Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism.

BACKGROUND: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. METHODS: Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. RESULTS: No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 x upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (> or = 1.5 x ULN), 32 (84%) were either TA7 homozygotes (n=18) or TA7 heterozygotes (n=14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3-32.2) compared with other genotypes. CONCLUSIONS: The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.

Exploratory data analysis of the multilevel anthropogenic copper cycle.

A comprehensive multilevel contemporary cycle for stocks and flows of copper is analyzed by the tools of exploratory data analysis (EDA). The analysis is performed at three discrete spatial levels--country (56 countries or country groups that comprise essentially all anthropogenic stocks and flows of copper), eight world regions, and the planet as a whole. Among the most interesting results are the following: (1) EDA is employable and valuable for use in the analysis of material flows, especially those across multiple spatial levels; (2) All distributions of country-level stock and flow data are highly skewed, a few countries having large magnitudes, many having small magnitudes; (3) Rates of fabrication of copper-containing products for the countries are poorly correlated with rates of extraction, reflecting the fact that many countries that extract copper do not fabricate products from copper to any significant degree and vice versa; (4) Virtually all countries are adding copper to stock (in pipe, wire, etc.); These rates of addition are highly correlated with rates of copper entering use in all regions and are higher in regions under vigorous development; (5) With weak confidence, the rate of copper landfilling by regions is about one-half the rate of copper discarded; (6) The statistical distributions of both country-level and regional-level copper cycle parameters have successively lower standard deviations at later life stages; and (7) Copper flow distributions at different life stages tend to reflect those of lower spatial level extreme values, but Asia's and Europe's regional patterns are much more reflective of country-level distributions as a whole.

[Correlation between clinical and molecular genetic findings in Leber's optic atrophy]. / Korrelation klinischer und molekulargenetischer Befunde bei Leberscher Optikusneuropathie (LHON).

Leber's hereditary optic neuropathy (LHON) is associated with point mutations of mitochondrial DNA (mtDNA) that appear to be pathogenetic for this disease. These mutations affect nucleotide positions 3460, 4160, 11,778, 14,484, and possibly 15,257. The pathogenetic significance of other mtDNA point mutations (secondary mutations) is less clear. We reviewed the clinical and molecular genetic characteristics of 29 visually symptomatic patients from 26 families. In addition, we studied 54 relatives of the maternal line of these patients. Sixteen of them underwent clinical and molecular genetic examination; 38 underwent only molecular genetic examination. The 29 affected individuals showed a male predominance of 93.1% (27/29) and ages of onset of visual loss ranging from 15 to 55 years. The time interval between affected eyes was never longer than 1 year. Tobacco and/or alcohol abuse was common. Peripapillary microangiopathy was found in 20.7% (6/29) of our patients. The number of patients with peripapillary microangiopathy seems to be small, but we could not examine all patients early after onset of the disease: the time of first examination is critical for the diagnosis of peripapillary microangiopathy. From the 16 relatives who underwent clinical examination, 62.5% (10/16) also had peripapillary microangiopathy. Eighteen patients were analyzed by brain computed tomography or magnetic resonance imaging. Four definitely pathological results seem remarkably high in comparison with the results of other authors. Our LHON patients and their relatives invariably had an identical pattern of point mutations, both primary as well as secondary. Of the LHON patients, 79.3% had the primary mutation at position 11,778, 20.7% at position 3460. Different numbers and combinations of secondary mutations were observed in a large portion of both groups. Three patients with the 11,778 mutation noticed remarkable visual recovery. There was no clear correlation between the type and number of point mutations in the individual and the severity of the disease.

Development of a sensitive enzyme immunoassay for the determination of vinpocetine in human plasma.

An Enzyme immunoassay for the quantitative determination of vinpocetine (CAS-42971-09-5) in human plasma has been developed. The lower limit of quantification is 0.1 ng/ml plasma. The assay shows no cross reactivity with the major metabolite apovincaminic acid. Because of a strong unspecific binding of vinpocetine to plasma proteins an extraction step was necessary. The inter- and intra-assay reproducibility of the test (coefficient of variation) is in a range of 1.1 and 18.3%.

