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Biomedical subjects

M Nitz

Publications and source records attributed to M Nitz.

13 recordsLinked to original sources
PubMed2001

Synthesis of di- to hexasaccharide 1,2-linked beta-mannopyranan oligomers, a terminal S-linked tetrasaccharide congener and the corresponding BSA glycoconjugates.

Homo oligomers of (1-->2)-beta-D-mannopyranosyl residues have been synthesized in order to study the unique immunological properties of the cell wall mannan of C. albicans. p-Chlorobenzyl-protected ulosyl bromide (2) in combination with the sterically hindered, participating solvent, pivaloyl nitrile, facilitated a new approach for the synthesis of these unique homooligomers ranging from disaccharide up to hexasaccharide. The glycosyl donor 2 demonstrates high diastereoselectivity over both the glycosylation and subsequent reduction step and minimizes the number of protecting group manipulations necessary for the synthesis. Congeners of the (1-->2)-beta-D-mannotetraose were synthesized containing a terminal S-linked (1-->2)-beta-D-mannopyranosyl residue. Deprotection of these compounds afforded the propyl glycosides as well as oligomers with amino terminated aglyconic tethers. The tethers were generated from the oligosaccharide allyl glycosides by photoaddition with 2-aminoethanethiol. The functionalized haptens were coupled to BSA via squarate conjugation, and the degree of incorporation was established by TOF mass spectrometry.

Candida albicans↗
PubMed2001

Localization of low affinity nerve growth factor receptor in the rat inferior olivary complex during development and plasticity of climbing fibres.

The rat olivocerebellar pathway has a precise topography from an inferior olive (IOC) to Purkinje cells in the contralateral hemicerebellum. While its development and plasticity have been documented, the molecular mechanisms underlying these events are not fully elucidated. Neurotrophins are a family of growth factors with diverse roles in development and neuronal plasticity, acting through a two-receptor system, including a low affinity receptor (LNGFR) which binds all neurotrophins with similar affinity. Since neurotrophins are present in the cerebellum during early postnatal development when LNGFR is synthesized in the IOC, they may act as target-derived trophic agents for climbing fibres during development and plasticity. To assess this, standard immunohistochemistry was used to document the distribution of LNGFR in the rat IOC during climbing fibre development and until cerebellar development was complete at postnatal day 28 (P28). LNGFR immunoreactivity (LNGFR-IR) was detected in the IOC from P0 until P15, however after P7 it diminished in intensity and distribution, a change which indicates a relationship between cerebellar neurotrophins and climbing fibre development. After denervation of the left hemicerebellum, there was an apparent increase in inferior olivary LNGFR-IR that was concurrent with climbing fibre re-innervation. Thus the results of this study support the hypothesis that neurotrophins are involved in climbing fibre development and suggest a possible contribution to the plasticity of the olivocerebellar pathway.

Animals↗
PubMed2000

Synthesis of a beta1,2-mannopyranosyl tetrasaccharide found in the phosphomannan antigen of Candida albicans.

The synthesis of a portion of the challenging beta1,2-mannosyl polymer found in the cell walls of Candida albicans was undertaken to develop a conjugate vaccine against C. albicans and to facilitate NMR conformational studies of this unique polysaccharide. The novel approach to the synthesis of tetrasaccharide 1 employed the modified ulosyl bromide 11 as the glycosyl donor which provided high diastereoselectivity. A participating solvent as well as p-chlorobenzyl protection facilitated the new approach.

Antigens, Fungal↗
PubMed2000

Efficient synthesis of 3, 6-dideoxy-beta-D-arabino-hexopyranosyl-terminated LacdiNac glycan chains of the Trichinella spiralis parasite.

The synthesis of a linear trisaccharide epitope of the Trichinella spiralis N-linked glycan, in a form amenable to glycoconjugate formation, is reported. The trisaccharide contains the synthetically challenging LacdiNAc [beta-GalpNAc(1-->4)-beta-GlcpNAc] element, as well as a terminal 3,6-dideoxy-beta-D-arabino-hexopyranose (tyvelose) residue. An orthogonal protection strategy is described, which permits the protection and manipulation of three amino groups present in the disaccharide beta-GalNAc(1-->4)-beta-GlcNAc and the tether used to prepare neoglycoconjugates. The beta-linked dideoxyhexose was generated in excellent yield by the introduction of the dideoxyhexose unit as a beta-D-ribo-hexopyranoside (paratose) followed by an oxidation-reduction sequence to generate the beta-D-arabino configuration in high diastereomeric excess. The required dideoxyhexose donor was synthesized in a series of high-yielding steps from glucose utilizing the p-methoxyphenyl glycoside.

Amino Sugars↗
PubMed1998

Insights into transition state stabilization of the beta-1,4-glycosidase Cex by covalent intermediate accumulation in active site mutants.

