Co-variation of free amino acids in brain interstitial fluid during pentylenetetrazole-induced convulsive status epilepticus

Effects of pentylenetetrazole (PTZ)-induced convulsive status epilepticus on free amino acids changes in venous blood, CSF and interstitial fluid (IF) of the brain were examined in dogs. A volume of brain IF sufficient for analysis was obtained by chronically implanted tissue cages. The onset of PTZ-induced convulsive seizures seemed mainly related to a marked increase of glutamate, aspartate, taurine, glycine and phosphoserine while, the maintenance and frequency of seizures seemed related to a marked increase of serine and glycine, in combination with a moderate rise of glutamate.

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-α-Aminoadipate was recovered in moderate amount in epileptic brain IF, while, in controls, this compound was present in minimal amount. The observed complex temporal variation of the amino acidic pattern may play a role in PTZ-induced seizures and, possibly, in pharmacological kindling and brain structural alterations induced by PTZ.     

In vitro impairment of human granulocyte functions by lead

Chemotaxis and receptor independent phagocytosis of human polymorphonuclear leukocytes (PMNs) exposed to lead in vitro (concentrations between 1.2 M and 115 M) were studied. Chemotaxis was measured in Boyden chambers and phagocytosis was investigated using latex beads.Additional methods were also applied. Superoxide anion formation from PMNs activated with preopsonized zymosan was quantified as superoxide dismutase-inhibitable reduction of ferricytochrome c. Steady state fluorescence polarization was performed using trimethylammonium diphenylexatriene (TMA-DPH).Lead concentrations were highly correlated both with decreased chemotactic activity r=0.70 p<0.01) and with decreased phagocytosis (r=0.68 p<0.01). Ferricytochrome c reduction was not significantly affected. An increase in fluorescence polarization was recorded at the highest concentration of lead used, i.e. 57.6 M and 115 M, both in unstimulated PMNs and in PMNs activated with N-formyl-methionyl-leucyl-phenylalanine chemotactic peptide (n-FMLP). Moreover, an increase in the fluorescence polarization was observed in PMNs pretreated with a microtubule disrupting drug, exposed to lead concentrations of 14.4 M and 57.6 M and then activated with n-FMLP; no increase was recorded at the lowest lead concentrations used, i.e. 1.2 M and 3.6 M.The possible interaction of lead with the membrane — cytoskeleton apparatus is discussed.     

Biosynthesis of the avermectins by Streptomyces avermitilis. Incorporation of labeled precursors

The biosynthesis of the avermectins, a group of 16 membered macrolides with potent anthelmintic and insecticidal activity produced by Streptomyces avermitilis, was studied by supplying cultures with 14C and 13C precursors. [1-14C] and [2-14C]acetate and propionate were poor precursors of the avermectins and were instead rapidly oxidized to 14CO2. The S-methyl of methionine in contrast was incorporated extensively and equally into the three methoxyl groups of the avermectins. The carbon backbone of methionine was not a precursor of the avermectins. Feeding of [1-13C]glucose yielded avermectins labeled specifically in the C1' and C1" of the oleandrose moiety and in the aglycone moiety in carbons known to be derived from the methyl of acetate. Feeding [U-13C]glucose showed that the entire avermectin molecule is derived from glucose carbons.     

Safety Analysis of Four Randomized Controlled Studies of Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or Mantle Cell Lymphoma

Background

Multiple studies have demonstrated the efficacy and safety of ibrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). This first-in-class inhibitor of Bruton's tyrosine kinase has become a standard treatment for patients with CLL and MCL.

Prevalence of antibodies to Bartonella henselae in patients with suspected cat scratch disease (CSD) in Italy

Cat scratch disease (CSD) is a relatively new diagnosed illness with clinical signs of self-limiting regional lymphadenopathy accompanied by symptoms of fever and malaise, to encephalopathy and neuropathy, occurring after a cat scratch or flea bite. Bartonella henselae is now accepted as the etiologic agent of CSD. From January 1994 to September 1998, 412 patients were evaluated for suspect CSD in Italy. Sera were tested for antibodies to B. henselae by a commercially available indirect immunofluorescent assay (IFA), based on B. henselae-infected Vero-cells as the antigen substrate. Of the 412 patients, 26 (6.3%) were considered positive having titers of immunoglobulin G (IgG) to B. henselae of 64 or higher. In these patients CSD was indeed confirmed by either histopathologic examination of lymph nodes biopsy or fourfold raise in antibody titers. Nevertheless, sera were tested by IFA for Afipia felis and one showed a double reactivity to B. henselae and A. felis. Finally, three sera, negative to B. henselae serology, were positive to A. felis. Three hundred and eighty-six patients received alternative diagnoses. One hundred and twenty-five serum samples from control subjects were negative by IFA for either B. henselae or A. felis. Moreover, a cross-reactivity with sera from patients affected by other diseases was not observed. Our study shows that the ascertained cases of CSD are etiologically determined by B. henselae, IFA assay is confirmed as a useful tool in the laboratory diagnosis and, over a 5 years period of study, the incidence of CSD in Italy has been low.     

Design and Evaluation of an Osmotic Pump Tablet (OPT) for Chlorpromazine Using (SBE)7m-β-CD

Purpose. The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) which exhibits pH-independent release profiles for a basic drug using a sulfobutyl ether--cyclodextrin, (SBE)_7m--CD, which acts as both a solubilizer and as an osmotic agent. Methods. Chlorpromazine free base (CLP) was chosen as a model drug for this study. The release of CLP from osmotic pump tablets was studied in vitro. In vivo absorption of CLP from the OPT was evaluated in male beagle dogs. Results. The CLP release profile from an OPT prepared from a core tablet composed of a 1:10 molar ratio of CLP to (SBE)_7m--CD was pH-independent, and was controlled by modulating the membrane thickness of the OPT. Another cyclodextrin, hydroxypropyl--cyclodextrin (HP--CD), and a sugar mixture of lactose and fructose resulted in pH-dependent release at the same molar ratio. An in vivo absorption study in dogs with an OPT containing (SBE)_7m--CD correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. Conclusions. In addition to serving as a solubilizer and osmotic agent, (SBE)_7m--CD can also serve as the controlling agent for pH independent release of CLP from OPTs. This system successfully modified the in vivo input rate of CLP without compromising oral bioavailability.     

Changes of membrane fluidity in erythrocytes of lead-exposed workers

Summary We have studied the effect of lead on the fluidity of erythrocyte membrane to clarify if lead can interact in vivo with biological membranes. Erythrocyte membranes were chosen in our study because a decrease of red cell osmotic fragility is also evident in the absence of laboratory and clinical signs of anaemia. The study was undertaken using the Electron Spin Resonance technique with two spin labels 5-doxyl stearate and 16-doxyl-stearate, which probe the physical state of the polar surface and the inner core of the membrane respectively.Red blood cells and erythrocyte ghosts were prepared from the blood of workers occupationally exposed to lead and from healthy controls. The determinations of Pb blood, Pb urine, urine coproporphyrin and -amino levulinic acid showed an increased internal dose of lead, but the ordinary metabolic and haematological parameters were in the normal range. Our results show that in lead workers there is a change in chemical physical state both in erythrocytes and erythrocyte ghosts consistent with a decrease of membrane fluidity, which is evident in the surface as well as in the inner core of the membrane. The degree of membrane fluidity modification does not appear correlated with blood lead level. Changes in the membrane structural organization could be the molecular basis of some pathological alterations induced by lead.