Neurotoxicity peripheral neuropathy

Vincristine -vinca alkaloid inhibits tubulin polymerization G2 phase specific -neurotoxicity—peripheral neuropathy -vesicant if extravasated -nausea and vomiting -bone marrow suppression—mild -transient transaminase elevation -constipation (often secondary to neuropathy induced ileus) —intrathecal injection is ALWAYS FATAL... 

Etoposide Etopophos, VePesid Carcinoma of lung, testes Blood disorders (anemia, leukopenia, thrombocytopenia] Gl distress (nausea, vomiting] hypotension, allergic reactions hair loss neurotoxicity (peripheral neuropathies, CNS effects]... 

Vincristine Oncovin, Vincasar Acute lymphocytic leukemia neuroblastoma Wilms tumor Hodgkin disease non-Hodgkin lymphomas Ewing sarcoma Neurotoxicity [peripheral neuropathies, CNS disorders] hair loss local irritation at injection site... 

Myelosuppression (neutropenia) neurotoxicity peripheral neuropathy (less common than with vincristine) constipation low back pain mild emetogen vesciant causes painful phlebitis with administration alopecia is uncommon... 

Major toxicities Nephrotoxicity Severe nausea and vomiting Neurotoxicity (peripheral neuropathy) Ototoxicity (tinnitus/hearing loss) M yelosuppression (mainly thrombocytopaenia)... 

A rabbit model of 2, 3 -dideoxycytidine neurotoxicity. Lab Invest 66(l) 63-74 Apostolski S, McAlarney T et al (1993) The gpl20 glycoprotein of human immunodeficiency virus type 1 binds to sensory ganghon neurons. Ann Neurol 34(6) 855-863 Araujo AP, Nascimento OJ et al (2000) Distal sensory polyneuropathy in a cohort of HIV-infected children over five years of age. Pediatrics 106(3) E35 Authier FJ, Gheradi RK (2003) Peripheral neuropathies in HIV-infected patients in the era of HAART. Brain Pathol 13(2) 223-228... 

The lack of corroborative case reports, epidemiological data, or animal data (see next paragraph) makes the association between dermal exposure to mineral oil hydraulic fluids and peripheral neuropathy uncertain. Nonetheless, the presence of organophosphate esters, some of which are demonstrated neurotoxic agents, in most mineral oil hydraulic fluids (they often are added as anti-wear agents) suggests that they may play a causative role if such an association exists. 

Therapy with INH results in a transient elevation in serum transaminases in 12% to 15% of patients and usually occurs within the first 8 to 12 weeks of therapy. Risk factors for hepatotoxicity include patient age, preexisting liver disease, and pregnancy or postpartum state. INH also may result in neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, seizures, and coma. Patients with pyridoxine deficiency, such as alcoholics, children, and the malnourished, are at increased risk, as are patients who are slow acetylators of INH and those predisposed to neuropathy, such as those with diabetes. 

The neurotoxicity of -hexane was first observed in the shoe industries of Japan and Italy in the 1960s and early 1970s. A number of epidemiological studies were initiated in response to outbreaks of apparent peripheral neuropathy in shoe workers. While the clinical course of the disease was well described, elucidation of a dose-duration response relationship has been difficult. In most cases, concentrations of -hexane in the workplace air were not measured until after disease developed. Also, in almost all cases, workers were concurrently exposed to other chemicals which may have affected their response to -hexane. 

Effect of Dose and Duration of Exposure on Toxicity. No studies were located where -hexane concentration was measured in workplace air before workers became ill, so no dose-response relationship can be defined for human neurotoxicity as the result of -hexane exposure. Information on duration of exposure leading to toxicity is available from some case series reports. An occupational exposure caused sensory disturbances in the lower extremities after approximately 2 months (Herskowitz et al. 1971). A case of peripheral neuropathy after 7 months of exposure was reported among press-proofing workers in Taipei (Wang et al. 1986) a serious case resulting in quadriplegia after 8 months of exposure was reported among sandal workers in Japan (Yamamura 1969). Based on case reports, it can be estimated... 

Route-dependent Toxicity. w-Hexane toxicity does not appear to be route-dependent. Peripheral neuropathy can be produced in rats by the oral route (Krasavage et al. 1980) at high doses (4,000 mg/kg/day). The clinical and histopathological signs were similar to those seen after inhalation exposure. No reports of neurotoxicity after dermal exposure were located. 

