The hippurate ratio as an indicator of functional hepatic reserve for resection of hepatocellular carcinoma in cirrhotic patients.

Predicting the ability of the cirrhotic liver to withstand resection remains a challenge for the surgeon. This study evaluates the use of the hippurate ratio, a novel assessment of glycine conjugation of para-aminobenzoic acid by the liver, as a preoperative indicator of functional hepatic reserve. Between 1998 and 2000, sixty-one cirrhotic patients were prospectively assessed for hepatic resection using the hippurate ratio, indocyanine green retention at 15 minutes (ICG R-15), and other standard measures of liver function. Twenty-six patients were excluded as candidates for resection on the basis of inadequate functional hepatic reserve. Patients excluded from resection had significantly higher ICG R-15 values (29% +/- 9% vs. 16% +/- 12%, P = 0.001), higher Child-Pugh scores (5.9 +/- 0.9 vs. 5.3 +/- 0.4, P = 0.01), and lower hippurate ratios (30% +/- 14% vs. 45% +/- 15%, P = 0.005). There was a significant correlation between the hippurate ratio and ICG R-15. Other indicators of liver function such as factor V, factor VII, albumin, bilirubin, prothrombin time, and transaminases were no different between patients who did and those who did not undergo resection. Of the 35 patients resected, there were seven (20%) who developed varying degrees of liver failure with three perioperative deaths (8.5%). Patients who had some degree of liver failure had significantly lower hippurate ratios than patients who had no liver failure (29% +/- 10% vs. 48% +/- 14%, P = 0.002). There was no difference in ICG R-15 values between patients who had liver failure and those who did not. The hippurate ratio offers information on hepatocellular reserve that is not provided by other measures of liver function and may allow better selection of cirrhotic patients for liver resection.

Some international approaches to aminoglycoside monitoring in the extended dosing interval era.

Aminoglycosides have rightly remained a cost-effective anti-microbial strategy for the treatment of gram-positive infections for some 25 years. However, in recent years there has been a review of the traditional thrice-daily administration regimen in favor of an extended dosing interval strategy that takes into account the individual patient's renal function. The general recommendations that have been provided to date have been adopted in various ways internationally. These approaches were a matter of discussion for the Clinical Pharmacokinetics Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology at its congress (Vancouver, Canada; November 1997), and will again be a workshop issue at the Cairns (Australia) congress of the Association (September 1999). The present report provides examples of how these practices have been applied at a group of centers from Canada (2 centers), The Netherlands, Egypt, and Australia. These reports demonstrate a variety of approaches and highlight the need for further research for assessing clinical outcomes from different dosing strategies.

Contamination of antibiotics resulting in severe pediatric methadone poisoning.

OBJECTIVE: To report an accidental contamination of antibiotic suspension by methadone that occurred in a retail Canadian pharmacy, leading to severe poisoning in a young child. CASE SUMMARY: A 4 1/2-year-old healthy Asian boy was prescribed amoxicillin suspension for cough and fever. Shortly after receiving the second dose of 5 mL he became drowsy and less responsive. On admission, he was arousable by deep pain, and pinpoint pupils were noted. A urine sample sent for a toxicology screen revealed the presence of methadone and its metabolite. Blood methadone concentrations were 0.23 and 0.14 mg/L, five and nine hours after the second dose of amoxicillin was given, respectively. The amoxicillin suspension was tested for methadone and was found to have a concentration of 2.4 g/L. The child gradually improved and was discharged on day 4 in good condition. The pharmacy in which the antibiotic was dispensed has been a dispensing center for a local methadone maintenance program, and methadone was accidentally mixed with the antibiotics. DISCUSSION: In this case, a near fatal outcome occurred when methadone was inadvertently mixed with antibiotics in a community pharmacy. A literature search revealed two previous reports of opiate toxicity in children following ingestion of oral antibiotic preparations. CONCLUSIONS: Prompt action is needed in Canadian pharmacies that dispense methadone in order to minimize such errors in the future. General practitioners, pediatricians, and emergency department physicians should recognize and suspect this rare cause of opiate toxicity in a child. In a patient presenting with a decreased level of consciousness and miosis, with or without respiratory depression, naloxone administration should be considered, whether or not a history of opioid ingestion is obtained.

