Characterization of binding mode of imatinib to human α1-acid glycoprotein.

Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.

Species-dependency in chiral-drug recognition of serum albumin studied by chromatographic methods.

Stereoselective binding of benzodiazepine and coumarin drugs to serum albumin from human and six mammalian species were studied by chiral chromatographic techniques. The applied methods were affinity chromatography on the albumins immobilized on Sepharose 4B, high-performance liquid chromatography (HPLC) separation on columns based on human serum albumin (HSA) and bovine serum albumin (BSA), and chiral HPLC analysis of ultrafiltrates of solutions containing the racemic drug and the native protein. Substantial differences in preferred configurations and conformations were detected among the species. The binding stereoselectivity of the 2,3-benzodiazepine drug, tofisopam, in human, is opposite to that in all other species. In the binding of 1,4-benzodiazepines, dog albumin is very similar to HSA. Highly preferred binding of (S)-phenprocoumon was found with dog albumin.

Stereoselective allosteric binding interaction on human serum albumin between ibuprofen and lorazepam acetate.

The effect of ibuprofen enantiomers on the stereoselective binding of 3-acyloxy-1,4-benzodiazepines to human serum albumin (HSA) was studied using both native and Sepharose-immobilized protein. (S)-Lorazepam acetate exhibited considerably enhanced binding, especially in the presence of (+)-(S)-ibuprofen. The phenomenon is an indication of cooperative allosteric interaction between different binding sites during multiple cobinding of two ligands.

Parenchymal neurocysticercosis: follow-up and staging by MRI.

We describe the evolution of parenchymal cerebral cysticerci on MRI, to assess signs of early cyst degeneration. We studied 15 lesions in four treated and one untreated patient. MRI was performed before therapy and repeated in the 1st month after each course of anticysticercus drugs, every 4 months during the 1st year and then annually; the follow-up period was 8-48 months. Lesions were classified according to changes in four features: cyst content and capsule signal, gadolinium enhancement and oedema signal. We were able to recognise each of the pathological phases; five MRI stages were identified. Stage 1 showed oedema and/or nodular gadolinium enhancement in the tissue invasion phase; stage 2 was cerebrospinal fluid-like signal within a cyst in the vesicular phase; stage 3 showed a thick capsule with an impure liquid content signal and surrounding oedema, in the cystic phase; stage 4 showed the disappearance of the cyst fluid content signal in the degenerative phase; stage 5 showed a calcified lesion in the residual phase. Stage 1 lesions disappeared after therapy; the other progressed from one stage to another. Stage 4 indicated the end of viability of the parasite and determined the point after which treatment was useless. On T2-weighted images changes in the cyst content differed according to the history of the lesion; nodular low intensity followed the natural degeneration of the parasite and a mixed fluid signal with punctate low signal seemed to represent the specific result of therapy. MRI staging can help in the evaluation of indications for treatment and facilitate clinical therapeutic trials.

Human serum albumin conformational changes as induced by tenoxicam and modified by simultaneous diazepam binding.

The binding of tenoxicam to human serum albumin has been shown by affinity chromatography proton titration and equilibrium dialysis to be dependent on the neutral to basic conformational change of the protein. The influence of diazepam on the interaction was also investigated using the same techniques, suggesting that diazepam increases the association of tenoxicam to albumin. Affinity chromatography revealed that the reciprocal effect also occurs. Displacement studies indicated that diazepam causes a significant increase in the affinity of tenoxicam to its main binding site, albumin site I, which is different from the diazepam site (site II). Tenoxicam seemed to cause an allosteric change in the conformation of the protein during its own binding, as did warfarin. The mechanism of this effect was a pH-dependent conformational change of albumin induced by electrostatic forces within the protein. Diazepam induced a distant accommodation of the protein, an effect accompanied by an enhanced inhibition of the release of protons from albumin.

Binding studies with recombinant human serum albumin obtained by expression of a synthetic gene in yeast. Stereoselective binding and allosteric interaction with benzodiazepine and coumarin ligands.

The specific ligand binding ability of recombinant human serum albumin produced in yeast using the synthetic gene was studied by affinity chromatographic method. It was found that synthetic protein possesses those stereoselective binding and binding interactions for several chiral benzodiazepine and coumarin compounds which are characteristic of the natural human serum albumin, suggesting identical tertiary structures.

Migraine and risk of ischaemic stroke: a case-control study.

