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PubMed2001

NMDA and dopamine D2 receptors in the caudate-putamen are not involved in control of motor readiness in rats.

RATIONALE: In reaction time (RT) paradigms, in which a variable preparation interval preceded the imperative stimulus, RT become shorter as a function of increasing time from the start of a trial until presentation of the imperative stimulus. The shortening of RT as the preparatory foreperiod elapses reflects increasing motor readiness; however, the underlying neurochemical mechanisms are still poorly defined. OBJECTIVE: The present study investigated in rats whether signals transmitted via the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and via dopamine D2 receptors in the caudate-putamen (CPu) are involved in motor readiness. METHODS: A simple RT task demanding conditioned lever release was used, in which the upcoming reward magnitude (5 pellets or 1 pellet) was signalled in advance by discriminative stimuli and the imperative stimulus was subsequently presented after a variable foreperiod (200, 500 or 800 ms). RESULTS: In intact rats, RT of conditioned responses was shortened with foreperiod lengthening and with expectancy of the high reward magnitude, but there was no interaction between both factors. Bilateral infusion of the competitive NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV) (2, 10 micrograms in 0.5 microliter/side), of the preferential dopamine D2 antagonist haloperidol (5, 12.5 micrograms in 0.5 microliter/side) or infusion of vehicle (0.5 microliter/side) into the central subregion of the CPu had no effect on progressive RT shortening with increasing foreperiod. CONCLUSION: The present data provide no clues to suggest that motor readiness relies on stimulation of dopamine D2 and NMDA receptors in the central CPu.

Animals↗

PubMed2001

Expression of p15 and p15.5 products in neuroendocrine lung tumours: relationship with p15(INK4b) methylation status.

The cell cycle inhibitor p15(INK4B) is frequently inactivated by homozygous deletions together with p16(INK4a)/p14(ARF) in many tumour types. Although it is now well established that p16(INK4a) and p14(ARF) act as tumour suppressor genes, the role of p15(INK4b) remains to be well defined. In order to explore the possibility of a selective deregulation of p15(INK4b) in human lung carcinogenesis, we studied p15(INK4b) status in neuroendocrine (NE) lung tumours where homozygous deletions of the p16(INK4a)/p14(ARF) locus are rarely observed. Expressions of p15 and p15.5 protein isoforms were analysed in a series of eight control normal lung, 12 tumour-associated normal lung, five low grade and 15 high grade neuroendocrine (NE) lung tumours and relationship with a specific p15(INK4b) methylation status was studied. Using Western blot analysis, we showed that p15 and p15.5 isoforms displayed a high heterogeneous pattern of expression in both normal and tumour tissues. P15 and p15.5 expressions were correlated in control normal lung (P<0.04) whereas they were not in tumours and associated normal lung. The level of p15.5 was significantly higher in associated normal lung and in tumours (P<0.02 respectively), specially in low grade tumours (P<0.01), than in control normal lung. Furthermore, p15.5 expression was more variable in tumours than in normal lung (P<0.01) and in low grade than in high grade NE lung tumours (P<0.02). Levels of p15 and p15.5 were distinct (up- or downregulated) from those observed in paired normal lung in 4/12 (33%) and 10/12 (83%) tumours respectively. Aberrant methylation at the 5' end of p15(INK4b) gene was observed in 15% of NE lung tumours using PCR-based assay, in a region proximal to the translation start where methylation did not occur in control and associated normal lung. However, no correlation could be assessed with protein status. MSP analysis of CpG islands proximal to the transcription start revealed methylation in all normal and tumour samples. No correlation was found between p15(INK4b) and p16(INK4a) or p14(ARF) status. These data suggest that complex deregulation of p15.5 is implicated in the carcinogenesis of human NE lung tumours independently of p16(INK4a) and p14(ARF) status.

Carcinoma, Neuroendocrine↗

PubMed2005

Positively charged GdIII cryptates: slow, associative water exchange.