Neurological Effects. The major public health concern regarding -hexane exposure is the potential for the development of neurotoxicity. Occupational studies have documented that human exposure to -hexane can result in a peripheral neuropathy that in severe cases can lead to paralysis (Altenkirch et al. 1977 Yamamura 1969 Wang et al. 1986). The dose-duration relationship has not been well characterized in humans, but concentrations of 500 ppm and above, and exposure for 2 months or more have been associated with human neurotoxicity. Brief exposure to extremely high concentrations of w-hexane may cause signs of narcosis in humans prostration and coma have been observed in animals exposed to a mixture of hexanes at concentrations of 70,000-80,000 ppm (Hine and Zuidema 1970). At these levels, however, explosion and fire would be the main concern. 

Clinical signs of peripheral neuropathy similar to those seen in human occupational exposures to w-hexane can be produced in rats via the inhalation and oral routes, but not in other test species (Altenkirch et al. 1982 De Martino et al. 1987 Dunnick et al. 1989 Frontali et al. 1981 Huang et al. 1989 IRDC 1981 Krasavage etal. 1980 NTP 1991 Schaumburg and Spencer 1976 Takeuchi etal. 1980). Paranodal axonal swelling in mice (Dunnick et al. 1989 NTP 1991) and leg weakness in chickens (Abou-Donia et al. 1985) can be produced with inhalation exposure to -hexane, but these conditions do not progress to the severe neurotoxicity observed in humans and rats. The molecular mechanism... 

The critical effect of intermediate-duration exposure to -hexane in humans is neurotoxicity, specifically peripheral neuropathy. No inhalation MRL was derived for this duration because the reports of neurological effects in humans were predominantly case reports with inadequate documentation of exposure levels or comparison with unexposed groups. A large database on neurological effects in rats exists for this duration however, the design of these experiments precluded documentation of clear dose-response relationships within a single study. Because of the limited database for oral exposure to -hexane and the lack of toxicokinetic data for this route, no MRL was derived for oral exposure to -hexane. 

Although w-heptane exposure produces narcotic effects, it has not been shown to cause the type of peripheral neuropathy associated with -hexane at the same exposure levels. A metabolic study of heptane in rats and humans showed that only a very small amount of 2,5-heptanedione, the purportedly neurotoxic metabolite responsible for peripheral neuropathy, is produced. Clinical damage to the peripheral nervous system after w-heptane exposure, therefore, seems unlikely. ... 

Hexanedione was found to be a major metabolite of MBK in several animal species peripheral neuropathy occurred in rats after daily subcutaneous injection of 2,5-hexanedione at a dose of 340mg/kg 5 days/ week for 19 weeks.Nonneurotoxic aliphatic monoketones, such as methyl ethyl ketone, enhance the neurotoxicity of MBK. In one rat study, the longer the carbon chain length of the nonneurotoxic monoketone, the greater the potentiating effect on MBK. It is expected that exposure to a subneurotoxic dose of MBK, plus high doses of some aliphatic monoketones, would also produce neurotoxicity. In addition, MBK itself potentiates the toxicity of other chemicals. ... 

Coadministration of didanosine buffered tablets, buffered powder for oral solution, and pediatric powder for oral solution with drugs that are known to cause peripheral neuropathy or pancreatitis or patients who have a history of neuropathy or neurotoxic drug therapy may have increased risk of toxicities. Closely observe patients who receive these drugs or have a history of neuropathy or neurotoxic drug therapy. 

Neurologic symptoms Motor weakness has been reported rarely. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barre syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy. Stavudine therapy has been associated with peripheral neuropathy, which can be severe and is dose-related. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine (see Adverse Reactions). 

Stavudine should be used with caution in patients at risk for hepatic disease and those who have had pancreatitis. Persons with peripheral neuropathy, the elderly, and those with advanced HIV disease are at increased risk for neurotoxicity. Dosage adjustment is required for patients with renal insufficiency. 

Vincristine Inhibits mitosis ALL, Hodgkin s and non-Hodgkin s lymphoma, rhabdomyosarcoma, neuroblastoma, Wilms tumor None Neurotoxicity with peripheral neuropathy, paralytic ileus, myelosuppression, alopecia, SIADH... 

Adverse Effects. Iodoquinol is neurotoxic and may produce optic and peripheral neuropathies when administered in large dosages for prolonged periods. Problems with muscle weakness and ataxia may also occur because of the neurotoxic effects of this drug. 

Generic Name Altretamine Trade Name Hexalen Primary Antineoplastic Indication(s) Ovarian cancer Common Adverse Effects Gl distress (nausea, vomiting, loss of appetite] blood disorders (leukopenia, thrombocytopenia] CNS neurotoxicity (unusual tiredness, dizziness, confusion, depression, anxiety] peripheral neuropathies... 

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