Natural Products

VINCA ALKALOIDS

Vincristine and vinblastine are alkaloid derivatives of the periwinkle plant, whose major and dose-limiting toxicity is neurological. The mechanism of action of these agents is probably related to inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage. Peripheral neuropathy is almost

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universal in patients receiving these drugs, and neurotoxicity is attributed to the inhibition of axoplasmic transport by their effect on axonal microtubules. y , y Patients with pre-existing neuropathy (diabetic, familial, compressive, or nutritional) may have more severe neuropathy. Generally, the longer the exposure, the more numerous and severe the neuropathic side effects.

The earliest and most consistent objective manifestation of vincristine neurotoxicity is suppression of the Achilles tendon reflex. This is followed rapidly by losses of other reflexes, distal symmetrical sensory loss (pin and temperature more than vibration and proprioception), weakness, footdrop, and muscle atrophy. Autonomic neuropathy with constipation, ileus, urinary retention, impotence, or postural hypotension may occur. Cranial neuropathy occurs, usually involving the oculomotor nerve, often causing bilateral ptosis. Affected nerves include the abducens, trigeminal, facial, and recurrent laryngeal nerves, the latter resulting in hoarseness or stridor. Nerve conduction velocities are normal, because the process is an axonopathy. '1 , y , y , y A painful myopathy may occur in children. Vincristine does not cross the blood-brain barrier, so CNS toxicity is rare, although seizures may develop as a result of inappropriate secretion of antidiuretic hormone. y Vinblastine has similar neurotoxic reactions but only at doses that are usually not prescribed because of concomitant severe hematological reactions. y l-ASPARAGINASE

L-Asparaginase is an enzyme that hydrolyzes asparagine to aspartic acid and ammonia, depleting asparagine and inhibiting protein synthesis. When it was first introduced, the drug was used at high doses that produced an acute encephalopathy that proved to be dose limiting. At usually prescribed doses, the encephalopathy is not seen.y

Because L-asparaginase inhibits protein synthesis, plasma protein deficits occur, including those involved in coagulation and fibrinolysis. Decreased levels of fibrinogen, factor IX, factor XI, plasminogen, antithrombin III, protein C, protein S, alpha 2 -antiplasmin, histidine-rich glycoprotein, and alpha 2 -macroglobulin also occur.y L-Asparaginase has been linked to hemorrhagic and thrombotic cerebrovascular complications, including cortical infarction, capsular infarction, intracerebral hemorrhage, hemorrhagic infarction, and cerebral venous and dural sinus thrombosis. During treatment, progressive prolongations in PT, PTT, and thrombin time are seen. In patients who have had complications resulting from L-asparaginase and who require further treatment, therapy to prevent subsequent complications is controversial. Fresh frozen plasma alone or with low-dose heparin or antithrombin III has been proposed. y Because fresh frozen plasma lessens the decrease in coagulation proteins normally seen with L-asparaginase, it is a reasonable treatment for patients with thromboembolic complications from the medicine.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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