[In vivo autofluorescence. Measurements of human crystalline lenses with cataract and normal findings after excitation with monochromatic light]. / In-vivo-Eigenfluoreszenz. Messungen von menschlichen Augenlinsen mit Katarakt und Normalbefund bei Anregung mit monochromatischem Licht.

In 25 eyes with nuclear cataract, 18 eyes with posterior subcapsular cataract, 25 eyes with cortical cataract, and 23 eyes without any pathological lens changes, the maximal fluorescence intensity was determined after excitation with monochromatic light at 365 nm, 405 nm, 436 nm, and 485 nm. The coefficient of variation was smaller than 5%. All eyes with cataract underwent cataract surgery a few days after the fluorescence measurements. The fluorescence spectrometer, especially constructed for in vivo measurements, consists of a modified slit lamp (Zeiss 75 SL) and an optical multichannel analyser (OMA) for gauging the data. The clinical trial was undertaken to determine whether, considering the influence of age, there is a difference between the fluorescence intensities in eyes with the above named cataracts and noncataractous eyes. The data were analyzed to determine the effect of age upon fluorescence intensity for all excitation wavelengths in both cataractous and noncataractous eyes. Age had an influence on the fluorescence intensities for all four excitation wavelengths. Assuming that the influence of age was not dependent on the state of the lens, it was quantified for all measurements and an "age-corrected" fluorescence intensity was calculated. The statistical analyses of these "age-corrected" fluorescence intensities revealed a significant difference (P < 0.001) for all of the types of cataracts examined and for normal eyes. The cataract types examined and the normal eyes showed differences in their fluorescence feature. To assess the fluorescence intensities obtained after excitation with the wavelengths mentioned above, one must take into consideration the influence of age on the measurements.

[Measuring scattered light with the Opacity Lensmeter 701 in normal eyes and eyes with cataracts. Correlation between scattered light and cataract-induced vision loss]. / Streulichtmessungen mit dem Opacity Lensmeter 701 bei Normalaugen und Augen mit Katarakt. Zusammenhang zwischen Streulicht und kataraktbedingter Visusreduktion.

In 50 eyes with nuclear cataract, posterior subcapsular cataract and cortical cataract and 34 normal eyes, the amount of scattered light was determined using the Opacity Lensmeter 701 to determine its accuracy in distinguishing between clear and cataractous lenses. Taking as a basis the manufacturer's statement that normal lenses show Opacity Lensmeter readings of less than 25 and that cataractous lenses show Opacity Lensmeter readings of more than 30, 94% of the nuclear cataract cases, 62% of the posterior subcapsular cases and 66% of the cortical cataract cases were identified as being pathologically opaque. Of the normal eyes, 88% had an Opacity Lensmeter reading of less than 25. Among the types of cataract examined, a significant linear relationship (P < 0.05) between visual acuity loss due to cataract and scattered light measurements could be found only in eyes with nuclear cataract, with the individual results heavily scattered around the linear regression. In the case of nuclear cataracts, measuring scattered light with the Opacity Lensmeter is suitable for making general statements on visual loss due to cataract for a whole group of patients. However, in individual cases the results can only be used together with other clinical examinations.

[Cataract diagnosis using scattered light at 700 nm]. / Katarakt-Diagnostik mittels Streulichtmessung bei 700 nm.

The present study was undertaken to determine whether the scattered light of lenses measured with the Opacity Lensmeter 701 can be used for objective, quantitative assessment of lens opacities, and how far pupillary diameter and the type of lens opacity affect the measurement. Visual acuity and scattered light were determined in 150 eyes with the Opacity Lensmeter set at 700 nm. In the group with nuclear cataract there was a significant correlation between visual acuity and the amount of scattered light measured by the Lensmeter. In the groups with cataracta scutellaris posterior and cortical cataract there was no significant correlation between visual acuity and scattered light measurements. While the Interzeag Opacity Lensmeter 701 is capable of furnishing data on fairly large populations with nuclear cataract, it is of limited value for assessing individual cases. The influence of pupillary diameter on the scattered light measurement was examined in 50 selected eyes. In all 30 of the eyes with cataract, significant correlations were found between pupillary diameter and scattered light measurements, while this was the case in only 10 of the 20 normal eyes. Therefore, when measuring stray light in cataract cases, the pupillary diameter should be stated.