OBJECTIVES: To determine whether migraine is a risk factor for ischaemic stroke. DESIGN: A case-control study. SETTING: Two hospitals in Paris. SUBJECTS: 212 patients with stroke (137 men and 75 women) and 212 controls matched for sex, age (to within five years), and history of hypertension. MAIN OUTCOME MEASURES: Ischaemic stroke, confirmed by brain computed tomography or magnetic resonance imaging, and history of headache, recorded with structured questionnaire during interview. RESULTS: Prevalence of migraine did not differ between patients with stroke and controls: 18/137 v 17/137 for men (odds ratio 1.1 (95% confidence interval 0.5 to 2.2), p = 0.86); 23/75 v 17/75 for women (odds ratio 1.6 (0.7 to 3.5), p = 0.24); and 41/212 v 34/212 for both sexes (odds ratio 1.3 (0.8 to 2.3), p = 0.33). When subjects were split into two age groups, however, prevalence of migraine was significantly higher among younger women (aged < 45) with stroke compared with their controls (13/20 v 6/20, odds ratio 4.3 (1.2 to 16.3), p = 0.03). Furthermore, the risk of ischaemic stroke was higher among younger women who smoked (7/20 v 1/20, odds ratio 10.2 (1.1 to 93.3)). CONCLUSIONS: Prevalence of migraine was not different between patients with stroke and matched controls except among women aged < 45, when migraine and stroke were significantly associated.

Stereoselective distribution of acenocoumarol enantiomers in human plasma: chiral chromatographic analysis of the ultrafiltrates.

Stereoselectivities for the binding of rac-acenocoumarol to human serum albumin (HSA), alpha 1-acid glycoprotein (AGP), and human plasma were determined by chiral HPLC analysis of the ultrafiltrates on a Chiral-AGP column. The results confirmed the previously detected inverse stereoselectivities; for HSA the ratio of the enantiomeric constants was KR/KS approximately 2, while for AGP it was KR/KS approximately 0.3. In plasma the contribution of HSA dominates, although in pathological states, elevated AGP levels may compensate for stereoselective distribution.

[Meningoradiculitis disclosing T-lymphocyte leukemia in HTLV-1 infection]. / Méningo-radiculite révélatrice d'une leucémie à lymphocytes T au cours d'une infection à HTLV1.

A case of HILV1-associated adult T cell leukaemia/lymphoma (ATLL) in à 21-year olf African woman is reported. The patient presented with lymphomatous meningoradiculopathy. The usual clinical features of ATLL were absent. Lumbar MRI showed a pial enhancement by DTPA-gadolinium of the conus medullaris which extended to the proximal cauda equina. Under systemic chemotherapy coupled with intrathecal chemotherapy the patient progressively improved, and at the second MRI examination complete disappearance of the lumbar enhancement was observed. MRI of the brain using axial and coronal T2-weighted sequences detected multifocal lesions of high-intensity signal in the subcortical white matter. ATLL is unusual in people of African origin. The ATLL-strongyloïdes infestation association has previously been reported, suggesting that parasitic infestation may be an important co-factor leading to the development of ATLL.

Ipsilateral cluster headache and chronic paroxysmal hemicrania: two case reports.

We report two patients with ipsilateral attacks of cluster headache and chronic paroxysmal hemicrania. The first patient, a 33-year-old man, started having attacks of chronic cluster headache at the age of 27. At 33, they were replaced by typical attacks of ipsilateral chronic paroxysmal hemicrania which showed a dramatic improvement with indomethacin 150 mg daily. After two days of complete remission, cluster headache attacks reappeared and persisted until verapamil, 360 mg a day, was added to indomethacin. The second patient, a 45-year-old man, first developed attacks of episodic cluster headache at the age of 35. At 44, he experienced ipsilateral typical attacks of chronic paroxysmal hemicrania, and two months later attacks of cluster headache. Under verapamil 240 mg daily, attacks of cluster headache disappeared, but those of chronic paroxysmal hemicrania increased in frequency until indomethacin 150 mg daily was added. These observations suggest a close relationship but not a similarity between cluster headache and chronic paraoxysmal hemicrania, and show the practical therapeutic interest of maintaining this distinction.

Chiral high-performance liquid chromatographic separations of vinca alkaloid analogues on alpha 1-acid glycoprotein and human serum albumin columns.

Separations of the stereoisomers of a series of tetracyclic and pentacyclic vinca alkaloid analogues having two or three chiral centres were performed on Chiral-AGP and Chiral-HSA high-performance liquid chromatographic columns. Phosphate buffers with pH 5-7 containing 5-35% acetonitrile or 2-propanol were used as mobile phases. The results were in accordance with previous binding data obtained with native AGP and on an HSA-Sepharose column. Whereas on Chiral-AGP the retention of the trans isomers having 1(R),12b(S)-indolo[2,3-a]quinolizidine or the corresponding 3(S),16(R)-eburnane absolute configurations was exceedingly high, on Chiral-HSA the trans isomers, independently of their absolute configurations, were more retained. Eburnane-type compounds could also be separated according to the configuration of the chiral centre at position 14. A comparison of the chromatographic properties of the vinca alkaloids on the Chiral-AGP and Chiral-HSA columns demonstrates that these compounds are bound with higher affinity to the AGP phase. The AGP column resolves a very broad range of vinca alkaloids compared with the HSA column. Higher stereoselectivity and a much better chromatographic performance were also obtained on the Chiral-AGP column.