Intravenous and oral propafenone for treatment of tachycardia in infants and children: pharmacokinetics and clinical response.

To elucidate contribution of an active metabolite to overall clinical responses to propafenone, steady-state disposition of propafenone and its active metabolite and the clinical responses to treatment were examined in pediatric patients receiving intravenous or oral propafenone. There were more than ten-fold interindividual differences in apparent clearance, resulting in a wide range of the steady-state trough plasma concentrations of propafenone. The active metabolite, 5-hydroxypropafenone, was detected in four of the six patients receiving oral propafenone; however, two neonates receiving oral propafenone and all eight receiving intravenous propafenone had no detectable levels of 5-hydroxypropafenone in plasma. In nine patients for whom electrocardiographic (ECG) data were available, the PQ interval was significantly increased, whereas the QRS duration and the QTc interval were not. There was no close relationship between plasma concentrations of propafenone or 5-hydroxypropafenone and ECG parameters. Lack of good correlation between serum concentrations and clinical response precludes using a serum-concentration targeting strategy with propafenone therapy.

Carbamazepine interference with an immune assay for tricyclic antidepressants in plasma.

BACKGROUND: Drug toxicological screening is commonly used as a diagnostic tool in patients with suspected toxic ingestion. False positive results due to cross-reactive compounds in drug assays may lead to misdiagnosis and mismanagement, especially when child abuse is suspected. CASE REPORT: Two of our patients with history of ingestion of carbamazepine were tested positive on screening with the tricyclic antidepressant immunoassay. The immunoassay's known cross-reactivity for carbamazepine is reportedly as low as 0.3%. Plasma samples of our patients were initially considered positive for tricyclic antidepressants because the cross-reaction of carbamazepine gave tricyclic antidepressant concentrations as imipramine equivalent sufficiently above the assay cut-off point (20 ng/mL). Later, confirmatory urine testing of both patients using high-performance liquid chromatography was negative for tricyclic antidepressants. CONCLUSION: This interference has significant clinical implications, and can be avoided on urine testing using a specific chromatographic assay such as high-performance liquid chromatography.

The digoxin-propafenone interaction: characterization of a mechanism using renal tubular cell monolayers.

When propafenone is given with digoxin, digoxin serum concentrations increase. Although the digoxin-propafenone interaction is well known clinically, the mechanism by which propafenone interferes with digoxin elimination is unclear. To test the hypothesis that propafenone or one or both of its two major metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), inhibit the P-glycoprotein-mediated net renal tubular secretion of digoxin, we examined the transport of digoxin and the well-studied P-glycoprotein substrate vinblastine across confluent Madin-Darby canine kidney cell monolayers in the absence and presence of propafenone, 5-OHP and NDPP. Propafenone and its two major metabolites significantly inhibit the secretory flux of digoxin and vinblastine (propafenone > 5-OHP >> NDPP). Despite decreases in net transport, cellular digoxin accumulation did not decrease, suggesting that neither propafenone nor its metabolites prohibited digoxin from entering the cells at the basolateral side. NDPP, but not 5-OHP, was detected after 48 hr of incubation of the cells with propafenone alone. When the cells were incubated with propafenone or 5-OHP, apical accumulation of 5-OHP, but neither propafenone nor NDPP, against a concentration gradient was observed. These findings are consistent with the hypothesis that the digoxin-propafenone interaction results from the inhibition of the renal tubular transport of digoxin by propafenone and its metabolites. Our data suggest that propafenone is an inhibitor of P-glycoprotein, whereas 5-OHP is a possible substrate.

Is saliva suitable for therapeutic monitoring of anticonvulsants in children: an evaluation in the routine clinical setting.

