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Biomedical subjects

A Adam

Publications and source records attributed to A Adam.

At least 19 recordsLinked to original sources
PubMed2000

High-performance cation-exchange chromatography and pulsed amperometric detection for the separation, detection, and quantitation of N-alkylated imino sugars in biological samples.

The use of imino sugars for the potential treatment of lysosomal glycolipid storage diseases and hepatitis virus infections requires accurate, quantitative measurement of these compounds in biological samples. We demonstrate here the versatility of cation-exchange chromatography and pulsed amperometric detection of a range of compounds that differ in both isometric structure and N-alkyl chain length. Although column retention appears dependent upon residual charge on the imine function, successful isocratic separation can be achieved by secondary hydrophobic interactions. A series of N-alkylated deoxynojirimycin compounds containing C(1-10) alkyl chains are readily separated and detected by pulsed amperometry after cation suppression. Using experimentally derived response factors for imino sugars and measurement of peak areas we have developed a reliable method for quantitatively determining concentrations in solution. A rapid protocol for the removal of protein and contaminants in biological samples is described. This has allowed the successful measurement of imino sugars in animal tissues and will be useful for understanding the factors involved in compound bioavailability and in the design of novel therapeutics.

1-Deoxynojirimycin↗
PubMed2000

Tim23 links the inner and outer mitochondrial membranes.

Tim23, a key component of the mitochondrial preprotein translocase, is anchored in the inner membrane by its C-terminal domain and exposes an intermediate domain in the intermembrane space that functions as a presequence receptor. We show that the N-terminal domain of Tim23 is exposed on the surface of the outer membrane. The two-membrane-spanning topology of Tim23 is a novel characteristic in membrane biology. By the simultaneous integration into two membranes, Tim23 forms contacts between the outer and inner mitochondrial membranes. Tethering the inner membrane translocase to the outer membrane facilitates the transfer of precursor proteins from the TOM complex to the TIM23 complex and increases the efficiency of protein import.

Animals↗
PubMed2000

Some physicochemical properties of mefenamic acid.

Mefenamic acid is a problematic drug in granulation, tableting, and dissolution due to its poor solubility, hydrophobicity, and tendency to stick to surfaces. In most cases, the specifications of a drug by the pharmacopoeia include identification and purity, but they do not describe the physicochemical drug properties precisely. To characterize the mefenamic acid particle size, surface area measurements, X-ray pattern, differential scanning calorimetry (DSC), wettability, crystal habit, and compression behavior of different batches from two manufacturers were investigated. Due to larger particle size and better wettability, mefenamic acid of Il Yang type was easier to handle in a granulation process. The compression behavior of both types was nearly the same, although particle size, crystal habit, and wettability were very different.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Factors influencing capping and cracking of mefenamic acid tablets.

The tendency of capping and longitudinal cracks of mefenamic acid tablets was evaluated in relation to the amount of the binder, the influence of the granulation technique, and the relative humidity of the granules. Tablets made from fluidized bed granules using methylcellulose in the granulating liquid showed significantly lower capping and longitudinal cracks than tablets from conventional granules prepared by wet granulation using methylcellulose as a dry binder.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Specific dual effect of cycloheximide on B lymphocyte apoptosis: involvement of CPP32/caspase-3.

Cycloheximide (CHX) is known to stimulate or to prevent apoptosis, according to the cell type used. We found that CHX, in a dose-dependent way, exerted the two opposite effects in B lymphocytes. CHXhigh (2.5 microg/mL) inhibited protein synthesis (>90%) and greatly increased B cell apoptosis but failed to prevent apoptosis induction by dexamethasone (DEX) or dibutyryl-cAMP (dbcAMP), which is in opposition with CHX activity in thymocytes. On the contrary, CHXlow (0.05 microg/mL), modestly inhibited protein synthesis (<15%) and reduced spontaneous as well as drug-induced apoptosis and further augmented the protection conferred by interleukin-4 or lipopolysaccharide. To examine the role of caspases in CHX effects, we used the broad spectrum peptide caspase inhibitor Z-VAD-fmk: it totally abrogated spontaneous as well as drug- and CHXhigh-induced cell death. Apoptosis was associated with CPP32/caspase-3 activation, since cleavage of CPP32/caspase-3 and caspase-3 activity were increased by DEX, dbcAMP as well as by CHXhigh treatment. Meanwhile, caspase-3 activity was reduced by CHXlow treatment. Therefore, CHX exerts opposite effects on B lymphocyte apoptosis which are associated with a dual action on caspase-3 activation.

