Pharmacokinetics of oxaliplatin and non-hematological toxicity in metastatic gastrointestinal cancer patients treated with chronomodulated oxaliplatin, 5-FU and sodium folinate in a pilot investigation.

OBJECTIVE: To analyze in a pilot study the association between the pharmacokinetics of chronomodulated administered oxaliplatin and non-hematological toxicity in patients with metastatic gastrointestinal cancer. METHODS: 16 patients received a 4-day chemotherapeutic regimen consisting of a 12-h chronomodulated infusion of oxaliplatin (25 mg/m2) followed by a 12-h chronomodulated infusion of 5-fluorouracil (750 mg/m2) and sodium folinate (150 mg/m2) daily. Plasma pharmacokinetics of oxaliplatin, measured as ultrafiltrable platinum, were determined. RESULTS: Pharmacokinetics and non-hematological adverse events could be assessed in all patients included in the study. Pharmacokinetic parameters showed moderate interpatient variability. The occurrence of nausea and vomiting, but not diarrhea, was significantly associated with the pharmacokinetics of ultrafiltrable platinum. Thus, increased AUC values were observed in patients who experienced nausea or vomiting. No differences in pharmacokinetic parameters were found between patients with and without oxaliplatin-induced neurotoxicity or the other selected non-hematological toxicities. CONCLUSION: The preliminary results in this pilot study suggest an association between pharmacokinetics of ultrafiltrable platinum and non-hematological toxicity such as nausea and vomiting. Furthermore, although the sample size is limited, systemic exposure to ultrafiltrable platinum appears to predict the risk of non-hematological toxicity in patients treated with chronomodulated oxaliplatin combined with 5-FU and FS.

Two-hour postdose concentration: a reliable marker for cyclosporine exposure in adolescents with stable renal transplants.

In pediatric renal transplant recipients, most patients receive maintenance treatment with cyclosporine (CsA) and mycophenolate mofetil (MMF). Until now, the 2-hour postdose CsA target level for combined maintenance treatment with MMF has not been defined. This prospective pilot study evaluated the pharmacokinetics of CsA under the influence of MMF to determine a reliable single CsA concentration time that correlates with the area under the curve (AUC(0-6h)) estimates for adolescents who were additionally treated with MMF during the late posttransplant period. The study included 13 adolescents (mean posttransplantation time, 3.5 +/- 2.55 years) with stable renal transplant function (S-Crea 121 +/- 40 micromol/L). CsA pharmacokinetic absorption profiles over a 6-hour dose interval (n = 26) were evaluated for the optimal single peak concentration using the CsA concentrations predose (C0) and at 1, 2, 3, 4, and 6 hours postdose (C1-6). Whereas C2 (mean 743.2 +/- 221.8 ng/mL) was the single point with the closest correlation to AUC(0-6h) (r2 = 0.86; P < .001), C0 (mean 120.5 +/- 35.2 ng/mL) showed the weakest correlation (r2 = 0.61, P = .002). C2 appears to be an accurate predictor of CsA exposure in adolescent kidney transplant recipients under maintenance immunosuppression in combination with MMF. Average values achieved with current dosing practices cluster around the target C2 ranges recommended for adults. The data provide a foundation for initiation of prospective clinical trials to assess the long-term risk for chronic allograft dysfunction among pediatric stable renal transplant patients in combination protocols.

Antioxidant status in acute stroke patients and patients at stroke risk.

BACKGROUND AND PURPOSE: Antioxidant enzymes like copper/zinc superoxide dismutase (SOD), catalase and gluthatione peroxidase (GSHPx) are part of intracellular protection mechanisms to overcome oxidative stress and are known to be activated in vascular diseases and acute stroke. We investigated the differences of antioxidant capacity in acute stroke and stroke risk patients to elucidate whether the differences are a result of chronic low availability in arteriosclerosis and stroke risk or due to changes during acute infarction. METHODS: Antioxidant enzymes were examined in 11 patients within the first hours and days after acute ischemic stroke and compared to risk- and age-matched patients with a history of stroke in the past 12 months (n = 17). Antioxidant profile was determined by measurement of glutathione (GSH), malondialdehyde (MDA), SOD, GSHPx and minerals known to be involved in antioxidant enzyme activation like selenium, iron, copper and zinc. RESULTS: In comparison to stroke risk patients, patients with acute ischemic stroke had significant changes of the GSH system during the first hours and days after the event: GSH was significantly elevated in the first hours (p < 0.01) and GSHPx was elevated 1 day after the acute stroke (p < 0.05). Selenium, a cofactor of GSHPx, was decreased (p < 0.01). GSHPx levels were negatively correlated with National Institutes of Health Stroke Scale (NIHSS) scores on admission (r = -0.84, p < 0.001) and NIHSS scores after 7 days (r = -0.63, p < 0.05). MDA levels showed a trend for elevation in the first 6 h after the acute stroke (p = 0.07). No significant differences of SOD, iron, copper nor zinc levels could be identified. CONCLUSIONS: Differences of antioxidant capacity were found for the GSH system with elevation of GSH and GSHPx after acute stroke, but not for other markers. The findings support the hypothesis that changes of antioxidant capacity are part of acute adaptive mechanisms during acute stroke.

Recurrent vomiting and ethylmalonic aciduria associated with rare mutations of the short-chain acyl-CoA dehydrogenase gene.

