FROM AWARD-WINNING AUTHOR DR GOVIND SHUKLA, NUTRITION EXPERT
CARNETO Capsules Robust treatment for Chemotherapy- Induced peripheral Neuropathy
Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN).
Peripheral neuropathy is a set of symptoms caused by damage to the nerves that are away from the brain and spinal cord. These distant nerves are called peripheral nerves. They carry sensations (feeling) to the brain and control the movement of our arms and legs. They also control the bladder and bowel.
In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment.Chemotherapy- induced peripheral neuropathy (CIPN) debilitating and painful condition effects 40% of patients who undergo chemotherapy treatment.
Cancer chemotherapy drugs, including the taxanes, vinca alkaloids, platinum drugs and others are associated with significant neurotoxicity, particularly when prescribed in high doses. Acetyl -L-carnitine (ALCAR) in CARNETO, an ester of amino acid L-carnitine, is synthesized in liver, brain, and kidneys and is essential for fatty acid oxidation, acetylcholine production, and cell membrane phospholipids synthesis. ALCAR in CARNETO has demonstrated significant neuroprotection from side effects of chemotherapy.
Pathophysiology – Chemotherapy-Induced Neuropathy (CIPN)
The incidence of CIPN varies depending on the conditions with severe neuropathy (3-7%) with single agent, but can arise up to 38%with combination regimens.
CIPN associated and paclitaxel appears to be associated with mitochondrial toxicity. Paclitaxel opens mitochondrial transition pore (mPTP).
In non-neural cells also paclitaxel cause opening of mPTP and results in swollen, vacuolated and functionally impaired mitochondria .
paclitaxel causes mitochondria in peripheral nerves deceits in ATP production and complex I and complex II mediated respiration.
Toxicity of oxaliplatin also appears to be related to action on IB4 (+) – nociceptors to induce oxidative stress. Loss of intraepidermal nerve fibers (IENF) is responsible for hyper-excitability. In neuropathy conditions, there is loss of Aδ and c fibers from epidermis causing allodynia . Cisplatin appears to reduce circulating levels of nerve growth factor (NFG) . Bortezomib leads to intra cytoplasmic vacuolation in dorsal root ganglia (DRG) satellite cells which is ascribed to mitochondrial and endoplasmic reticulum enlargement, these results in inhibiting mitochondrial electron transport and ATP synthesis producing painful peripheral neuropathy and also attenuate TNF- alpha induced mechanical hyperalgesia.
Vincristine produces pain hypersensitivity including allodynia and hyperalgesia. Vincristine is mainly attributed to disruption of microtubule structure leading to impairment of axoplasmic transport and neuropathy.
Mechanism of action of Carneto capsules in chemotherapy-Induced Neuropathy
Acetyl-L- Carnitine (ALCAR) in CARNETO prevents the opening of mitochondrial permeability transition pore (mPTP) normalizing mitochondrial function and attenuating development of paclitaxel-induced neuropathic pain. Acetyl-L- Carnitine (ALCAR) in CARNETO have shown to alleviate the cytotoxicity in schwann cell treated with bortezomib.
The molecular properties Acetyl-L- Carnitine (ALCAR) in CARNETO have led to the suggestion that it may play a role in histone acetylation by elevating endogenous histone H4 and histone H3 there by indicating that Acetyl-L- Carnitine (ALCAR) in CARNETO can act as donor molecule of acetyl groups to histones and consequently in facilitating gene expression.
Acetyl-L- Carnitine (ALCAR) in CARNETO regulates cellular levels of acetyl-CoA , which directly modulates the process of acetylation of histones thereby lowering the levels of NGF (nuclear growth factor) leading to up-regulation of genes of which the expression is required to counteract the toxicity of anti neoplastic drugs. Patients on chemotherapy may be deficient in acetyl-L-carnitine. A study of 11 patients on carboplatin found increased urinary excretion of both ALCAR and L-carnitine. Deficiencies of these two nutrients were also found in animal model of cisplatin- Induced nephrotoxicity; the deficiency in turn results in neurotoxicity.