A combined variable-temperature and multiple field 17O NMR, EPR and NMRD study has been performed for the first time on gadolinium(III) complexes of cryptand ligands, L1 and L2, where L1 contains three 2,2'-bipyridine units ([bpy.bpy.bpy]) and L2 is the disubstituted methyl ester derivative of L1. The experimental data have been analysed in a simultaneous fit in order to determine parameters for water exchange, rotational dynamics and electronic relaxation for both complexes. The cryptates have three water molecules in the inner sphere which exchange with a rate of k(ex)298 = 1.8 x 10(6) s(-1) and 0.97 x 10(6) s(-1) for [GdL1(H2O)3]3+ and [GdL2(H2O)3)]3+, respectively. The k(ex)298 values obtained for these positively charged cryptates are smaller than those of the negatively charged Gd-poly(amino carboxylate) complexes. The water exchange mechanism was assessed for [GdL2(H2O)3]3+ by variable-pressure 17O NMR relaxation measurements. Based on the activation volume, DeltaV++ = -2.5 cm3 mol(-1), the water exchange is an associative interchange process. The proton relaxivities, r1, of the cryptate complexes are 9.79 mM(-1) s(-1) for [GdL1(H2O)3]3+ and 11.18 mM(-1) s(-1) for [GdL2(H2O)3]3+ (298 K, 20 MHz), which, due to the presence of three inner sphere water molecules, represent much higher values than those obtained for Gd3+ poly(amino carboxylate) complexes of similar molecular weight.

Cations↗

PubMed1999

Tobacco O-methyltransferases involved in phenylpropanoid metabolism. The different caffeoyl-coenzyme A/5-hydroxyferuloyl-coenzyme A 3/5-O-methyltransferase and caffeic acid/5-hydroxyferulic acid 3/5-O-methyltransferase classes have distinct substrate specificities and expression patterns.

The biosynthesis of lignin monomers involves two methylation steps catalyzed by orthodiphenol-O-methyltransferases: caffeic acid/5-hydroxyferulic acid 3/5-O-methyltransferases (COMTs) and caffeoyl-coenzyme A (CoA)/5-hydroxyferuloyl-CoA 3/5-O-methyltransferases (CCoAOMTs). Two COMT classes (I and II) were already known to occur in tobacco (Nicotiana tabacum) and three distinct CCoAOMT classes have now been characterized. These three CCoAOMT classes displayed a maximum level of expression at different stages of stem development, in accordance with their involvement in the synthesis of lignin guaiacyl units. Expression profiles upon tobacco mosaic virus infection of tobacco leaves revealed a biphasic pattern of induction for COMT I, COMT II, and CCoAOMTs. The different isoforms were expressed in Escherichia coli and our results showed that CCoAOMTs and, more surprisingly, COMTs efficiently methylated hydroxycinnamoyl-CoA esters. COMT I was also active toward 5-hydroxyconiferyl alcohol, indicating that COMT I that catalyzes syringyl unit synthesis in planta may operate at the free acid, CoA ester, or alcohol levels. COMT II that is highly inducible by infection also accepted caffeoyl-CoA as a substrate, thus suggesting a role in ferulate derivative deposition in the walls of infected cells. Tobacco appears to possess an array of O-methyltransferase isoforms with variable efficiency toward the diverse plant o-diphenolic substrates.

Acyl Coenzyme A↗

PubMed2026

Scion-based drought stress memory affects potato response to water deficit.

A scion-based stress memory signal, which was derived from drought-primed potato plants, was transmitted to new potato plants generated through vegetative reproduction. This affected potato tuber yield. Drought is one of the most significant threats to agricultural productivity worldwide. The cultivated potato (Solanum tuberosum L.) is a crop species that is sensitive to drought stress. This study investigated the impact of scion-based drought stress memory on tuber yield, physiological parameters, gene expression, and DNA methylation in the vegetative progeny of grafted plants. The tuber progeny plants remembered the drought stress signal transmitted from the drought-primed scion. Significant changes were observed in the expression of genes, primarily those related to photosynthetic metabolic pathways, as well as those associated with chromatin remodeling, DNA repair, and the plant's response to abiotic stresses. The gene expression landscape corresponded with variability in chlorophyll fluorescence parameters. In the first and the second generation of vegetatively propagated plants, scion-based memory had a positive effect on tuber yield. This was achieved by buffering the decline in yield caused by drought, as compared to plants grown under control conditions. Whole-genome bisulfite sequencing analysis revealed no correlation between changes in DNA methylation and gene expression. Drought-induced alterations in DNA methylation were erased in the second progeny generation. We propose that there is a direct causal relationship between scion-based memory of drought stress and photosynthetic efficiency, as well as potato tuber productivity.

