James C. Standefer

Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies

Ten of 11 patients with ovarian cancer receiving cisplatin developed a distal sensory neuropathy, manifested early by decreased vibratory sensibility in toes and depressed ankle jerks and later by uncomfortable paresthesias. Eleven patients receiving cisplatin, 50 mg/m2 monthly (mean total, 580 mg/m2) were studied prospectively with monthly neurologic examinations and conduction velocity determinations of median, peroneal, and sural nerves. Early signs were decreased vibratory sensibility in toes (mean dose, 417 ± 132 mg/m2 [SD]) and loss of ankle jerks (mean dose, 455 ± 86 mg/m2). With continued therapy, four developed paresthesias. Strength was unaffected. Sural nerve responses abruptly disappeared in six patients (mean dose, 383 ± 103 mg/m2). Other conduction velocities remained normal. Electron microscopy of peripheral nerves from four patients showed axonal degeneration and secondary myelin breakdown. Platinum concentrations in three patients were similar in tumor (3.3 μg/g), sural nerves (3.5 μg/g), and spinal ganglia (3.8 μg/g), but lower in brain (0.17 μg/g). This may explain the cisplatin toxicity of peripheral nerves with relative sparing of the central nervous system.

Failure of single dose methotrexate followed by citrovorum factor in nonmetastatic gestational trophoblastic neoplasia.

With increasing cost of medical care, newer methods of administering chemotherapy on an outpatient basis are being sought to reduce the need for hospitalization and protracted losses of valuable time for patients with nonmetastatic gestational trophoblastic neoplasia (NMGTN). To achieve this end, two NMGTN patients were treated with a single course of one dose of methotrexate (MTX) followed by multidose Citrovorum Factor (CF) without observing the expected response. Failure to respond appeared to be due to the schedule of administration. Although the dose and plasma concentrations of MTX were considered to be adequate for cell kill, fractionation--as established by conventional schedules of MTX administration--appeared necessary for response by exposing the maximum number of trophoblastic cells to inhibitory levels of MTX during the S-phase of the cell cycle.

Trophoblastic cell sensitivity to 8-day chemotherapy in nonmetastatic gestational trophoblastic neoplasia

Serial radioimmunoassay determinations of serum beta hCG and methotrexate were compared in two patients with nonmetastatic gestational trophoblastic neoplasia (NMGTN) treated with Goldsteins modification of Bagshawes intermediate-dose methotrexate-citrovorum factor rescue-treatment program. Pretreatment beta hCG levels (mIU/ml) ranged within the outer limits of the 10(3) log level. Following intravenous methotrexate, sharp serum peaks between 10(-6) and 10(-5) M were observed. Plasma disappearance was rapid with a 3 log drop noted within 24 hr to levels incapable of inhibiting DNA synthesis. beta hCG levels manifested a 1 to 1.5 log drop over the 8 days of chemotherapy and complete remission was noted within 5 to 6 weeks of the first dose of methotrexate. No significant clinical or laboratory toxicity was observed. Although cell culture studies show that 100% of cell death can be achieved with serum levels of 10(-5) M in methotrexate-resistant choriocarcinoma, similar data do not exist for previously untreated trophoblastic neoplastic cells. These preliminary observations suggest that serum methotrexate levels are important for establishing sensitivity levels in a heterogeneous population of trophoblastic cells in NMGTN and that the total dose of methotrexate may be safely preselected on the basis of the pretreatment beta hCG.

Phase II and pharmacokinetic study of high-dose methotrexate in the treatment of advanced gynecologic malignancy: A Southwest Oncology Group trial

Fifteen patients with advanced or recurrent gynecologic malignancy were treated with high-dose methotrexate (HDMTX) (1-8 g/M2) and citrovorum factor rescue (10-100 mg/M2). One complete response (13%) and two improved responses occurred in eight patients (25%) with squamous cell carcinoma and one of seven patients (14%) with nonsquamous nontrophoblastic carcinoma had stable disease for 7 months. The median duration of survival in the squamous group was 9 months and in the nonsquamous groups 6.5 months. Mean serum MTX concentrations were proportional to the doses administered and typical two compartment plasma disappearance curves were seen. Adverse toxic reactions were not observed at serum MTX levels less than 7.8 X 10(-7) M at 24 hr and 1 X 10(-7) M at 48 hr post-MTX. Hematopoietic toxicity occurred most frequently with leukopenia observed in 19.5% of courses. Hepatic, renal, gastrointestinal, and dermatologic toxicities were observed infrequently. Drug-induced nephrotoxicity occurred in one patient and possibly related leukoencephalopathy occurred in another patient. On the basis of the relatively low response rate observed in this trial and the high expense of HDMTX therapy, the value of such therapy may be limited in advanced nontrophoblastic gynecologic cancer.

A Review of Toxic Drugs and Chemicals in Man, Volume II

The objective of the two-volume series Disposition of Toxic Drugs and Chemicals in Man is to provide reference information on the pharmacokinetics and metabolism of drugs commonly encountered in forensic and clinical practice as well as to provide useful interpretative and diagnostic information for the toxicologist. Volume I provides this information on commonly encountered centrally acting drugs while Volume II provides information on peripherally acting drugs and toxins not commonly requested in toxicology laboratories. Because these drugs are not frequently encountered, Volume II is a valuable reference source. For example, the pharmacokinetics, toxicity, and analysis of pancuronium is well described and in a brief study one can adequately review its pharmacology. Other peripheral toxins that are well referenced include anions (such as cyanide and nitrate), metals (such as arsenic and thallium), pesticides (such as aldrin, lindane, and paraquat), and volatiles (such as ethylene glycol and fluorocarbons). The data for each toxin include pharmacokinetics, metabolism, postmortem concentrations, and analytical approaches. while this information is provided in a brief format, adequate references are included. A very useful addition to Volume II is an appendix that contains a list of the therapeutic and toxic concentrations of common drugs in a format similar to that published by Baselt et al in Clinical Chemistry, Vol. 21, 1975, pp. 44–62. This list relates drug dose to blood and tissue concentrations and provides the clinical conditions associated with blood concentrations.