Zul Verjee

Cyclosporine excretion into breast milk.

Although many female patients of childbearing age who are receiving cyclosporine have successful pregnancies, these women may be advised not to breast-feed. During recent years, cases of uneventful pregnancies and subsequent successful breast-feeding have been reported in the literature. The infants blood cyclosporine concentration was usually very low. Based on these findings and the lack of detectable adverse effects, some investigators have suggested that women on cyclosporine may breast-feed, challenging the conventional view that cyclosporine is contraindicated during breast-feeding. Here, we report our experience with cyclosporine use during breast-feeding in five mother-infant pairs. We show a wide range of infant exposures to the drug in milk, noting that one of the infants had therapeutic blood concentrations of cyclosporine despite relatively low concentrations of the drug in milk.

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.

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 immunoassays 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.

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.

Acute digoxin overdose in a newborn with renal failure: use of digoxin immune Fab and peritoneal dialysis.

Digitalis intoxication is a common problem, mainly because of the narrow margin of safety of digoxin. These patients may have concomitant renal failure. In patients who have renal failure and who have been treated with digoxin-Fab, the elimination of the digoxin-Fab complex is significantly delayed, and there is a risk of dissociation of the complex with rebound of free digoxin and recurrence of toxicity. The high molecular weight of digoxin and digoxin-Fab complex prevents its elimination by hemodialysis or continuous arteriovenous hemofiltration. A 3-day-old newborn with digoxin overdose and acute renal failure was treated with digoxin immune Fab and peritoneal dialysis. Low levels of total digoxin were measured in the dialyzate, indicating poor elimination of the digoxin-Fab complex through peritoneal dialysis.

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.

Glycine conjugation of para-aminobenzoic acid (PABA): a pilot study of a novel prognostic test in acute liver failure in children.

BackgroundFulminant hepatic failure (FHF) is associated with high mortality; few patients survive without liver transplantation. It is important to have a sensitive, specific early predictor of outcome to distinguish potential survivors (S) from nonsurvivors (NS). ObjectiveBecause we had previously shown that glycine conjugation of para-aminobenzoic acid (PABA) quantitatively reflects liver function in children with chronic liver disease, in this pilot study we wanted to determine whether the measurement of the glycine conjugates of PABA could distinguish S from NS in FHF in comparison with standard prognostic indices. MethodsTwenty-four patients were studied: acute severe hepatitis (n = 7), subfulminant hepatic failure (n = 7), and FHF (n = 10). Assessment of Kings College criteria, measurement of factor V and VII levels, PABA testing, and transjugular liver biopsies were performed in almost all patients within 48 hours of admission. Serum PABA and its glycine conjugates (para-aminohippurate (PAHA) and para-acetamidohippurate (PAAHA)) were measured thirty minutes after oral administration by high-pressure liquid chromatography. Poor prognostic categories as previously established in the literature were defined as factor V < 0.20U/ml, factor VII < 0.08 U/ml, % necrosis >70%, hippurate ratio = 0%, and PAHA = 0M. ResultsThe measurement of PAHA was the best predictor of a poor outcome in patients with acute liver failure with a sensitivity of 92%, and negative predictive value (NPV) of 92% compared with a sensitivity of 54% and a NPV of 63% with Kings College criteria. ConclusionMeasurement of serum PAHA is the best early prognostic marker of death in children who suffer from FHF.

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.

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.

Increased serum vitamin A and E levels after lung transplantation.

Background. Adult cystic fibrosis (CF) patients experience significant increases in serum vitamin A and E levels after lung transplantation. It is unclear whether this finding is specific to the CF population or inherent to the lung transplantation process. Methods. The objectives of this study were to assess pre- and postlung transplantation serum vitamin A and E levels in subjects with end-stage lung disease secondary to all causes. The study population consisted of adults who received a lung transplant at the Toronto Lung Transplant Program between 2004 and 2009. The mean change in serum vitamin A and E levels pre- and postlung transplant was evaluated using a paired t test, while differences in vitamin A and E levels between CF and non-CF subjects were determined using a Students t test. Results. Thirty-two CF and 21 non-CF subjects who underwent lung transplantation were included in the study. Mean serum vitamin A and vitamin E levels increased significantly after transplant, from 1.2 to 3.5 &mgr;mol/L (P<0.0001) and from 21.9 to 33.2 &mgr;mol/L (P<0.0001), respectively. The proportion of individuals with serum levels above the upper limit of normal increased from 7.6% to 88.7% (P<0.0001) and from 11.3% to 24.5% (P=0.02) for vitamin A and vitamin E, respectively. The dosage of vitamin supplementation did not increase after transplant. Conclusions. Significant increases in serum vitamin A and E levels were seen in both CF and non-CF subjects after lung transplantation. Further research is needed to understand the cause and clinical implications of these findings.