Solanum tuberosum↗

PubMed1999

Synthesis and analgesic activity of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters, acetic acids, and acetamides.

A group of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters (7), weak acetic acids (8), and acetamides (9) were designed for evaluation as less acidic non-ulcerogenic non-steroidal antiinflammatory drugs (NSAIDs). In this respect, the model compound 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetic acid (8a), unlike traditional arylacetic acid NSAIDs, was shown to be a weak acid with a pKa of 9.17. In contrast to arylacetic acid NSAIDs, the alpha-methylacetic acid sodium salt of 8a, or the methyl alpha-methylacetate ester (7a) did not inhibit cyclooxygenase-1 (COX-1) or -2 (COX-2). In vitro stability studies showed that the methyl alpha-methylacetate ester (7a) acts as a prodrug to the alpha-methylacetic acid derivative (8a), undergoing rapid (< 10 minutes) and quantitative conversion upon incubation with rat plasma, or incubation with rat liver homogenate (t1/2 = 25 min). In contrast, the alpha-methylacetamide (9a) underwent negligible (< 2%) conversion to the alpha-methylacetic acid derivative (8a) upon incubation with either rat plasma, or rat liver homogenate, for incubation times up to 24 h. The effect of a C-3 para-substituted-benzoyl substituent (R1 = H, Cl, Me), a C-4 substituent (R2 = aryl, benzyl, cyclohexyl, alkyl), and the nature of the N1-acetic acid moiety [methyl ester (R3 = OMe), acetic acid (R3 = OH), acetamide (R3 = NH2)] on analgesic activity was determined using the 4% NaCl-induced abdominal constriction (writhing) assay. Compounds 7-9 inhibited writhing 27-95% relative to the reference drug aspirin (58% inhibition). The analgesic potency with respect to the para-benzoyl substituent was H > Cl or Me. Although the effect of the C-4 R2-substituent on analgesic activity was variable within the ester, acid and amide sub-groups of compounds, compounds having a R2-cyclohexyl substituent generally provided superior analgesic activity relative to those having a lipophilic alkyl substituent. The nature of the R3-substituent (OMe, OH, NH2) was a determinant of analgesic activity where the potency order was acetic acid methyl ester > acetic acid or acetamide, except when the C-4 R2-substituent was cyclohexyl or benzyl where the potency order was acetamide > acetic acid methyl ester or acetic acid. Reduction of the 5,6-olefinic bond of the 1,4-dihydropyridyl compound (9a, 94% inhibition) to the corresponding 1,2,3,4-tetrahydropyidyl derivative (10, 69% inhibition) reduced analgesic activity.

Acetamides↗

PubMed1975

Brain tissue transplanted to the anterior chamber of the eye: 3. Substitution of lacking central noradrenaline input by host iris sympathetic fibers in the isolated cerebral cortex developed in oculo.

Fetal parietal cerebral cortex was homologously transplanted to the anterior chambers of the eyes of adult rats. The transplants got vascularized, proliferated, as measured by in vivo stereoscopic inspections, and differentiated into brain tissue similar to cortex cerebri in situ and survived for long times, greater than 41/2 months. Fibers from the intact sympathetic adrenergic ground plexus of the iris were able to innervate the transplants in an organotypic way regarding fluorescence morphology, pattern of distribution of the nerve terminals and, to a certain extent, density of innervation, the only variable parameter being density of innervation. Thus, in unpretreated or MAO inhibited transplants only rather few to scattered terminals could be found, while after preincubation in 10(-5)M alpha-methyl-noradrenaline the number of visible terminals was normal or slightly less than normal, as compared to cortex cerebri in situ. When superior cervical ganglia (SCG) were transplanted together with fetal cortex tissue to sympathetically denervated eyes the ingrowth in the cortex tissue was similar to that after single cortex transplantation combined with 5 day old SCG, while a marked hyperinnervation was encountered when combined with adult SCG. It is concluded that the developing cortex cerebri, deprived of its normal CNS source of adrenergic nerves, is able to receive sympathetic adrenergic nerves from the iris in an organotypic way upon transplantation to the anterior chamber of the eye.

Animals↗

PubMed2005

Investigation on the interactions between diperoxovanadate and substituted phenanthroline.

