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.

Increase in serum uric acid level associated with cisplatin therapy. Correlation with liver but not kidney platinum concentrations.

Hyperuricemia associated with cisplatin therapy is considered to be a consequence of cisplatin-induced nephrotoxic reactions. We correlated changes in serum uric acid levels in patients with malignant neoplasms with tissue levels of platinum and the total dose of cisplatin. In 15 patients, the serum uric acid level increased from 6.1 +/- 1.0 mg/dL to 8.3 +/- 1.3 mg/dL during the time they were receiving cisplatin therapy. The change in uric acid level from baseline to peak correlated with both the total dose of cisplatin and the liver platinum concentration. There was no correlation with platinum concentration in the renal cortex and medulla.

Free radical formation during ketamine anesthesia in rats: a cautionary note.

Ketamine is a useful anesthetic agent with good analgesic properties; however, when ketamine was used to anesthetize rats for spin trapping studies of alcohol-induced free radicals, liver extracts contained a strong electron paramagnetic resonance (EPR) signal of a novel radical. The same EPR signal was observed in liver extracts when rats which had not received alcohol were anesthetized with ketamine. When ketamine was added to liver microsomes and NADPH, a nitroxide radical derived from ketamine could be detected in organic extracts. When the spin trapping agent POBN was also added, microsomes produced both a ketamine nitroxide radical and a spin adduct. Similar results were obtained during ketamine oxidation by hydrogen peroxide in a tungstate-catalyzed reaction, or in a Fenton reaction system. The data suggest that the secondary amine group of ketamine can be oxidized to a stable nitroxide which produces an EPR spectrum in the absence of a spin trapping agent. The POBN spin adduct detected may be from a carbon-centered radical in the cyclohexanone ring of ketamine. Because several types of radicals can be formed from ketamine, this agent may not be appropriate as an anesthetic for many types of in vivo spin trapping experiments.

Relationship between serum phosphate and parenteral nutrition--associated increase in serum glutamic-oxaloacetic transaminase.

Transient increases in SGOT are seen in patients receiving parenteral nutrition. We found the magnitude of the increase in SGOT to correlate significantly (r = 0.69, p less than 0.001) and inversely with the serum phosphate level measured at the same time as when the SGOT level was at its peak. Although the presence of the correlation does not implicate an etiological role for hypophosphatemia in the pathogenesis of hepatocellular injury, hypophosphatemia could possibly worsen the degree of fatty infiltration which is responsible for this increase in SGOT.

Macrophage migration inhibitory factor expression in male and female ethanol-fed rats.

Macrophage migration inhibitory factory (MIF) regulates macrophage accumulation at sites of injury and can promote the inflammatory response. We studied MIF expression in the intragastric feeding rat model for alcoholic liver injury. Male and age-matched female rats were fed ethanol or dextrose with fish oil. Two groups of male rats were fed medium-chain triglycerides with ethanol or dextrose. Analysis of liver histopathology, lipid peroxidation, endotoxin, mRNA, and immunohistochemistry for MIF, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were carried out. Male and female rats fed fish oil and ethanol showed necroinflammatory liver injury and had the highest expression of MIF, TNF-alpha, and IFN-gamma in the liver. Decreased levels of MIF protein were seen in rats with higher endotoxin levels, suggesting that preformed MIF is released into the circulation. MIF is an important mediator of the inflammatory response in alcoholic liver disease and a potential therapeutic target.

Ethanol-induced changes in membrane ATPases: inhibition by iron chelation.

The effect of chronic ethanol intake, with and without an iron chelator, on the activity of rat membrane ATPases was investigated. Using the intragastric feeding model, male Wistar rats (250 g) were fed a liquid diet and ethanol for 1 month. In control pair-fed animals, ethanol was isocalorically replaced by dextrose. In addition to the above groups, two groups of animals (dextrose or ethanol-fed) also received an oral iron chelator (1,2-dimethyl-3-hydroxypyrid-4-one, L1) (25 mg/kg/day for 30 days). The blood ethanol levels were maintained between 150 and 300 mg/dL. Red cells were washed immediately with ice-cold saline, membranes were prepared, and ATPases were measured. The mean Ca2+ pump ATPase in animals fed ethanol was lower than in dextrose-fed controls. In contrast, Na+/K+ pump ATPase was enhanced following chronic ethanol treatment. The addition of L1 to the diet prevented the changes in both the Ca(2+)-ATPase and Na+/K(+)-ATPase in ethanol-fed rats. Although the exact mechanism for the prevention of changes in ATPase activity by L1 is unknown, it is not a result of non-specific interaction between the chelator and membranes. Incubation of purified membranes with different concentrations of L1 for 60 min at 37 degrees had no effect on the activity of the ATPase. In conclusion, chronic intake of ethanol specifically inhibited Ca2+ pump ATPase and enhanced Na+/K(+)-ATPase in rat red blood cell membranes. The iron chelator, L1, corrected both of these ethanol-induced changes.