Animals↗
PubMed1999

Tim9, a new component of the TIM22.54 translocase in mitochondria.

We have identified Tim9, a new component of the TIM22.54 import machinery, which mediates transport of proteins into the inner membrane of mitochondria. Tim9, an essential protein of Saccharomyces cerevisiae, shares sequence similarity with Tim10 and Tim12. Tim9 is located in the mitochondrial intermembrane space and is organized into two distinct hetero-oligomeric assemblies with Tim10 and Tim12. One complex contains Tim9 and Tim10. The other complex contains Tim9, Tim10 and Tim12 and is tightly associated with Tim22 in the inner membrane. The TIM9.10 complex is more abundant than the TIM9.10.12 complex and mediates partial translocation of mitochondrial carriers proteins across the outer membrane. The TIM9.10.12 complex assists further translocation into the inner membrane in association with TIM22.54.

Amino Acid Sequence↗
PubMed1999

Intimal hyperplasia within biliary Wallstents: failure of recanalisation by insertion of a second endoprosthesis.

We report two patients with benign biliary strictures in whom we attempted recanalisation of metallic biliary endoprostheses, occluded by intimal hyperplasia, by the insertion of further endoprostheses within the occluded stents. Initial technical success was achieved in deploying the stents and restoring patency with elimination of mural filling defects. However, we found the intimal hyperplasia to be restrained for less than 48 h. From our initial results it appears that biliary metallic stent occlusion by intimal hyperplasia is not effectively treated by insertion of a second endoprosthesis.

Aged↗
PubMed1999

Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema.

Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (ACEi) is a rare, but potentially life-threatening adverse reaction. Several studies have suggested that bradykinin (BK) is responsible for ACEi-induced AE, but the mechanism remains unclear. We investigated the metabolism of BK and des-Arg9-BK in the serum of 20 patients with a history of ACEi-associated AE and 21 control (C) subjects. Synthetic BK was incubated with the sera for various periods of time and residual BK and generated des-Arg9-BK were quantified by specific and sensitive enzyme immunoassays. No significant difference of half-life (t1/2) of both BK and des-Arg9-BK could be measured between C subjects and patients with AE (AE) in absence of ACEi. However, an analysis according to the prolonged (+) or not (-) t1/2 of des-Arg9-BK allowed a new stratification of C subjects and AE patients in four subgroups. The preincubation of sera with enalaprilat at a concentration inhibiting ACE significantly prevented the rapid degradation of BK and des-Arg9-BK in these four subgroups. In presence of ACEi, a subgroup (50%) of AE patients (AE + ) had a particularly significant rise of the t1/2 of des-Arg9-BK. Once ACE was inhibited, the concentration or the nature of the ACEi had no significant effect on the t1/2 of des-Arg9-BK. However, a test dilution of AE + sera with a control (C) serum showed that an enzyme defect rather than a circulating inhibitor could be responsible for the abnormal metabolism of des-Arg9-BK when ACE is inhibited. In conclusion, half of the patients with ACEi-associated AE present in serum had an enzyme defect involved in the des-Arg9-BK metabolism leading to its accumulation. The B1 agonist could be responsible, at least in part, for the local inflammatory reaction associated with the AE.

Adult↗
PubMed1999

Des-Arg9-bradykinin metabolism in patients who presented hypersensitivity reactions during hemodialysis: role of serum ACE and aminopeptidase P.

Bradykinin (BK) has been proposed as the principal mediator of hypersensitivity reactions (HSR) in patients dialyzed using negatively charged membranes and concomitantly treated with angiotensin-converting enzyme (ACE) inhibitors. We investigated the metabolism of exogenous BK added to the sera of 13 patients dialyzed on an AN69 membrane with a history of HSR (HSR+ patients) and 10 others who did not present such a reaction (HSR- patients) while dialyzed under the same conditions. No significant difference in the t1/2 of BK was found between the patient groups. However, the t1/2 of generated des-Arg9-BK was significantly increased (2.2-fold) in HSR+ patients compared to HSR-subjects. Preincubation of the sera with an ACE inhibitor (enalaprilat) significantly increased the t1/2 of both BK and des-Arg9-BK in both groups. There was no significant difference between the groups with respect to the t1/2 of BK, but there was a significantly greater increase (3.8-fold) in the t1/2 of des-Arg9-BK in HSR+ patients compared to HSR-subjects. The level of serum aminopeptidase P (APP) activity showed a significant decrease in the HSR+ sera when compared to HSR-samples. In HSR- and HSR+ patients, a significant inverse relation (r2 = 0.6271; P < 0.00005) could be calculated between APP activity and des-Arg9-BK t1/2. In conclusion, HSR in hemodialyzed patients who are concomitantly treated with a negatively charged membrane and an ACE inhibitor can be considered as a multifactorial disease in that a decreased APP activity resulting in reduced degradation of des-Arg9-BK may lead to the accumulation of this B1 agonist that could be responsible, at least in part, for the signs and symptoms of HSR.