The catalytic mechanism of 'retaining' beta-glycosidases has been the subject of considerable interest and debate for many years. The visualization of a covalent glycosyl enzyme intermediate by X-ray crystallography was first accomplished with a saccharide substrate substituted with fluorine at its 2-position. The structure implicated major roles for residue His 205 and for the 2-hydroxyl position of the proximal saccharide in binding and catalysis. Here we have studied the kinetic behavior of various His 205 mutants. One of these mutants, a double mutant H205N/E127A, has been used to stabilize a covalent glycosyl-enzyme intermediate involving an unsubstituted sugar, permitting crystallographic analysis of the interactions between its 2-hydroxyl group and the enzyme.

Binding Sites↗
PubMed1993

Genotype and phenotype of glutathione S-transferase class mu isoenzymes mu and psi in lung cancer patients and controls.

Glutathione S-transferase class mu (GSTM1) is known to detoxify certain carcinogens or their activated metabolites. In a previous study using phenotyping methods, individuals genetically devoid of this enzyme activity were significantly overrepresented among lung cancer patients compared to controls, suggesting that this trait is a risk factor for lung cancer. Here, GST class mu status has been determined both pheno- and genotypically, i.e., (a) by ex vivo measurement of trans-stilbene oxide conjugation in lymphocytes, (b) by GSTM1 quantification in blood using an immunoassay, and (c) by the application of polymerase chain reaction to genomic DNA with characterization of an inactivating mutation responsible for the null allele and a G/C single base allelic variance corresponding to the polymorphism of GSTM1 isoenzymes mu and psi, respectively. One hundred seventeen lung cancer patients and 155 control patients were studied. The two groups were of German origin and were similar with respect to age, sex, smoking history, and catchment area. In about 97% of cases, the three methods of assigning activity type of GSTM1 gave corresponding results. By genotype, 55 of 117 lung cancer patients (47.0%) and 73 of 155 control patients (47.1%) were GSTM1 active. The control group was confirmed by analysis of GSTM1 genotype in 200 further, independently studied reference patients; 101 of them were GSTM1 active (50.5%). Thus, the hypothesis of heritable GSTM1 deficiency as a host factor predisposing to lung cancer proved inappropriate. Detailed analysis of subgroups with respect to smoking habits, age, and sex failed to reveal an impact of GST class mu genotype on lung cancer risk. Among the total of 272 patients studied, 36 individuals carried at least one psi allele; however, no unexpected frequency distribution was observed.

Adult↗
PubMed1993

Population kinetics of gentamicin in neonates.

A population kinetic analysis was carried out on sparse plasma gentamicin (GE) concentration data from 469 neonates obtained as part of a routine therapeutic drug monitoring (TDM) programme in the hospital neonatology unit. The best predictors of the kinetic parameters of the monoexponential model, volume of distribution (Vd) and clearance (CL), were the weight (WT) and gestational age (GA). Vd of the neonates was only related to WT, whereas the half-life was only related to the GA. The clinical implications of the findings are that the initial dose per WT administered to premature infants should be larger than that for term infants, because of a larger Vd per unit WT, and the intervals between maintenance doses should extended due to the prolonged half-life. Apart from these general guidelines, specific dose recommendations are also given.

Body Weight↗
PubMed1991

System analysis in multiple dose kinetics: evidence for saturable tubular reabsorption of the organic cation N1-methylnicotinamide in humans.

The renal clearance of N1-methylnicotinamide (NMN) was studied in 8 young women at physiological steady state and at steady state following a combined loading bolus and iv infusion. Urinary NMN concentrations were determined using a new HPLC method, plasma levels by a conventional fluorescence method. At physiological levels net tubular secretion of NMN was evident due to a renal fractional excretion, i.e., a ratio of renal NMN clearance to creatinine clearance, above unity. Increasing plasma concentrations lead to an increase in the fractional excretion, indicating saturation of the underlying tubular reabsorption process. Binding to plasma proteins was excluded by ultra-filtration experiments. Clearances measured at physiological levels were about one half of the maximum renal clearance attained following the infusion. This maximum value was approximately six times the creatinine clearance and may be a useful approximation of the renal plasma flow. System analysis, including a novel method to calculate the net response following a multiple input, was used to determine the pharmacokinetic system parameters.

Absorption↗
PubMed1991

Pharmacokinetics of galanthamine in humans and corresponding cholinesterase inhibition.