Effect of chronic ethanol feeding on plasma and liver alpha- and gamma-tocopherol levels in normal and vitamin E-deficient rats. Relationship to lipid peroxidation.

The effects of chronic ethanol intake on the levels of alpha-tocopherol and gamma-tocopherol in serum and liver of both vitamin E-deficient and normal rats were studied. An intragastric feeding rat model was used. Both normal and vitamin E-deficient animals were fed a liquid diet and ethanol for 1 month. In pair-fed animals, dextrose was isocalorically replaced by ethanol. The blood ethanol level in the ethanol-fed animals was between 150 and 250 mg/dL. Liver peroxidation was determined by measuring thiobarbituric acid reactive substances (TBARS). Plasma alanine aminotransferase (ALT) was increased by 3-fold in vitamin E-deficient ethanol-fed rats compared with normal ethanol-fed rats. Plasma alpha- and gamma-tocopherol were decreased in the normal ethanol-fed rats by 22.3 and 65%, respectively (P < 0.01). Liver alpha- and gamma-tocopherol were also decreased by 51.7 and 76%, respectively (P < 0.01). Vitamin E-deficient animals had significantly lower mean plasma alpha-tocopherol (5670 vs 530 ng/mL, P < 0.01), and ethanol feeding did not decrease the levels any further. However, ethanol feeding decreased liver alpha- and gamma-tocopherol by 58.5 and 56.5% (P < 0.01), respectively, beyond the already low levels observed in this group. There was an inverse correlation between liver TBARS and liver alpha-tocopherol (r = -0.59, P < 0.05) and gamma-tocopherol (r = -0.65, P < 0.02). Also of significance is that ethanol feeding decreased the plasma and liver gamma-tocopherol more than the alpha-tocopherol in both normal and vitamin E-deficient animals. In conclusion, ethanol feeding markedly decreased both alpha- and gamma-tocopherol in livers of normal and vitamin E-deficient rats, but it only decreased plasma levels of tocopherols in normal rats. The higher ALT in vitamin E-deficient animals and the inverse correlation between TBARS and alpha- and gamma-tocopherol suggest that enhanced lipid peroxidation is associated with greater severity of liver injury induced by ethanol in vitamin E-deficient rats.

Ethanol-induced suppression of interleukin 1-like activity: reversal by a quinone derivative.

Chronic ethanol intake impairs several parameters of immune function. Since there is evidence that cytokine production by immune cells may contribute to the immunosuppressive effect of ethanol, we examined interleukin 1 (IL1) production by liver non-parenchymal cells (NPC) in ethanol-fed rats. Male Wistar rats (225-250 g) were fed by continuous intragastric infusion. The source of fat was either saturated fat or polyunsaturated fat. In addition, the effect of a quinone compound on IL1 production was assessed. Animals were fed for various periods: 1 week, 2 weeks, 1 month and 2 months. NPC were isolated and stimulated by lipopolysaccharide. IL1 production by NPC and the ratio of stimulated to unstimulated (S:U) IL1 production were evaluated in the different groups and related to the presence of liver injury. As expected, animals fed corn oil and ethanol (CO+E) developed pathologic liver injury, whereas animals fed saturated fat and ethanol (SF+E) had no liver injury. A progressive decrease in the S:U IL1 ratio was seen in the CO+E group over the 8-week period. The ratio in the SF+E group was higher. The quinone compound reversed the suppressive effect of ethanol on IL1 production. In summary, ethanol-induced suppression of IL1 production was modulated by diet and the presence of liver injury. This suppression of IL1 production was reversed by a quinone compound; the exact mechanism for the reversal of this inhibition is unknown.

Asystole and ventricular fibrillation associated with cocaine intoxication.

We discuss a patient with cocaine intoxication in whom the initial presentation was that of asystole and ventricular fibrillation. Cocaine has a direct toxic action on the heart and also sensitizes cardiac tissue to the action of catecholamines. Cocaine intoxication should be considered in any patient with unexplained cardiac arrest or ventricular arrhythmias.

Use of a multichannel analysis profile for the assessment of risk of developing coronary heart disease.