Role of substance P in immediate-type skin reactions induced by staphylococcal enterotoxin B in unsensitized monkeys.

The staphylococcal enterotoxin B (SEB)-induced immediate-type skin reaction in unsensitized monkeys was used as a nonimmunologic mast cell stimulation to search for possible involvement of local neural mechanisms. Evidence is presented that substance P (SP) plays a predominant role in mediating intradermal SEB challenge in unsensitized monkeys. With a rabbit SP antiserum directed against the C-terminal region of SP, a concentration-dependent inhibition of SEB-induced skin reactivity could be demonstrated. Furthermore, a rabbit antiserum directed against the mast cell activating N-terminal part of SP was capable of impeding SEB-induced skin reactions totally. By use of SP antagonists, significant reduction of skin reactions evoked by SEB was found. Finally, capsaicin pretreatment of the skin caused a substantial inhibition of SEB-induced skin reactivity. These data suggest that SEB exerts its effect on cutaneous mast cells via stimulation of primary sensory neurons that contain SP. Moreover, a new in vivo model is described for studies of nerve-mast cell interactions.

Protection against the staphylococcal enterotoxin-induced intestinal disorder in the monkey by anti-idiotypic antibodies.

The staphylococcal enterotoxin serotype B (SEB)-induced enteric intoxication and the immediate-type reaction in the skin of unsensitized monkeys was used to define whether agents competing with SEB for target cell receptors may inhibit pathophysiological effects. For this purpose a duodenal provocation test was developed by use of a pediatric gastroscope, allowing the evaluation of the influence of antagonists on the intestinal disorder upon SEB challenge at the same duodenal site. First, carboxymethylation of histidine residues of SEB caused a complete loss of emetic and skin-sensitizing activity without changing the immunological specificity. However, carboxymethylated SEB is a strong inhibitor of enteric intoxications and immediate-type skin reactions upon SEB challenge. Second, after immunization of BALB/c mice with monoclonal anti-SEB antibodies, monoclonal antiidiotypic antibodies (anti-Id) were obtained by the "hybridoma technique" and purification by idiotype-affinity chromatography. Anti-Id specifically inhibited the binding of horseradish peroxidase-labeled anti-SEB to the ligand, and SEB blocked as well the interaction of these two antibody species, indicating a high degree of binding-site selectivity. Anti-Id completely protected against emetic response and diarrhea upon duodenal provocation with SEB and inhibited immediate-type skin reactions as well. Further, anti-Id acted as an antagonist without triggering biologic functions themselves. This shows that anti-Id constitute a useful tool to protect against a bacterial toxin-induced intestinal disorder.

Comparative evaluation of disk- and trileaflet valves in left-ventricular assist devices (LVAD).

Two identical LVADs were equipped with different types of heart valve prostheses (Björk-Shiley disk and PU-valves) and tested in two simultaneous calf experiments for 28 days each. Noise levels, accelerations of the pump housing and thrombus formation were higher for the mechanical valve pump.

Mutual relationship among cytosolic pH, Na+ and Ca2+ ions in the degranulation of rat leukemic basophils.

Reagents which affect the cytosolic concentrations of protons and sodium ions markedly affect the degranulation process of mast cells. The proton-sodium exchanging ionophore, monensin, is found to cause noncytolytic dose dependent serotonin release from the rat leukemic basophils (line RBL-2H3). Its half maximal dose of ca. 2 microM leads to secretion of ca. 20% of these cells' serotonin content. Monensin induced serotonin secretion increases with external pH and decreases upon lowering external sodium ion concentrations, yet is independent on external calcium. Monitoring cytosolic pH and free Ca2+ concentrations with BCECF and quin2, respectively, shows that a rise in pHi and [Ca2+]i is caused by the ionophore. Amiloride, the blocker of cellular Na+/H+ antiporter, is found to be an effective inhibitor of antigen or monensin induced serotonin release. However, it does not by itself cause secretion. In contrast, ouabain, which inhibits the cellular Na+/K+ ATPase, does induce secretion. Cellular levels of pH, Na+ and Ca2+ ions are evidently linked and involve a manifold of activities. Though exchanging protons for sodium seems to be effective in causing mediator release, the present results do not provide sufficient support for proton/sodium ions having a second messenger role in the immunologically induced mediator release.