Studies performed in the research setting suggested that saliva instead of blood may be used for therapeutic drug monitoring (TDM) of anticonvulsants in children. This is an attractive alternative because its collection is painless, and simpler and cheaper than blood drawing. Citric acid stimulation of saliva secretion facilitates sampling in the youngest patients. The aim of the study was to evaluate the suitability of saliva in routine TDM of anticonvulsants in infants and children with epilepsy. Blood and saliva samples were obtained simultaneously during routine TDM in 170 patients on chronic anticonvulsant drug therapy attending a neurology clinic. Saliva, plasma total, and plasma free concentrations of anticonvulsants were measured by high-performance liquid chromatography and enzyme multiplied immunoassay technique. Strong and highly significant correlations between saliva and plasma concentrations were found over a wide range of concentrations for carbamazepine, phenytoin, clobazam, and desmethylclobazam, and for phenobarbital in children > or = 8 years of age (r = 0.90 to 0.97; p < 0.001). Correlations between saliva and plasma concentrations were poor for phenobarbital in children < 8 years of age and for valproate. Correlations between saliva and plasma-free anticonvulsant concentrations were equal or only slightly better than between saliva and plasma total concentrations. Citric acid-stimulated saliva constitutes a convenient alternative for TDM of carbamazepine and phenytoin therapy in pediatric patients and of phenobarbital in children > or = 8 years of age.

A case of nondigitalis cardiac glycoside toxicity.

A case is presented of cardiac glycoside poisoning in a 1-year-old patient from the plant Nerium oleander (common oleander). The patient had bradycardia, vomiting, altered level of consciousness, and no history of ingestion. Antibody-based digoxin assays may cross-react with other cardiac glycosides nonquantitatively. Chromatographic techniques can be used in the specific diagnosis.

Measurement of serum acetylsalicylic acid in a porcine model of aspirin overdose.

Although the pharmacokinetics of acetylsalicylic acid (ASA) absorption and metabolism in therapeutic doses are well described, there is little information for overdose. A porcine model was developed to study ASA pharmacokinetics in overdose and to establish the feasibility of using area-under-the-curve (AUC) for serum ASA vs time rather than salicylate vs time as an indirect method of quantifying total drug absorption. Such a model could be useful in comparing the effectiveness of different methods of gastrointestinal decontamination in poisoning. The hydrolysis of ASA to salicylate, known to be a first-order process in therapeutic doses, was confirmed to remain first-order at high serum concentrations using iv aspirin in 2 pigs. Five simulated overdoses were then carried out in 4 pigs using 500 mg ASA/kg administered enterally as intact tablets. Serial determinations of both serum ASA and salicylate concentration were carried out over 72 h. Plots of ASA concentration vs time for each of the trials revealed delayed, multiple and erratic peaks consistent with a bolus effect from sudden dissolution of aspirin concretions, suggesting our model accurately simulates human overdose. Despite the variable peaks, the AUC of ASA concentration vs time for the 5 trials revealed a coefficient of variation of only 13%, compared with 27% for salicylate concentration vs time AUC. This suggests that serial measurements of serum ASA in a porcine ASA overdose model can be used to measure total drug absorption and thereby compare the effectiveness of different methods of gastrointestinal decontamination.

Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy.