The use of serum total cholesterol: high density lipoprotein cholesterol (TC:HDL-C) is well-established. Because HDL-C measurements are expensive, and cholesterol is part of the multichannel analysis profile, the author attempted to determine whether other parameters which are part of this profile could be useful indicators of the TC:HDL-C ratio. Based on an inverse correlation obtained in healthy men (42-59 years of age) between HDL-C and fasting plasma glucose (r = 0.40, P less than 0.001), triglycerides (r = 0.51, P less than 0.001), and uric acid (r = 0.29, P less than 0.01), a GUT (glucose, uric acid, triglyceride) score was calculated and correlated with the TC:HDL-C ratio (r = 0.86, P less than 0.001). In over 90% of cases the GUT score was able to predict whether an individual was likely to have a TC:HDL-C ratio of less than 4.5 or greater than 4.5. Thus, the GUT score is a useful indicator for an individual who is likely to require a lipid profile which includes HDL-C measurement.

Relationship between body weight and total leukocyte count in morbid obesity.

The authors studied the relationship between total leukocyte count and body weight in 42 morbidly obese patients (weight range, 101.5-206.8 kg). None of the patients had a recent history of infection, hematologic disorders, chronic respiratory disease, or were smoking more than 5 cigarettes/day. The range of total leukocyte count was 4.2-12.0 X 10(9) cells/L. Twelve of the 42 patients had a leukocyte count of 10 X 10(9) cells/L. There was a significant correlation between body weight (kg) and total leukocyte count (r = 0.68, P less than 0.001). Morbid obesity should be considered as one of the causes of physiologic leukocytosis.

Near-patient testing. Quality of laboratory test results obtained by non-technical personnel in a decentralized setting.

The authors evaluated the quality and reliability of four desktop analyzers in the outpatient clinic. Twenty-seven nontechnologists (NTs) participated in the study. These included nurses, physicians, and medical students. The instruments and tests evaluated were as follows: Reflotron (glucose, cholesterol, triglycerides, gamma-glutamyltransferase and urea); Seralyzer (creatinine, glucose, potassium, aspartate aminotransferase, and hemoglobin); Vision (glucose, urea, cholesterol, triglycerides, alkaline phosphatase, and uric acid); and DT60 (sodium, potassium, glucose, amylase, uric acid, bilirubin, and creatinine). For precision studies, low and high control material was used, and method comparison was done with methods in routine use in the laboratory. The range of coefficients of variation (CVs) for the analyzers with NTs was as follows: Reflotron: CV, 2.4-7.9%; Seralyzer CV, 1.4-18.7%; Vision: CV, 1.5-2.7%; DT60: CV, 2.5-46.8. The percentage results that is different by greater than 10% between the NTs and trained technologists was related to the complexicity of procedure for each analyzer and was the lowest for the Vision analyzer and greatest for the Seralyzer.

Use of total cholesterol/albumin ratio as an alternative to high density lipoprotein cholesterol measurement.

In a study of apparently healthy males, we noted a correlation between serum albumin and high density lipoprotein cholesterol (HDL-C) (r = 0.32, p less than 0.001). We then correlated the total cholesterol:albumin ratio (TC:Alb) with the TC:HDL-C ratio (r = 0.89, p less than 0.001). We used the TC:Alb ratio to determine whether this was better than TC by itself in predicting whether an individual had a TC:HDL-C ratio of less than or greater than or equal to 5. The ratio performed better than TC and correctly classified 89% of individuals (66% with TC) (p less than 0.001). Since measurements of TC and Alb are routinely available on multichannel analysers, use of this ratio would provide a less expensive alternative to HDL-C measurement.

Comparison of hospital staff performance when using desk top analysers for "near patient" testing.

The quality and reliability of four desk top analysers were evaluated. In the context of an outpatient clinic, intensive care unit, and a mock up of a physician's office. Seventeen nurses, 14 physicians, and 12 medical office personnel took part in the study. The instruments and tests evaluated were Reflotron (glucose, cholesterol, triglycerides, gamma-glutamyl transferase), Seralyzer (creatinine, glucose, potassium, aspartate aminotransferase), Vision (glucose, (creatinine, glucose, potassium, aspartate aminotransferase), Vision (glucose, urea, cholesterol, triglycerides alkaline phosphatase, uric acid), and DT60 (sodium, potassium, glucose, amylase, uric acid and creatinine). Of the 320 tests performed on the Vision, only two differed by more than 10% between the specialist staff and other groups. For those performed on the Seralyzer, 95 of 254 results differed by more than 10%, 19 of 199 by more than 10% for the Reflotron, and 50 of 318 by more than 10% for the DT60. In general, the nurses were more adept at using the analysers than the physicians and medical office personnel.