Acrylic Resins↗
PubMed1999

Absence of effect of chronic angiotensin II type 1 receptor blockade on endogenous kinin concentrations-induced paw edema model in the rat.

The effects of chronic treatment with losartan. an AT1 receptor antagonist, on the tissue content of bradykinin (BK) and des-Arg9-BK and on their pharmacological effects were examined in the carrageenan-induced paw edema model (0.5% solution, 50 microl/paw) in the rat. These effects were compared with those of angiotensin-converting enzyme inhibitors (ACEi). For this purpose, rats were chronically treated with losartan (3, 10 and 30 mg/kg/day) and enalapril or quinapril (1 mg/kg/day). Endogenous BK and des-Arg9-BK tissue contents at the site of local inflammation were measured by highly sensitive and specific enzyme immunoassays. Losartan 3 mg/kg/day for 7, 14 and 28 days had no significant effect on carrageenan-induced paw edema, but both losartan 10 and 30 mg/kg/day for 14 days significantly increased the hindpaw volume by 50% at 3 h and by 59% at 5 h. These effects, similar to those measured for ACEi, were inhibited by icatibant, a B2 kinin receptor antagonist (32.5 nmol/paw), that reduced carrageenan-induced paw edema to the level seen in vehicle-treated rats. In the same model, and contrary to ACEi, losartan 3, 10 and 30 mg/kg/day for 14 days had no significant effect on endogenous BK and des-Arg9-BK levels in the local inflammatory site or on circulating and tissue ACE activities. These results show, at least in that model, that the potentiating effects of losartan on carrageenan-induced paw edema are independent of the concentrations of endogenous kinins.

Angiotensin II↗
PubMed1999

IL-4 inhibits apoptosis and prevents mitochondrial damage without inducing the switch to necrosis observed with caspase inhibitors.

We previously demonstrated that the broad-spectrum caspase inhibitor, zVAD-fmk, totally deviated apoptosis to necrosis in B lymphocytes. We report here that, in contrast with zVAD-fmk, IL-4 protected B cells from spontaneous and from dexamethasone-induced apoptosis and actually maintained cell viability. This was assessed by morphological and biochemical criteria and accompanied by the maintenance of mitochondrial transmembrane potential (DeltaPsiCm) and elevated glutathione (GSH) levels. Under these conditions, zVAD-fmk also totally inhibited apoptosis in thymocytes, but it partly preserved cell viability with a parallel increase in the percentage of cells exhibiting high DeltaPsiCm and elevated GSH levels. Nevertheless, non-rescued cells were deviated to necrosis. Therefore, the pathway leading to either apoptosis or necrosis appears to involve common mitochondrial dysfunctions which could not be reversed by caspase inhibition, suggesting that the pharmacological inhibition of cell death should occur at an earlier stage.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Anomaly of the des-Arg9-bradykinin metabolism associated with severe hypotensive reactions during blood transfusions: a preliminary study.

BACKGROUND: Severe hypotensive reactions have been described after the transfusion of platelets or red cells through negatively-charged bedside white cell-reduction filters. The possibility of a role for bradykinin (BK) in the genesis of these reactions has been raised. STUDY DESIGN AND METHODS: To understand if an anomaly of BK metabolism is associated with these reactions, the metabolism of BK and des-Arg9-BK was studied in the sera of four patients who presented with a severe hypotensive transfusion reaction. Tests were performed in the absence and the presence of complete in vitro inhibition of angiotensin-converting enzyme (ACE) activity by enalaprilat. RESULTS: In the presence of ACE inhibition (enalaprilat), the half-life (t1/2) of BK measured in the sera of patients who presented with a severe hypotensive transfusion reaction (361 +/- 90 sec) was not significantly different from that measured in the sera of normal controls (249 +/- 16 sec). In the presence of ACE inhibition (enalaprilat), the t1/2 of des-Arg9-BK was significantly greater in patients who presented with a severe hypotensive transfusion reaction (1549 +/- 319 sec) than in normal controls (661 +/- 38 sec) (p < 0.001). CONCLUSION: A metabolic anomaly mainly affecting the degradation of des-Arg9-BK could be responsible for its accumulation in vivo. Des-Arg9-BK could be responsible, at least in part, for severe hypotensive transfusion reactions.

