Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia

The enzyme asparaginase is an important element in the therapy of acute lymphoblastic leukaemia (ALL). The usual asparaginase dose as prescribed in the ALL-BFM-86/90 treatment protocol for the therapy of ALL is 10 000 IU/m² at 3 d intervals and had been developed on the basis of the E. coli asparaginase preparation Crasnitin^TM from the Bayer company. Using the described schedule the E. coli asparaginase preparation from the Medac company shows significantly higher biological activity than the Bayer preparation. These findings prompted an attempt to reduce the dose of the Asparaginase medac^TM under careful pharmacokinetic and pharmacodynamic monitoring. At the first step of dose reduction in ALL treatment protocol I, 11 children received 5000 IU/m² of Asparaginase medac^TM. Another 15 children were given 2500 IU/m² of the enzyme at the second step of dose reduction. Prior to each asparaginase dose, blood samples were taken to determine amino acids and trough enzyme activity. Concurrent with the asparaginase monitoring, the coagulation parameters were measured. 96% of samples from the first step of dose reduction (5000 IU/m² every third day) showed complete L-asparagine depletion (<0.1 μM ), the median trough enzyme acitivity was 265 IU/l. At the second step of dose reduction (2500 IU/m²) complete L-asparagine depletion was seen in 97% of samples, and the median trough enzyme acitivity was 102 IU/l. Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Asparaginase medac^TM dose reduced from the usual 10000 IU/m² down to 5000 IU/m² or 2500 IU/m², applied at 3 d intervals, was sufficient to achieve complete L-asparagine depletion in serum. Changes of the fibrinogen levels was significantly less pronounced in the group on 2500 IU.     

Utility of diagnostic tests for detection of Helicobacter pylori in children in northeastern Mexico

BACKGROUND: The presence of Helicobacter pylori in pediatric population has been associated with recurrent abdominal pain (RAP), although this association is unclear. One of the major problems in studying the role of H. pylori in RAP is that methods used to detect the bacteria in children have poor sensitivity and specificity. The aims of the present study were to determine the prevalence of H. pylori in pediatric patients with RAP in northeastern Mexico and to assess the diagnostic utility of invasive tests and serology in this population. METHODS: A total of 40 patients (mean age, 7.9 years; range 2-16 years; F: M, 0.81), who underwent an endoscopy procedure for RAP, were studied. The presence of H. pylori was assessed using invasive diagnostic tests (culture, rapid urease test, polymerase chain reaction and histology) and one non-invasive test: determination of IgG antibodies. The prevalence of H. pylori in the present group and the diagnostic utility for each test were evaluated. RESULTS: The prevalence of H. pylori in the present pediatric group with RAP was 12.5-42.5% depending on the criteria of positivity used. The non-invasive methods (serology) had acceptable values in sensitivity and specificity in comparison with invasive tests. CONCLUSIONS: This is the first report on prevalence of H. pylori in pediatric patients with RAP from the northeastern region of Mexico. The prevalence of H. pylori was low compared with the adult population in the same geographic region. Serology had the best diagnostic utility.     

Origin and course of the coronary arteries in normal mice and in iv/iv mice

This paper reports on the origin and distribution of the coronary arteries in normal mice and in mice of the iv/iv strain, which show situs inversus and heterotaxia. The coronary arteries were studied by direct observation of the aortic sinuses with the scanning electron microscope, and by examination of vascular corrosion casts. In the normal mouse, the left and right coronaries (LC, RC) arise from the respective Valsalva sinus and course along the ventricular borders to reach the heart apex. Along this course the coronary arteries give off small branches at perpendicular or acute angles to supply the ventricles. The ventricular septum is supplied by the septal artery, which arises as a main branch from the right coronary. Conus arteries arise from the main coronary trunks, from the septal artery and/or directly from the Valsalva sinus. The vascular casts demonstrate the presence of intercoronary anastomoses. The origin of the coronary arteries was found to be abnormal in 84% of the iv/iv mice. These anomalies included double origin, high take-off, slit-like openings and the presence of a single coronary orifice. These anomalies occurred singly or in any combination, and were independent of heart situs. The septal artery originated from RC in most cases of situs solitus but originated predominantly from LC in situs inversus hearts. Except for this anomalous origin no statistical correlation was found between the coronary anomalies and heart situs or a particular mode of heterotaxia. The coronary anomalies observed in the iv/iv mice are similar to those found in human hearts. Most coronary anomalies appear to be due to defective connections between the aortic root and the developing coronaries. iv/iv mice may therefore constitute a good model to study the development of similar anomalies in the human heart.     

Mercuric chloride induced autoimmune disease in Brown-Norway rats: sequential search for anti-basement membrane antibodies and circulating immune complexes

Mercuric chloride induces in the Brown-Norway rat a biphasic autoimmune disease characterized initially by linear IgG deposits along the glomerular basement membrane followed later by granular IgG deposition. In the present study, anti-glomerular basement membrane antibodies and immune complex-like material were sequentially assessed in serial serum samples. Both were transiently found at the same period. Glomerular linear IgG deposits were present on day 11 but circulating anti-glomerular basement membrane antibodies were only found later on day 16. Circulating immune complexes were first detectable on day 8 before the earliest granular IgG deposits were first observed in the spleen vessels on day 16. The disappearance of circulating anti-glomerular basement membrane antibodies and of circulating immune complexes, although HgCl2 injections were pursued, is in agreement with the self-limited character of mercuric chloride induced autoimmune disease and suggests the induction of immunosuppressive mechanisms.     

Role of CD8+ T Cells in Mercury-Induced Autoimmunity or Immunosuppression in the Rat

In Brown-Norway (BN) rats mercuric chloride induces an autoimmune disease characterized by an increase in serum IgE concentration, and by the production of anti-glomerular basement membrane antibodies responsible for a glomerulonephritis with a heavy proteinuria. (i) This disease results from a B-cell polyclonal activation probably due to frequent anti-class II T cells. (ii) The self limitation observed in this model is associated with both a decrease in the frequency of anti-class II T cells and the emergence of CD8+ T cells able to suppress these autoreactive T cells. (iii) In Lewis (LEW) rats which do not develop autoimmunity, HgC12 provokes the appearance of non-antigen-specific CD8+ T cells responsible for a depression of T-cell functions. The aim of this work was to test the effect of treatment with an anti-CD8 monoclonal antibody (MoAb) in both BN and LEW rates, Anti-CD8 MoAb-treated rats were effectively depleted in CD8+ T cells. However, neither the induction nor regulation phases of mercury-induced autoimmunity were modified in BN rats. Mercury-induced immunosuppression in LEW rats was abrogated; however, depletion in CD8+ T cells did not allow the disease to occur in that strain. Finally, CD8 depletion induced in normal BN rats rats the appearance of rare anti-class II T cells showing that these cells are normally present in that strain but negatively controlled by suppressor T cells.     

Successful thrombolysis on a mechanical tricuspid prosthesis

Recombinant tissue-type plasminogen activator (rt-PA) is presentlyused for the treatment of different clinical entities, mostlymyocardial infarction. Its use for treatment of thrombotic dysfunctionof prosthetic cardiac valves is more recent and has been onlyrarely reported. A 33-year-old woman with a St Jude Medicalprosthesis in the tricuspid position, had suffered from thromboticdysfunction of her prosthesis for more than 2 months. She wastreated with rt-PA, and after infusion of 70 mg, the prosthesisfunctioned normally. She showed a moderate systemic fibrinolyticstate associated with mild bleeding complications.