Detailed investigations were carried out to explore the interaction systems of NH4VO3/H2O2/5,6-dimethyl-1,10-phenanthroline and NH4VO3/H2O2/5-methyl-1,10-phenanthroline in aqueous solution under physiological conditions by NMR spectroscopy, such as 1D 1H, 13C, 51V variable temperature, and 2D COSY, NOESY, HETCOR, COLOC techniques as well as density functional calculations. New species [OV(O2)2(5,6-dimethyl-1,10-phenanthroline)]- and [OV(O2)2(5-methyl-1,10-phenanthroline)]- including isomers were formed in a bidentate coordination fashion which were stable under the experimental conditions. The solution structures of these new species were proposed based on the direct NMR experimental information and confirmed by the theoretical calculations. All the 1H and 13C NMR peaks were assigned. The calculated 1H and 13C chemical shifts on the whole are in fair agreement with the experimental values. The methyl groups on the aromatic ring of the three new complexes were found to have a steric hindrance effect on the coordination process. Experimental results show that the order of coordination capability of phenanthroline and its derivants was: 1,10-phenanthroline>5-methyl-1,10-phenanthroline>5,6-dimethyl-1,10-phenanthroline.

Magnetic Resonance Spectroscopy↗

PubMed2003

How specific are deficits in mismatch negativity generation to schizophrenia?

BACKGROUND: Mismatch negativity (MMN) is an auditory event-related potential that provides an index of auditory sensory memory. Deficits in MMN generation have been repeatedly demonstrated in chronic schizophrenia. Their specificity to schizophrenia has not been established. METHODS: Mismatch negativity to both duration and frequency deviants was investigated in gender- and age-matched patients with schizophrenia or schizoaffective disorder (n = 26), bipolar disorder (n = 16), or major depression (n = 22) and healthy control subjects (n = 25). RESULTS: Only patients with schizophrenia demonstrated significantly smaller mean MMN than did healthy control subjects. Detailed analyses showed significantly smaller MMN to both duration and frequency deviants in patients with schizophrenia than in healthy control subjects; however, the reduction of frequency MMN in patients with schizophrenia was not significant in the comparison across all groups. Mismatch negativity topography did not differ among groups. No consistent correlations with clinical, psychopathologic, or treatment variables were observed. CONCLUSIONS: Mismatch negativity deficits, and by extension deficits in early cortical auditory information processing, appear to be specific to schizophrenia. Animal and human studies implicate dysfunctional N-methyl-D-aspartate receptor functioning in MMN deficits. Thus MMN deficits may become a useful endophenotype to investigate the genetic underpinnings of schizophrenia, particularly with regard to the N-methyl-D-aspartate receptor.

Adult↗

PubMed1997

Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine.

Interpatient differences in the oral clearance of cyclosporine (INN, ciclosporin) have been partially attributed to variation in the activity of a single liver enzyme termed CYP3A4. Recently it has been shown that small bowel also contains CYP3A4, as well as P-glycoprotein, a protein able to transport cyclosporine. To assess the importance of these intestinal proteins, the oral pharmacokinetics of cyclosporine were measured in 25 kidney transplant recipients who each had their liver CYP3A4 activity quantitated by the intravenous [14C-N-methyl]-erythromycin breath test and who underwent small bowel biopsy for measurement of CYP3A4 and P-glycoprotein. Forward multiple regression revealed that 56% (i.e., r2 = 0.56) and 17% of the variability in apparent oral clearance [log (dose/area under the curve)] were accounted for by variation in liver CYP3A4 activity (p < 0.0001) and intestinal P-glycoprotein concentration (p = 0.0059), respectively. For peak blood concentration, liver CYP3A4 activity accounted for 32% (p = 0.0002) and P-glycoprotein accounted for an additional 30% (p = 0.0024) of the variability. Intestinal levels of CYP3A4, which varied tenfold, did not appear to influence any cyclosporine pharmacokinetic parameter examined. We conclude that intestinal P-glycoprotein plays a significant role in the first-pass elimination of cyclosporine, presumably by being a rate-limiting step in absorption. Drug interactions with cyclosporine previously ascribed to intestinal CYP3A4 may instead be mediated by interactions with intestinal P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1985

Synthesis and hypoglycemic activity of N-alkylated hydrazonopropionic acids.

