Nadia Z. Mikhael

Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods

Objective: To assess factors that affect cisplatin nephrotoxicity. Methods: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. Results: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2–5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. Conclusions: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes. (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney.

DETECTION OF DRUGS IN SALIVA OF IMPAIRED DRIVERS

This study examined the feasibility of detecting drugs using saliva samples obtained from impaired drivers. Screening procedures on 1- to 2-mL samples were for cannabinoids, volatiles, benzodiazepines, and other acidic/neutral/basic drugs. Methodology consisted of enzyme multiple immunoassay technique (EMIT) and temperature programmed gas chromatography with confirmation by gas chromatography/mass spectrometry (GC/MS). Fifty-six samples were obtained from drivers arrested for suspicion of impaired driving. Other than alcohol, the major drugs detected were cannabinoids and diazepam. Cocaine was found in one case.

Platinum concentrations in human autopsy tumor samples

Platinum concentrations were determined in autopsy tumor samples obtained from 27 patients who had received cisplatin 40–1,029 mg/m2 from 0 to 240 days antemortem. Liver metastases had significantly higher platinum concentrations than did tumors in other sites (p < 0.005). Platinum concentrations in liver metastases were similar to platinum concentrations in normal liver. Platinum concentrations in gliomas and brain metastases were similar to platinum concentrations in other extrahepatic tumors. Platinum concentration generally decreased with increasing distance into brain from tumor. By multiple stepwise linear regression analysis, the factors that were independently most closely associated with tumor platinum concentration were time from last cisplatin treatment, cumulative lifetime dose of cisplatin, route of cisplatin administration (intraarterial vs. other), and site of tumor deposit (liver vs. other) (r = 0.69, p < 0.001). Patients whose tumors had responded to cisplatin-containing regimens had mean tumor platinum concentrations that were higher than the mean tumor platinum concentrations in patients whose tumors had not responded to cisplatin (p < 0.05).

Renal and hepatic concentrations of platinum: relationship to cisplatin time, dose, and nephrotoxicity.

Autopsy tissues were obtained from 30 patients who had received cisplatin antemortem; the tissues were assayed for platinum by flameless atomic absorption spectrometry. Patients with antemortem evidence of renal toxicity had higher renal cortical platinum concentrations than did patients without evidence of kidney damage. In addition, patients with nephrotoxicity were more likely than patients without toxicity to have renal cortical platinum concentrations that were higher than renal medullary platinum concentrations. Overall, the two variables most closely associated with an increase in serum creatinine with treatment were renal cortical platinum concentration (P less than .02) and cumulative dose of cisplatin (P less than .05). These two variables were important independently of one another. Renal cortex platinum concentrations correlated inversely with time from last treatment until death, whereas hepatic platinum concentrations did not. In contrast, hepatic platinum concentrations correlated with dose of cisplatin while renal platinum concentrations did not. Our results suggest the following: (1) cisplatin-induced renal toxicity is tissue-platinum-concentration dependent and cisplatin-dose dependent; and (2) cisplatin may be handled differently at the molecular level in liver and kidney.

Hyperuricemia and hypoalbuminemia predispose to cisplatin-induced nephrotoxicity

SummaryThe usefulness of pretreatment biochemical parameters in the prediction of nephrotoxicity associated with cisplatin treatment was studied. Twenty-two patients, who received 29 cycles of cisplatin, were evaluated. Cisplatin was given every 3–4 weeks with saline and mannitol. Azotemia occurred in almost all patients and was transient, peaking 1–2 weeks after therapy. The change in serum creatinine from baseline to peak correlated inversely with pretreatment serum albumin (r=-0.73; P<0.01) and with pretreatment uric acid (r=0.76; P<0.01). Ten patients with uric acid level of <6 mg/dl were receiving allopurinol. The competition between organic anions and cisplatin for excretion may, in part, explain the protective effects of hypouricemia. Hypoalbuminemia affects peritubular oncotic pressure and may in turn affect platinum excretion. Hypoalbuminemia also reduces the half-life of cisplatin, exposing the kidney to more of the unbound filterable drug.

Use of skin surface sampling and ion mobility spectrometry as a preliminary screening method for drug detection in an emergency room

We have evaluated the use of a novel method for detecting drug residues on the hands of emergency patients suspected of drug overdose. The residues are collected by means of a suction probe and subsequently analyzed by thermal desorption directly into an ion mobility spectrometer. All patients admitted to the Emergency Room had their palms, fingers and nostrils sampled. Of the 101 drug related ingestions, 50 were related to tablets, 47 to film or sugar-coated tablets and 4 to cocaine powder. Positive identification was possible in 42% of tablet related ingestions, 29% of coated tablet or capsule ingestions and in all patients using cocaine. In 53% of the cases where positive drug identification was made, sampling had been carried out within 30 minutes of the patients arrival at the Emergency Room.