BACKGROUND: External beam radiotherapy is standard treatment for medium and large, or visually threatening, intraocular retinoblastoma but markedly increases the risk of cosmetic deformities and second malignant neoplasms in children with germline RB1 mutations. Large tumors and those with vitreous seeds do poorly despite radiotherapy. Chemotherapy traditionally is ineffective for intraocular retinoblastoma, perhaps because many retinoblastomas overexpress the multidrug resistance protein, P-glycoprotein. OBJECTIVE: To avoid radiotherapy in the management of intraocular retinoblastoma by using chemotherapy and focal therapy. INTERVENTIONS: We shrank retinoblastomas in 40 eyes of 31 patients that conventionally should be enucleated or receive radiotherapy by using chemotherapy (ie, vincristine-teniposide, 8 eyes; additional carboplatin, 32 eyes) combined with the administration of cyclosporine, a known multidrug-resistance-reversal agent. We then consolidated these responses to chemotherapy by subsequent 532- and 1064-nm laser therapy and cryotherapy. RESULTS: At the median follow-up of 2 2/3 [corrected] years (range, 1/10-4 3/4 years), the results of treatment were excellent. The actuarial relapse-free rate was 89% in patients not previously treated (91% for 28 eyes) and 67% in patients treated after relapse from previous therapy (70% for 12 eyes). For the eyes with the worst prognosis (ie, vitreous seeds), the relapse-free rate was 88%, better than previously reported. Cyclosporine is nontoxic and did not enhance the expected toxic effects of chemotherapy. Most eyes required laser therapy, cryotherapy, or both for consolidation of tumor control. CONCLUSIONS: This pilot study suggests that most retinoblastomas are curable by combining chemotherapy with cyclosporine therapy, laser therapy, and cryotherapy, without requiring external beam radiotherapy. We propose a randomized trial to clarify the role of cyclosporine.

Delayed diagnosis of diltiazem overdose in a patient presenting with thrombosis of femoral artery.

Previous cases of diltiazem overdose described patients who presented with hypotension, heart block, bradycardia, or ultimately death. This report concerns an elderly patient presenting to the emergency room with hypotension, an ischemic leg and confusion. He underwent an emergency thrombectomy of the femoral artery. He had severe lactic acidosis, persistent hypotension requiring prolonged inotropic support and difficulty being weaned from the ventilator after the operation. Subsequent investigations confirmed that he attempted suicide by taking an unknown quantity of diltiazem. Because diltiazem has been increasingly prescribed to treat various cardiovascular disorders, overdose may become a more common problem. A high index of suspicion is required to ensure prompt diagnosis and appropriate treatment when patients taking this medication present with sudden circulatory collapse. A guide to the management of diltiazem overdose is provided.

Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation.

Chemotherapy without radiation has not controlled most intraocular retinoblastoma, perhaps because of the common high expression of multidrug resistance P-glycoprotein that we found in retinoblastoma. Cyclosporin blocks P-glycoprotein-induced efflux of vincristine and teniposide in vitro, and possibly modulates responses to carboplatin. To avoid eye irradiation in bilateral retinoblastoma patients with RB1 germline mutations, which incurs a high second malignancy rate, we added cyclosporin A to a vincristine-teniposide-carboplatin protocol and consolidated chemotherapy responses with focal therapy. We scored patients requiring irradiation, enucleation, or focal ablation of central vision as failures. In 21 study patients, the overall relapse-free rate at a median follow-up of 3.3 years was 76%, with a rate of 92% for newly diagnosed and 50% for previously treated, relapsed retinoblastoma. Our results for the most unfavorable tumors with vitreous seeds (86% at 3.5 years) are better than published success rates of irradiation for similar tumors, or irradiation with the same chemotherapy without cyclosporin (45% at 2. 6 years). These results also exceeded our historic success rate with similar chemotherapy without cyclosporin, focal therapy, and/or radiation in 19 equivalently poor-risk patients (relapse-free rate 37% at a median follow-up of 5.6 years, P = 0.032), 16 of whom were previously untreated (relapse-free rate also 37%, P = 0.012). A better outcome occurred with higher cyclosporin blood levels and projected tissue exposure. Cyclosporin did not enhance the usual chemotoxicity. This clinical study suggests that cyclosporin improves the long-term response of retinoblastoma to chemotherapy, possibly by more than one mechanism.

Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: pharmacokinetic characteristics.

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 +/- 2.6 (mean +/- S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 +/- 1.0 (range 0.5-2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m2 of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity.

Effect of multiple-dose activated charcoal on the clearance of high-dose intravenous aspirin in a porcine model.

