A prospective study of suramin-induced peripheral neuropathy

Abstract

Suramin is an investigational drug that has shown therapeutic activity in hormone-refractory metastatic prostate cancer in Phase I/II trials. Dose-limiting neurotoxicity remains the most serious complication of suramin treatment. We performed a prospective study to define the incidence, severity, characteristics, and dose relationships of suramin-induced peripheral neuropathy. Twenty-two patients who received suramin in a Phase-I trial underwent baseline and serial follow-up neurological evaluations consisting of history, examination, nerve conduction studies and quantitative sensory testing (QST). Suramin was administered intravenously in escalating dosages by using a 5-day schedule (repeated monthly), with the dose, determined by a population pharmacokinetic model, to accomplish 30-min post-infusion concentrations of 300 micrograms ml-1 (cohort I), 350 micrograms m-1 (cohort II) and 400 micrograms ml-1 (cohort III). Twelve patients developed a mild, axonal, length-dependent, sensory-motor poly-neuropathy. Three other patients developed a subacutely progressive, functionally disabling, demyelinating neuropathy; sural nerve biopsy in two patients showed lymphocytic inflammation. These three patients improved after drug discontinuation and plasmapheresis. Although there was no apparent correlation between the cumulative dose and the severity of the neuropathy, no patient from cohort I, but 88% of patients from cohorts II and III, developed neuropathy. We conclude that when suramin is used at peak concentrations of > or = 350 micrograms ml-1 its administration is associated with two patterns of neuropathy, a distal axonal neuropathy and an inflammatory demyelinating neuropathy that is partially reversible. Neurological monitoring for development of neuropathy will improve the safety of suramin use in future clinical studies.

Longitudinal assessment of oxaliplatin-induced neuropathy

“…A change of 2 TNS points has been considered to be meaningful in other studies. 10,11 The change in IENFD at the distal leg was more pronounced than at the distal thigh IENFD. Subjects 1, 3, 7, and 8 had a skin biopsy at day 360, 6 months after their last dose of oxaliplatin.…”

“…No subject received radiotherapy. Nerve conduction testing, punch biopsies, and clinical examinations with calculation of a rTNS 10,11 were performed at each time point. The TNS is a validated peripheral nerve scoring system that encompasses subject symptoms, signs, and results of quantitative testing.…”

Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects

“…For each subject, the total neuropathy score was also calculated. 1,2 Primary end points included adverse events and clinical laboratory tests. Secondary end points included pharmacokinetic profiles for single dosing and multiple dosing, and evaluation of biologic effects of r-metHuNT3 on neurologic function.…”

Suramin potently inhibits the enzymatic activity of PSM

“…In addition to the neovasculature and the prostate, PSM/PSMЈ expression is abundant in nervous tissues and in the kidney [31,34,35]. Interestingly, the most common side effects in patients that caused discontinuation of suramin treatment were neurotoxicity [7][8][9]36,37] and acute renal failure [38][39][40]. It is also possible that suramin may inhibit the enzymatic activity of PSM in these target organs at therapeutic doses, and that the toxicities associated with treatment could be related to this PSM/ PSMЈ enzyme inhibition.…”