Hyperuricemia and hypoalbuminemia predispose to cisplatin-induced nephrotoxicity.

The 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 less than 0.01) and with pretreatment uric acid (r = 0.76; P less than 0.01). Ten patients with uric acid levels of less than 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.

Markedly increased serum aspartate aminotransferase activity in congestive heart failure.

Congestive heart failure usually features a mild to moderate increase in aspartate aminotransferase (AST) activity. A marked increase in AST may occur rarely and is usually preceded by prolonged shock or hypotensive episodes and is accompanied by hyperbilirubinemia. I report two patients with congestive heart failure in whom the AST activity was greater than 8000 U/L. No prior episodes of shock or hypotension occurred in these patients and the accompanying increase in bilirubin was slight. In both cases, the enzyme activity decreased sharply with improvement in the patients' circulatory status. Recognition of this entity is important to distinguish it from viral or drug-induced hepatitis.

Falsely-elevated serum creatinine values in diabetic ketoacidosis -- clinical implications.

Unusual elevations of serum creatinine (S-CR) out proportion to increases in serum urea nitrogen (S-UN) are frequently observed in patients with diabetic ketoacidosis when S-CR is measured by the Jaffe end-point reaction. This has been ascribed to interference from acetoacetate but this is not however observed with kinetic DuPont ACA methodology. Eighteen patients with diabetic ketoacidosis were studied: SCR measurements were done using the end point Technicon SMA 6/60 method (Group a, 10 patients) or the kinetic DuPont ACA method (Group B, 8 patients). The values for S-CR in Group A patients (mean value and S-D were 3.3 +/- 1.1 mg/dl) were significantly different from Group B patients (1.6 +/- 0.24 mg/dl) (P less than 0.01). A significant positive correlation was obtained between the "excess anion gap" and S-CR in Group A patients (r = + 0.81, p less than 0.01). The results from two patients in whom serial measurements of S-UN, S-CR and the anion gap were carried out further demonstrate the analytical interference. The study demonstrates that in diabetic ketoacidosis elevated creatinine values measured by an end-point method should not necessarily be interpreted as evidence of significant renal impairment and if possible should be verified by a kinetic method which is free of "ketone" interference.

Antibody interference with biochemical tests and its clinical significance.

Antibody interference with routine biochemical tests is becoming increasingly recognized as a cause of spurious results. It is important to recognize these interferences because inappropriate investigation may be instituted in response to the abnormal test result. The present review deals with the various biochemical tests in which antibody interference occurs. The tests include measurement of enzymes, hormones, immunoglobulins, vitamin B12, and a variety of other molecules and ions.

Ketone interference in estimation of urinary creatinine; effect on creatinine clearance in diabetic ketoacidosis.

Acetoacetate is known to spuriously raise serum creatinine concentration in patients with diabetic ketoacidosis. Its effect on urinary creatinine has not been studied. Since the renal threshold for ketoacids is low, large amounts of acetoacetate may be present in the urine of uncontrolled diabetics. We investigated this interference using three different automated analysers. We found that +3 or +4 reactions with Ketostix, equivalent to greater than 10 - 15 mmol/L of acetoacetate caused significant interference with the Abbott VP and Beckman Astra instruments. This could cause errors in the calculation of creatinine clearance especially when serum creatinine is close to a normal level. We recommend that measurement of creatinine clearance be delayed until better diabetic control is achieved or the creatinine be measured by a method which is free from ketone interference, e.g., by the Dupont aca.

Ticarcillin associated hypokalemia.

We evaluated the presence and degree of hypokalemia associated with ticarcillin disodium (ticarcillin) therapy in 16 patients. Four of these patients who received less than 10 grams of ticarcillin did not develop significant hypokalemia, but this condition developed in 6 of 9 patients receiving a daily dose of greater than 18 grams of this drug, and the mean urinary potassium was elevated in this group (mean = 78 mEq/24 hrs). The degree of hypokalemia was correlated with the volume status of the patient as judged by the serum urea nitrogen: creatinine ratio. A positive correlation (r = 0.66, p less than 0.05) was obtained between the two parameters. Hypokalemia did not develop in three patients with the syndrome of inappropriate secretion of anti-diuretic hormone who were receiving more than 18 grams of ticarcillin daily, indicating the absence of a stimulus for sodium conservation. Aggressive potassium and fluid replacement should be considered in patients with hypokalemia associated with ticarcillin therapy.