly affect quality of life.

Is cisplatin-induced cell death always produced by apoptosis?

In summary, a growing body of evidence suggests that cisplatin-induced cell death does not always come from “classic”apoptosis. Depending on both cisplatin dose and cellular status, cisplatin may also induced cell death by a defective apoptotic program or even by necrosis.

How does cisplatin affect the cell cycle?

Broadly, cisplatin is known to bind DNA and form DNA adducts, which is aimed to subsequently inhibit cell cycle progression and induce apoptosis.

Which is the mode of inhibition for 5-FU?

Prodrugs of 5-FU Inhibition of DPD activity may be competitive with 5-FU, as in the case of uracil and 5-chloro-dihydropyridine; 5-ethynyluracil acts as a suicide inhibitor by inactivating DPD.

What enzyme does 5-FU inhibit?

In mammalian cells, 5-FU is converted to fluorodeoxyuridine monophosphate (FdUMP), which forms a stable complex with thymidylate synthase (TS), and thus inhibits deoxythymidine mono-phosphate (dTMP) production.

What are the causes and prevention of hearing impairment?

Aging and chronic exposure to loud noises both contribute to hearing loss. Other factors, such as excessive earwax, can temporarily reduce how well your ears conduct sounds. You can’t reverse most types of hearing loss. However, you and your doctor or a hearing specialist can take steps to improve what you hear.

How does cisplatin damage hearing?

What factors affect ototoxicity?

Risk factors

  • Aging. Degeneration of inner ear structures occurs over time.
  • Loud noise. Exposure to loud sounds can damage the cells of your inner ear.
  • Heredity.
  • Occupational noises.
  • Recreational noises.
  • Some medications.
  • Some illnesses.

Is ototoxicity from cisplatin reversible?

Dose limiting side effects of cisplatin include nephrotoxicity, neurotoxicity and ototoxicity. While nephrotoxicity can to some extent be reversed by increasing saline hydration as well as mannitol diuresis, there are no known cures or preventative treatments available for ototoxicity and neurotoxicity.

How does cisplatin induce apoptosis?

Is cisplatin cytotoxic or cytostatic?

Platinum-based therapies such as cisplatin and less potent but better tolerated carboplatin are examples of cytotoxic drugs, which function by triggering apoptosis [39].

How does cisplatin prevent DNA replication?

Cisplatin prevents DNA replication in cancer cells by a ligand replacement reaction with DNA in which a bond is formed between platinum and a nitrogen atom on guanine.

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