A series of N-alkylated 2-hydrazonopropionic acids have been synthesized and evaluated for their hypoglycemic activity. Most of the compounds exhibit a remarkable blood glucose lowering activity in fasted guinea pigs. Some of the structural variables studied were the effects of branching, unsaturation, or substitution on the alkyl side chain and the effect of nuclear substitution on the aralkyl analogues. From these compounds, 2-[[(E)-2-methyl-3-phenyl-2-propenyl]hydrazono]propionic acid (BM 42.304; 42) was selected for further investigation.

Animals↗

PubMed2006

Functionalization of titanium oxide surfaces by means of poly(alkyl-phosphonates).

The use of a multiple attachment sites strategy is considered in order to improve the stability of monomolecular adlayers. The hypothesis was tested in the case of PEG-ylated compounds carrying phosphonate groups, known for their affinity toward titanium oxide surfaces. As a result, a new class of co- and terpolymers were synthesized by free-radical polymerization of three different monomers: dialkyl(methacryloyloxyalkyl)phosphonates, PEG methyl ether methacrylate, and/or butyl methacrylate monomers. Adlayers were formed following a simple dip-and-rinse protocol using diluted aqueous polymer solutions and were characterized by evaluating their thicknesses with variable angle spectroscopic ellipsometry (VASE) and their elemental compositions with X-ray photoelectron spectroscopy (XPS). The same techniques were used to determine changes of the adlayer as a function of exposure to electrolytes at different pH values and to monitor nonspecific protein adsorption upon serum exposures. The results indicated that the poly(alkyl-phosphonate)-based adlayers combine multiple site attachment of phosphonic groups and presentation of PEG side chains to the aqueous environment, resulting in both improved stability over a wide pH range in comparison to the tested reference surfaces and excellent resistance to protein adsorption when exposed to full human serum.

Magnetic Resonance Spectroscopy↗

PubMed2000

Purification and characterization of intestinal adenosine deaminase from mice.

Adenosine deaminase (ADA) was isolated from small intestine of mice and purified to utmost homogeneity. SDS-PAGE of purified ADA gave a molecular weight of 41 kDa. Western blot analyses gave a single reactive band at 41 kDa and the other band was an associated ADA binding protein. The purified enzyme was more stable in the alkaline pH. The optimum pH and the pI values were about 7.0 and 4.96, respectively. Km values of the small intestinal ADA for adenosine and 2'-deoxyadenosine were 23 and 16 microM, respectively. Purine riboside was a competitive inhibitor with Ki of 5 microM, whereas 2'-3'-o-isopropylidene adenosine acted as an uncompetitive inhibitor (Ki 66 microM). Activity of ADA was inhibited by the presence of theophylline (-40%), caffeine (-30%), and L-cysteine (-50%). Significantly, Hg2+ (100 microM) inhibited 98% of the initial ADA activity. In addition, various purine analogs such as inosine, purine, alpha-adenosine and adenine showed variable inhibitions on the activity of ADA. Relative ADA activity towards 3'-deoxyadenosine and 6-chloropurine riboside was lower by 30% and 40%, respectively. However, the activity towards 2'-o-methyl adenosine was higher (30%) compared to the activity obtained using adenosine.

Adenosine Deaminase↗

PubMed1989

The effect of some preservatives used in nasal preparations on mucociliary clearance.

The effect of methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, chlorbutol, chlorocresol, EDTA, benzalkonium chloride, chlorhexidine, phenylmercuric nitrate and phenylmercuric borate on mucociliary transport rate of the frog palate has been examined. Following a variable number of applications all these preservatives halted transport, the first three reversibly. However, applications of thiomersal (0.01%) were well tolerated. The frog palate possesses a ciliated epithelium protected by mucus, since some of our findings are at variance with those previously reported results where the protective effect of mucus was negligible in the in-vitro model (usually trachea) employed, it would appear that the contribution of mucus to effective mucociliary clearance should not be underestimated.

Administration, Intranasal↗

PubMed1991

An investigation into the influence of vasopressin on perfusion of the cortex and papilla of the rat kidney.