STUDY OBJECTIVE: To study the effect of multiple-dose activated charcoal (MDAC) on salicylate clearance in pigs given high-dose i.v. aspirin. DESIGN: In a crossover design, six fasted pigs received 300 mg/kg i.v. aspirin followed by no treatment or MDAC (1 g/kg hourly for 6 doses by gastrostomy). Serum salicylate samples were obtained every 30 minutes for 6 hours. RESULTS: The mean peak salicylate concentrations were 47.4 +/- 6.2 mg/dL and 48.4 +/- 3.9 mg/dL (P = .74), and the areas under the time-serum salicylate concentration curve over 6 hours were 171,000 +/- 24,000 mg.minute/L and 188,000 +/- 18,000 mg.minute/L for the control and treatment arms, respectively (P = .22). This study had a 90% power to detect a 30% difference between arms. CONCLUSION: MDAC does not enhance the clearance of salicylate after administration of high-dose i.v. aspirin.

Glycine conjugation of para-aminobenzoic acid (PABA): a quantitative test of liver function.

OBJECTIVE: To evaluate glycine conjugation of para-aminobenzoic acid (PABA) to the hippurated metabolites, para-aminohippuric acid (PAHA), and para-acetamidohippuric acid (PAAHA) as a quantitative liver function test in patients with liver disease. DESIGN AND METHODS: Serum concentrations of PABA and metabolites were measured by high pressure liquid chromatography in 24 controls and 50 patients with hepatobiliary disease. RESULTS: Hippurate formation was significantly decreased in all patient groups with chronic liver disease versus controls. The hippurate ratio (% hippurated metabolites formed) correlated with severity of disease, serum albumin, and factor VII concentrations. PAHA concentration was a better prognostic indicator than factor VII concentrations in patients with acute liver disease; concentrations of zero correctly predicted a poor outcome in patients with fulminant liver failure. CONCLUSIONS: Glycine conjugation of PABA may be useful as a quantitative liver function test in patients with hepatobiliary disease and as a prognostic index in patients with fulminant liver failure.

Isoniazid-associated rhabdomyolysis.

We report the occurrence of rhabdomyolysis and hepatitis in a 17-year-old girl after the ingestion of up to 10.8 g of isoniazid. The initial isoniazid concentration in the blood was 1,230 mmol/L. There were no findings indicating the ingestion of other substances known to be associated with rhabdomyolysis. In addition to rhabdomyolysis (peak creatine phosphokinase 88,000 U/L), the patient had a significant elevation of her liver enzymes (peak aspartate aminotransferase 1,980 U/L). She recovered completely without evidence of liver or renal damage. Rhabdomyolysis and isoniazid-induced hepatitis are complications that should be considered when caring for patients with acute isoniazid ingestion.

Evaluation of therapeutic drug monitoring of methotrexate in saliva of children with rheumatic diseases.

Pediatric patients with leukemia, other malignancies, and rheumatological disease receive methotrexate chronically. Because of the documented correlation between methotrexate levels of compliance and clinical outcome, it is conceivable to verify appropriate systemic exposure to the drug. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is ethically limited. Our study shows poor correlation between serum total/free methotrexate concentrations and saliva levels, precluding the clinical use of this test.

Acute renal insufficiency in ibuprofen overdose.

Since the introduction of ibuprofen as a nonprescription drug in the US, there have been reports of significant toxicity associated with large ingestions (> 400 mg/kg) in both children and adults. Acute renal insufficiency is a rare, reversible effect of ibuprofen overdose documented in adults, but we could find no published pediatric cases. We report a case of a healthy two-year-old boy, without a previous history of renal problems, who developed reversible acute renal insufficiency after a toxic ingestion of approximately 640 mg/kg ibuprofen. By 11 hours, his initially normal creatinine began to rise, reaching a peak value of 181 mmol/L (2.1 mg/dl) by 27 hours. His urinalysis showed moderate microscopic hematuria without the presence of casts or proteinuria. No problems arose with fluid management. Normalization of his renal function occurred by 72 hours. A serum ibuprofen concentration obtained by high-performance liquid chromatography and drawn approximately four hours after ingestion was 1724 mumol (therapeutic serum concentration, 50-250 mumol). This case demonstrates that acute, reversible renal insufficiency can occur in healthy children after a severe overdose of ibuprofen; hence, renal function should be monitored in such instances.