Measurements were done to determine the plasma concentrations of galanthamine and two of its metabolites, as well as the corresponding inhibition of acetylcholinesterase activity in erythrocytes after applying 5 and 10 mg galanthamine hydrobromide as a constant-rate intravenous infusion for 30 minutes and single oral doses of 10 mg in eight healthy male volunteers. The data obtained revealed first-order pharmacokinetics, complete oral bioavailability, and a mean terminal half-life of 5.68 hours (95% confidence interval, 5.17 to 6.25 hours). Renal clearance accounted for only 25% of the total plasma clearance (CL = 0.34 L.kg-1.hr-1). Only negligible quantities of the putative metabolites, epigalanthamine and galanthaminone, were detected in blood and urine. The inhibition of acetylcholinesterase activity was closely correlated with the pharmacokinetics of galanthamine, a median maximal value of 53% being achieved by applying 10 mg galanthamine intravenously. Analysis of in vitro and ex vivo concentration responses revealed no differences, indicating that no metabolites of galanthamine exert additional inhibition of acetylcholinesterase activity.

Acetylcholinesterase↗
PubMed1990

Nonlinear kinetics of the thiamine cation in humans: saturation of nonrenal clearance and tubular reabsorption.

The pharmacokinetics of thiamine in plasma and urine was investigated in 13 healthy and 3 renal-insufficient volunteers. Doses ranging from 5 to 200 mg thiamine hydrochloride were administered either as an iv bolus or a 50-min infusion. A sum of 3 exponentials was used as the unit impulse response function to characterize plasma kinetics. Drug input was mathematically described as a rectangular pulse of length 2 or 50 min. Total clearance, defined as the reciprocal of the area under the unit impulse response function, was found to depend on dose and creatinine clearance, as shown by a multiple nonlinear regression analysis. The nonrenal component of the total clearance was demonstrated to be dose-dependent, whereas its mean renal component was only dependent on creatinine clearance. At high plasma concentrations renal clearance approached renal plasma flow, and remained constant during the decline to near physiological plasma levels. With further decline under a characteristic threshold concentration, renal clearance decreased far below the glomerular filtration rate, indicating tubular reabsorption. Binding to plasma proteins was excluded by ultrafiltration experiments. The process of renal excretion can be described by a combination of glomerular filtration, flow-dependent tubular secretion, and saturable tubular reabsorption. The concentration dependency of renal clearance was reflected in its mean value, which was only 76% of its maximum value measured in the higher concentration range. In the dose range studied, most of the given dose had already been linearly excreted before tubular reabsorption became evident, and consequently the measured mean renal clearances did not differ enough from one another to exhibit the expected dose dependency. With increasing dose a shift of the cleared dose fraction from the nonrenal to the renal side was observed. Saturated nonrenal clearance alone could explain this effect.

Adult↗
PubMed1988

Debrisoquine hydroxylation phenotype, acetylation phenotype, and ABO blood groups as genetic host factors of lung cancer risk.

Bronchogenic carcinoma is closely associated with cigarette smoking although additional environmental or individual factors might regulate a person's susceptibility to that disease. To further define such risk factors, the prevalence of the genetic debrisoquine 4-hydroxylation deficiency was determined before therapeutic intervention in 270 lung cancer patients. Nineteen homozygous carriers of this defect (poor metabolizers) were found (7.0%, 95% confidence limits 4.3%-10.8%), a number being lower than 30 out of 270 reference patients (11.1%, 95% confidence limits 7.6%-15.5%). The odds ratio of 0.61 was of marginal statistical significance (P = 0.067). Subdividing the collective according to histology revealed a trend towards underrepresentation of poor metabolizers especially among patients with adenocarcinoma (1 out of 37, P = 0.086) and among young patients not older than 50 years (none out of 32, P = 0.028). All poor metabolizers (PMs) in the cancer group were smokers. In 18 patients the phenotype assignment was confirmed by a second test several weeks after surgical or other treatment. In 220 of the lung cancer patients the N-acetyltransferase polymorphism was evaluated by means of the molar ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after ingestion of caffeine (coffee). There were 111 (50.5%) slow acetylators and 109 (49.5%) fast acetylators. A statistically significant clustering of either phenotype after stratification according to histology, or debrisoquine hydroxilator status was lacking. Moreover, there was no difference in the ratio of both phenotypes as compared to the reference collective of 245 patients (53.5% slow and 46.5% fast acetylators). As a third genetic host factor the AB0 blood group frequencies were evaluated in 263 lung cancer patients. The frequency ratio of A/O was significantly higher as compared to 41,423 blood donors (odds ratio 1.37, 95% confidence limits 1.02-1.84, P less than 0.05). A/O tended to be especially high in young patients not older than 50 years. The ratio B/O in bronchial cancer was significantly higher than expected. The results suggest that the debrisoquine hydroxilator status might have an impact on an individual's susceptibility to lung cancer. This association is either a weak one and/or is restricted to certain histological cancer types or to patients with certain characteristics. The acetylator phenotype could not be established as a risk factor, whereas AB0 blood groups seem to influence lung cancer susceptibility.

ABO Blood-Group System↗