An investigation was undertaken to examine the effects of vasopressin on blood pressure and perfusion of the cortical and papillary regions of the kidney, and to determine the receptor subtype involved. Pentobarbitone-anaesthetized rats were used and laser-Doppler flowmetry applied to measure regional renal haemodynamics. Infusion of vasopressin at 10, 20 and 40 mU kg-1 min-1 caused dose-related increases in blood pressure and reductions in cortical and papillary perfusion of approximately 21, 35 and 41%, respectively at the highest dose. Administration of the V1-receptor antagonist, [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]-Arg8-vasopressin, at 1 microgram kg-1 plus 5 micrograms kg-1 h-1 or four times this dose had no effect on the basal levels of any variable. Vasopressin administration during the low dose of antagonist increased blood pressure and reduced papillary perfusion, the magnitudes of which were only slightly less than those obtained in the absence of the drug, whereas there was a significant attenuation of the response in cortical perfusion. During infusion of the V1 antagonist at 4 micrograms kg-1 plus 20 micrograms kg-1 h-1, vasopressin had no effect on either blood pressure or renal haemodynamics. Infusion of the V2 antagonist, [d(CH2)5, D-Phe2, Ile4, Arg8, Ala9-NH2]-vasopressin at 1 microgram kg-1 plus 5 micrograms kg-1 h-1, and twice this dose had no effect on the basal value of any variable and had no effect on the ability of vasopressin to induce an increase in blood pressure or cause reductions in renal cortical and papillary perfusions. However, the administration of the V2 antagonist at 4 micrograms kg-1 plus 20 micrograms kg-1 h-1 significantly attenuated blood pressure, cortical and papillary perfusion responses to the vasopressin. These studies have shown that vasopressin, given at doses which increased blood pressure, caused dose-related decreases in perfusion of renal cortex as well as the papilla. The data further show that these systemic and renal actions were mediated primarily by V1-receptors and that the contribution of V2-receptors at these vascular beds was very small.

Angiotensin Receptor Antagonists↗

PubMed1967

Cultural characteristics and fatty acid composition of Corynebacterium acnes.

A detailed study of the cultural characteristics and cellular fatty acid composition of 27 isolates of Corynebacterium acnes was performed to establish the properties by which this organism may be identified and characterized. The fatty acids were extracted directly from whole cells and examined as methyl esters by gas-liquid chromatography. Each strain possessed a similar fatty acid profile which was characterized by a large percentage of C15 branched-chain acid. Uniformity in certain biochemical reactions and cultural characteristics was also observed. All strains were catalase-positive, nonmotile, and urease-negative, reduced nitrate, liquefied gelatin, failed to hydrolyze esculin and starch, and gave a positive methyl red test. Glucose, fructose, and glycerol were fermented, but not lactose, salicin, sucrose, maltose, xylose, or arabinose. Production of hydrogen sulfide and indole, fermentation of mannitol, and hemolytic activity were variable characteristics. Two species of the genus Propionibacterium were also tested and found to be similar to C. acnes both in cultural characteristics and fatty acid composition. The results strengthen previous suggestions that C. acnes should be classified in the genus Propionibacterium.

Acids↗

PubMed2004

Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients.

PURPOSE: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes. EXPERIMENTAL DESIGN: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. RESULTS: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (V(D)), 30.3 liters; absorption constant rate, 5.8 h(-1); elimination half-time, 2.1 h; transfer rate from plasma to CSF (K(plasma-->CSF)), 7.2 x 10(-4)h(-1) and the backwards rate, 0.76 h(-1). Body surface area significantly influenced both clearance and V(D), and clearance was sex dependent. The AUC(CSF) corresponded to 20% of the AUC(plasma). A trend toward an increased K(plasma-->CSF) of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. CONCLUSIONS: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC(CSF)/AUC(plasma) ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

Adult↗

PubMed1995

Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.

Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects. The recent discovery of mutations in the common gamma chain (gamma c) gene, a constituent of several cytokine receptors, in XSCID provided an opportunity to test directly whether a previously unrecognized mutation in this same gene was responsible for XCID. The status of X chromosome inactivation in blood leukocytes from obligate carriers of XCID was determined from the polymorphic, short tandem repeats (CAG), in the androgen receptor gene, which also contains a methylation-sensitive HpaII site. As in XSCID, X-chromosome inactivation in obligate carriers of XCID was nonrandom in T and B lymphocytes. In addition, X chromosome inactivation in PMNs was variable. Findings from this analysis prompted sequencing of the gamma c gene in this pedigree. A missense mutation in the region coding for the cytoplasmic portion of the gamma c gene was found in three affected males but not in a normal brother. Therefore, this point mutation in the gamma c gene leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.

Amino Acid Sequence↗