Factors affecting human autopsy kidney-cortex and kidney-medulla platinum concentrations after cisplatin administration

The objective of this study was to determine factors that affect cisplatin concentrations in human kidney cortex. We used flameless atomic absorption spectrophotometry to assay platinum in autopsy specimens of kidney cortex obtained from 83 cisplatin-treated patients. Concentrations were correlated with pretreatment factors and treatment conditions using univariate nonparametric statistics. Hierarchical stepwise multiple regression analyses of transformed (to normalize) data were then used to assess which factors were most important, controlling for other factors. Kidney-cortex platinum concentrations varied from 0 to 14.8 μg/g (median, 2.04 μg/g). The cumulative lifetime dose of cisplatin ranged from 10 to 1120 mg/m2 (median, 112 mg/m2). The time from the last cisplatin dose to death was <1–609 days (median, 38 days). According to univariate statistics, factors that correlated (P<0.05) with kidney-cortex platinum concentrations were the cisplatin dose per course, the pretreatment serum urea level, metoclopramide use (positive correlations), the time from the last cisplatin treatment to death, and the pretreatment serum albumin value (negative correlations). Factors that approached significance (0.05≤P≤0.10) were a history of hypertension, hyperbilirubinemia (positive), the serum calcium level, and phenytoin use (negative). In the multiple regression analysis, after controlling for the cisplatin dose per course and the time from the last treatment to death, only concurrent metoclopramide and phenytoin use entered the model. The hydration volume did not affect corrected kidney-cortex or kidney-medulla platinum concentrations. The following conclusions were reached: (1) it may be feasible to use lower hydration volumes than those used routinely, (2) any effect of hydration volume on cisplatin nephrotoxicity may not be mediated via a reduction in kidney-cortex platinum concentrations, (3) higher cisplatin doses might be tolerated with new 5-hydroxytryptamine-3 (5HT-3) antiemetics than were tolerated with metoclopramide, and (4) phenytoin should be tested for its ability to reduce cisplatin nephrotoxicity.

The clinicopathological significance of cytomegalovirus inclusions demonstrated by endocervical biopsy

Summary A healthy 20 yr old woman presented for evaluation following a cervical smear which showed viral effects typical of human papilloma virus. Colposcopy showed changes of cervicitis with the main finding on histologic examination of biopsy material being an acute and chronic cervicitis associated with typical features of cytomegalovirus (CMV) infection. Viral identification was confirmed by immunoperoxidase staining, in situ hybridization and electron microscopy. The patient was lost to follow up for 18 mths. Following this, a repeat colposcopy again showed inflammation, with cervicitis, mild dysplasia and CMV inclusions on biopsy. Full immunological work‐up, including human immunodeficiency virus (HIV) study, was performed and was normal. Only 11 other cases of endocervical biopsies with histological evidence of CMV inclusions were found in the literature, although the reported rate of detection of genital CMV in women on culture is 4–12%. In the 9 cases where information was available, endocervical inflammation was present. One patient was on immunosuppressive medication for systemic lupus erythematosus and another was found to have Acquired Immune Deficiency Syndrome (17% of total). These cases demonstrate that although histologic examination is an insensitive marker for CMV within the cervix, its presence may signify immunodeficiency and so immunological assessment of a patient with this finding is advisable.

Human autopsy tissue distribution of the epipodophyllotoxins etoposide and teniposide

Autopsy tissues were collected from ten patients who had received etoposide, 150–3480 mg, from 1 to 412 days antemortem and from five patients who had received teniposide, 234–1577 mg, from 3 to 52 days antemortem. Tissues were assayed for etoposide and teniposide using high-pressure liquid chromatography with electrochemical detection. Etoposide was detectable in tissues of three of four patients dying <5 days after their last etoposide treatments to cumulative doses of 150–432 (median, 280) mg but was detectable in tissues of only one of six patients dying 7–412 (median, 37) days after their last etoposide treatment to a cumulative dose of 607–3600 (median, 1553) mg. The highest tissue concentrations were in the small bowel, prostate, thyroid, bladder, spleen, and testicle. Intermediate concentrations were found in the lymph node, skeletal muscle, adrenal gland, stomach, tumor, liver, lung, pancreas, and kidney, and the lowest concentrations were found in the heart, brain, diaphragm, vagina, and esophagus. Teniposide was detectable in one patient dying 3 days after a cumulative teniposide dose of 576 mg (spleen, prostate, heart > large bowel, liver, pancreas > thyroid, adrenal, stomach, small bowel, bladder, testicle, and skeletal muscle) but was not detectable in any tissue from four patients dying 5–52 (median, 8) days after their last treatment to a cumulative teniposide dose of 234–1577 (median, 520) mg. The very short tissue half-life contrasts with our previous observations for human autopsy tissue concentrations of mitoxantrone, doxorubicin, menogaril metabolites, diaziquone, and amsacrine. The short tissue half-life may help explain the schedule dependency of epipodophyllotoxin efficacy and may also help explain the lack of visceral toxicity of these compounds.

Hypoalbuminemia in Patients Receiving Cisplatin: Correlation between Liver Platinum and Decrease in Serum Albumin

We evaluated changes in serum albumin concentrations in 15 patients with advanced malignancy who were also receiving cisplatin. All 15 patients had serial measurements of serum albumin. The decrease in serum albumin from the time of the first dose of cisplatin to death correlated with liver platinum levels at autopsy (r = 0.46, p less than 0.05). The decrease in serum albumin concentration associated with liver platinum concentration of less than or equal to 1.5 micrograms/g was 0.16 +/- 0.23 g/dl (range 0-0.6). The decrease associated with liver platinum concentrations of greater than 1.5 micrograms/g was 1.0 +/- 0.45 g/dl (range 0.5-1.9; p less than 0.02). The decrease in serum albumin may be secondary to a hepatotoxic effect of cisplatin.