MRI and neurological complications of adult T-cell leukemia/lymphoma.

We report the assessment by MRI of a lumbosacral lymphomatous localization of adult T-cell leukemia/lymphoma (ATLL) with human T-cell lymphotropic virus-1 infection in an African patient. Brain MRI detected associated multifocal lesions of increased signal intensity in the subcortical white matter. These MRI abnormalities are compatible with reported necropsy findings in cases of ATLL with neurological complications.

[Non hypertrophic amyloid myopathy with muscular inflammation in plasma cell dyscrasia]. / Myopathie amyloïde non hypertrophique avec inflammation musculaire au cours d'une dyscrasie plasmocytaire.

The case of a 41 year old woman with amyloid myopathy is reported. Clinical involvement consisted of limb girdle muscle weakness, mild scapular muscle atrophy and dysphagia. In contrast with the published cases, abnormal firmness, pseudohypertrophy of the musculature and macroglossia were absent. Muscle biopsy showed endo- and perimysial amyloid deposits but also inflammatory infiltrates. Inflammatory cells typing was studied by immunocytochemical methods and revealed a predominant T-helper cell infiltration. Free kappa light chains were present in serum and urine. Serum immunoglobulin levels were reduced. Bone marrow examination revealed mild plasmocytosis without abnormal cells. Immunofluorescence and immunoperoxidase techniques for identification of the type of amyloid fibrils showed positivity with antisera to kappa light chains. A 4-year follow-up revealed a progressive worsening of muscle weakness despite immunosuppressive treatment. No malignant plasmocytosis occurred. The unusual inflammatory muscle infiltration observed in this case may suggest an associated polymyositis.

Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings.

Three patients from a single family of six siblings had homocystinemia and homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency and had severe recurrent strokes in adult life. Two of the patients died 1 year after clinical onset.

Binding of vinca alkaloid analogues to human serum albumin and to alpha 1-acid glycoprotein.

The binding of a series of vinca alkaloid analogues having eburnane or indolo[2,3-a]quinolizidine skeletons was studied with human serum albumin (HSA) by affinity chromatography and with alpha 1-acid glycoprotein by means of competition experiments. On HSA the binding occurs at the benzodiazepine-indole binding site via hydrophobic interaction and shows slight stereoselectivity preferring the trans isomers. The binding to alpha 1-AGP proved to be highly stereoselective in favour of the trans isomers having 3(S),16(R)eburnane or 1(R),12b(S)indolo[2,3-a]quinolizidine absolute configurations.

Stereoselective effect of warfarin and bilirubin on the binding of 5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2- one enantiomers to human serum albumin.

The binding of the title benzodiazepine enantiomers and its modulation by warfarin and bilirubin were studied by chromatography on human serum albumin (HSA) immobilized on Sepharose 4B, and also by a combination of ultrafiltration and circular dichroism (UF-CD) methods. In the absence of warfarin and bilirubin the binding of the benzodiazepine was not stereoselective. (S)-Benzodiazepine and (S)-warfarin mutually increased the binding of each other, while the binding of (R)-benzodiazepine was preferentially enhanced on HSA saturated with bilirubin.

Inverse stereoselectivity in the binding of acenocoumarol to human serum albumin and to alpha 1-acid glycoprotein.

Stereoselective binding of rac-acenocoumarol to human serum albumin (HSA) and alpha 1-acid glycoprotein (alpha 1-AGP) was investigated by affinity chromatography and by combined ultrafiltration (UF) and circular dichroism (CD) methods. For HSA, the ratio of the enantiomeric constants was KR/KS = 2, while for alpha 1-AGP, KS/KR = 3.

The role of configuration and conformation in the binding of 2,3-benzodiazepines to human serum albumin.

2,3-Benzodiazepines containing a centre of asymmetry at C-5 possess both central and helical chiralities, and the solution of their racemates contains four molecular species. The binding of these compounds to human serum albumin (HSA) was studied by affinity chromatography. The binding strength depended both on the steric orientation of the 5-ethyl substituent and on the conformation of the diazepine ring. Conformation P (defined by the positive sign of C-1-N-2-N-3-C-4 torsion angle) is favoured, while the quasiaxial orientation of the 5-ethyl substituent is not favoured by the albumin molecule.