Adolescent↗
PubMed1999

Effect of synthetic lipids on apoptosis and expression of alkaline phosphatase in B-lymphocytes: influence on lipopolysaccharide action.

Synthetic lipids were examined for their ability to mimic or to antagonize lipopolysaccharide (LPS) action in murine B-lymphocytes. Several recognized effects of LPS were analyzed: prevention of spontaneous apoptosis, expression of alkaline phosphatase (ALP) and stimulation of proliferation. Three synthetic lipids were used for that purpose: a lipopeptide (compound MTPP) which carries non-hydroxylated fatty acids, and is thus unrelated to LPS, and two glycolipids with hydroxylated fatty acids (compounds D2 and PPDm2-B), structurally related to the lipid A region of enterobacterial and Rhodopseudomonas LPS, respectively. We found that the ability of these lipids to induce LPS-like responses was not correlated with their structural analogy with LPS. Thus, the lipopeptide, MTPP, mimicked LPS in the three activities, whereas the glycolipid, D2, did not. In contrast, the ability of synthetic lipids to block LPS effects was correlated with their structural analogy with LPS. We thus observed that compound D2 selectively blocked LPS-induced ALP expression and that PPDm2-B selectively inhibited LPS-induced prevention of apoptosis. These synthetic lipids could therefore be useful for studying the LPS-mediated signals involved in B-cell activation and apoptosis.

Alkaline Phosphatase↗
PubMed1999

Bradykinin metabolism in the postinfarcted rat heart: role of ACE and neutral endopeptidase 24.11.

The respective role of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) in the degradation of bradykinin (BK) has been studied in the infarcted and hypertrophied rat heart. Myocardial infarction (MI) was induced in rats by left descendant coronary artery ligature. Animals were killed, and hearts were sampled 1, 4, and 35 days post-MI. BK metabolism was assessed by incubating synthetic BK with heart membranes from sham hearts and infarcted (scar) and noninfarcted regions of infarcted hearts. The half-life (t1/2) of BK showed significant differences among the three types of tissue at 4 days [sham heart (114 +/- 7 s) > noninfarcted region (85 +/- 4 s) > infarcted region (28 +/- 2 s)] and 35 days post-MI [sham heart (143 +/- 6 s) = noninfarcted region (137 +/- 9 s) > infarcted region (55 +/- 4 s)]. No difference was observed at 1 day post-MI. The participation of ACE and NEP in the metabolism of BK was defined by preincubation of the membrane preparations with enalaprilat, an ACE inhibitor, and omapatrilat, a vasopeptidase inhibitor that acts by combined inhibition of NEP and ACE. Enalaprilat significantly prevented the rapid degradation of BK in every tissue type and at every sampling time. Moreover, omapatrilat significantly increased the t1/2 of BK compared with enalaprilat in every tissue type and at every sampling time. These results demonstrate that experimental MI followed by left ventricular dysfunction significantly modifies the metabolism of exogenous BK by heart membranes. ACE and NEP participate in the degradation of BK since both enalaprilat and omapatrilat have potentiating effects on the t1/2 of BK.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Increase in blood bradykinin concentration after eccentric weight-training exercise in men.

The purpose of this study was to verify the possible appearance in the blood of bradykinin (BK) and des-Arg(9)-bradykinin (des-Arg(9)-BK) after eccentric exercise in 13 male subjects. Eccentric exercise (5 x 10 leg presses at 120% maximal voluntary concentric contraction) resulted in muscle damage and inflammation, as suggested by the significant increase in serum creatine kinase activity (from 204 +/- 41 to 322 +/- 63 U/l 12 h postexercise) and by severe lasting pain, which also peaked at 12 h postexercise. Blood BK and des-Arg(9)-BK concentrations were measured by competitive enzyme immunoassays using highly specific polyclonal rabbit IgG. Des-Arg(9)-BK concentration was not modified (preexercise: 44 +/- 14 pmol/l; pooled postexercise: 47 +/- 4 pmol/l). In contrast, BK concentration significantly increased immediately after the exercise session (68 +/- 9 vs. 42 +/- 3 pmol/l preexercise) and returned to basal values at 12, 24, and 48 h (pooled value: 40 +/- 4 pmol/l). This observation suggests that the inflammatory process due to eccentric exercise-induced muscle damage could be mediated in part by BK.

Adult↗