We report identification of short-chain acyl-CoA dehydrogenase (SCAD) deficiency in a 12-year-old boy who suffered from recurrent attacks of vomiting once or twice a year from infancy. Growth and development were normal and there were no muscular symptoms. Metabolic screening was performed during a hospitalization at 8 years of age and revealed an increased excretion of ethylmalonic acid (EMA; 45-80 mmol/mol creatinine, normal 0.2-6.6), suggesting a degradation defect of short-chain fatty acids. An increased n-butyrylcarnitine was found in freshly collected serum (0.9 micromol/L; normal <0.4) but not in dry blood spots. Neither of the frequent SCAD gene variants 625G>A and 511C>T was present, but direct sequencing of the promoter and coding regions of the SCAD gene revealed that the patient had mutations on both alleles: 417G>C (Trpl15Cys) and 1095G>T (Gln341His). Neither mutation has been described before in compound heterozygosity or homozygosity. Enzymatic investigations subsequently confirmed a defect of SCAD in both fibroblasts and muscle extracts. Furthermore, expression studies of both mutations demonstrated impaired enzyme function or structure. To our knowledge, this case is the first description of a patient with proven SCAD deficiency presenting with recurrent emesis but without other symptoms, and emphasizes the wide clinical phenotype of this disorder.

Identification of the site of glucocorticoid action on neutral amino acid transport in superficial nephrons of rat kidney.

Glucocorticoid hormones enhance the reabsorptive capacity of filtered amino acids in rat kidney, as it was shown in previous in vivo clearance experiments. In the present study, the site of glucocorticoid action on neutral amino acid transport in superficial nephrons of rat kidney was investigated using in vivo micropuncture technique. Adult female Wistar rats were treated with dexamethasone (DEX), and fractional excretion of L-glutamine (L-Gln) and L-leucine (L-Leu) were determined and related to inulin after microinfusion into different nephron segments. DEX reduced fractional excretion of both neutral amino acids as a sign of enhanced reabsorptive capacity. The site of main DEX action on L-Leu reabsorption has been localized in the proximal straight tubule. However, in the case of L-Gln, the inhibition of gamma-glutamyltranspeptidase (gamma-GT) by administration of acivicin indicated the importance of this brush border enzyme in reduced L-Gln excretion. DEX enhanced gamma-GT activity by tubular acidification. It can be presumed a DEX-inducible transport system for neutral amino acids mainly localized in proximal straight tubules of rat kidney.

Laparoscopic diagnosis and management of malignant ascites.

Malignancy is the second most common cause of ascites. Tissue diagnosis is often difficult because the cytology of ascitic fluid is positive in only 57% of cases. Peritoneovenous shunting is often used as palliation in such patients and has proven superior to nonoperative management for some patients. We present three cases of malignant ascites with negative cytologies managed by using laparoscopic biopsies to confirm intraperitoneal cancer and assist in the placement of a peritoneovenous shunt. Results suggest that exploratory laparoscopy and shunt placement is a valuable procedure in these patients with a limited life expectancy and is preferable to open laparotomy.

A missense mutation (Thr-6Pro) in the lysosomal acid lipase (LAL) gene is present with a high frequency in three different ethnic populations: impact on serum lipoprotein concentrations.

A frequent missense mutation (Thr-6Pro) found in the prepeptide of the lysosomal acid lipase (LAL) gene was analyzed in a cohort of 1003 randomly selected samples from Germany, Japan and Sardinia (Italy). Using the mutagenically separated polymerase chain reaction (MS-PCR), allele frequencies of 0.269, 0.238 and 0.245 were determined in the three populations, respectively. Statistical analysis showed a lack of association with a dyslipidemic phenotype in all three groups. Additionally, in a subgroup of 126 German individuals no association was observed between genotype and LAL activity. We conclude that this mutation appears to be a frequent LAL gene polymorphism causing no impaired function of the enzyme and no measurable dyslipidemia in the general population.

A novel variant of lysosomal acid lipase (Leu336-->Pro) associated with acid lipase deficiency and cholesterol ester storage disease.

Cholesterol ester storage disease (CESD) is associated with premature atherosclerosis, hepatomegaly, elevated LDL cholesterol levels, and in most cases, low HDL cholesterol levels. Previous studies have shown a G-->A mutation at the 3' splice junction of exon 8 (E8SJM) of the gene encoding lysosomal acid lipase (LAL) in two kindreds with CESD. In a Canadian-Norwegian kindred with this disease, we show this mutation in conjunction with an as yet unknown T-->C transition in exon 10 predicting a Leu336-->Pro (L336P) replacement and an A-->C transversion in exon 2 predicting a T-6P replacement in the prepeptide. Identification of the L336P rather than the T-6P replacement as the second defect underlying CESD in our patient is deduced from three lines of evidence. First, the E8SJM allele is located in cis with the mutation predicting the T-6P-encoding allele but in trans with the L336P-encoding allele; second, the L336P but not the T-6P replacement cosegregates with low LAL activity in the family; third, the T-6P replacement was found in 6 of 28 alleles from subjects with normal lysosomal acid lipase activity, suggesting that this variant represents a frequent nonfunctional polymorphism. Since the residual LAL activity is higher and the clinical phenotype based on plasma lipid values and severity of hepatosplenomegaly is milder in this case than in a previously studied case who was homozygous for the E8SJM allele, we conclude that the L336P variant appears to be associated with a phenotypically mild form of CESD.