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JAN KELDER CAREL FUNKE THUS DE BOER LEON DELBRESSINE DIRK LEYSEN VICTOR NICKOLSON 《The Journal of pharmacy and pharmacology》1997,49(4):403-411
Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pKa value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the α1-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin. 相似文献
3.
Six-Month Exposure of Strain A/J Mice to Cigarette Sidestream Smoke: Cell Kinetics and Lung Tumor Data 总被引:3,自引:1,他引:2
Male strain A/J mice were exposed to sidestream smoke (SS) generatedfrom burning Kentucky 1R4F reference cigarettes. Chamber concentrationswere 4 mg/m3 of total suspended respirable particulate matter(TSP). Animals were exposed 6 hr a day, 5 days a week. One-weekcumulative labeling indices were significantly increased inthe large intrapulmonary airways during the 1st week and inthe respiratory epithelium of the nasal and maxillar turbinatesduring the first 3 weeks of exposure and then returned to controlvalues. Subsequently, signs of increased cell proliferationwere again found in the nasal and maxillar turbinates duringthe 9th and 16th exposure weeks. The experiment was terminatedafter 6 months. The number of animals bearing lung tumors wasthe same in smoke-exposed as in filtered airexposed animalsas was the average number of tumors per lung. Analysis of theDNA of individual tumors obtained from exposed and control micefor K-ras mutations suggested that exon 2 might be a specifictarget for SS. It was concluded that (1) duration of exposurewas too short or (2) concentration of TSP was too low to reveala possible carcinogenic potential of SS in strain A/J mice orthat (3) SS is not carcinogenic in strain A mice. 相似文献
4.
Stochastic models for geriatric in-patient behaviour 总被引:1,自引:0,他引:1
Departments of geriatric medicine engage in two distinct formsof clinical activity: acute/rehabilitative and long-stay care.These are organizationally distinct and have very differentresource needs. Current hospital planning models, however, assumethat patients all move through the system at the same rate,thereby ignoring this effect of inherent heterogeneity in patientbehaviour. The present paper describes the movement of patientsthrough geriatric hospitals by a two-stage continuous-time Markovmodel, where the stages represent acute/rehabilitative and long-staypatients respectively. Patients are initially admitted to thefirst stage, from which they may depart from the system, bydeath or discharge, or move into the second stage, from whichthey eventually depart by death or discharge (unlikely). Admissionsare modelled in two ways: either as replacements for departuresor as a Poisson stream. Expressions for the distribution andmovement of numbers of patients are derived and evaluated fordata from a number of hospitals. Such an approach has the advantage,over previous crude models, of taking into account differenttypes of patients and introducing variability, thus making itpossible to extract variances as well as means of numbers ofgeriatric patients requiring hospital care. 相似文献
5.
ALEKSANDRA MISICKA ANDRZEJ W. LIPKOWSKI ROBERT HORVATH PEG DAVIS FRANK PORRECA HENRY I. YAMAMURA VICTOR J. HRUBY 《Chemical biology & drug design》1994,44(1):80-84
Further efforts to correlate the topography of the bioactive structures of DPDPE and the deltorphins, two δ-opioid receptor active peptide families, are reported. A number of DPLPE-deltorphin chimeric peptides have been synthesized in which the C-terminal dipeptide δ-address of the deltorphins (-Val-GlyNH2, -Nle-GlyNH2) have been linked to the highly δ-opioid selective cyclic peptides DPDPE or DPLPE. These studies demonstrate that a major structural feature determining high potency of hybrid analogues is the chirality of the amino acid residue in position 5. The radioligand binding assays have revealed a decrease in potency (compared to DPDPE) at §-receptors when the C-terminal dipeptides were added to DPDPE. On the other hand, chimeric peptides of DPLPE with these same C-terminal dipeptides retained high δ-selectivity and affinity. Similar results were obtained using the mouse vas deferens (MVD) and guinea pig ileum (GPI) bioassays. The importance of the hydrophilicity of amino acids in positions 2 and 5 for δ-selectivity is consistent with the previous finding for DPLPE and DPDPE. On the other hand, the replacement of phenylalanine-4 with p-chlorophenylalanine-4 did not increase δ-selectivity as in DPDPE. These findings suggest that the δ-receptor interacts with hybridized enkephalins and deltorphins somewhat differently than with DPDPE. 相似文献
6.
EDWARD VICTOR ROSS MD NATHAN S. UEBELHOER DO YACOV DOMANKEVITZ PHD 《Dermatologic surgery》2007,33(12):1466-1469
BACKGROUND Purpura-free elimination of telangiectases with a single pass of a pulsed dye laser with a large spot has proved difficult.
OBJECTIVE The purpose of this report was to define parameters that achieve single-pass purpura-free telangiectasia reduction.
MATERIALS Thirty patients between the ages of 23 and 78 years were treated with a pulsed dye laser with a 10-mm spot and fluences ranging from 9 to 10 J/cm2 . The macropulse width was 20 ms. Each macropulse was composed of eight pulselets. Treatments were carried out over facial areas with discrete telangiectases.
RESULTS Smaller telangiectases (<600 μm) showed transient bluing followed by stenosis. Larger vessels (600–10,000 μm) showed bluing but inconsistent closure. A second pass typically resulted in closure.
CONCLUSION A modified pulsed dye laser was capable of single-pass purpura-free reduction with a 10-mm spot size. 相似文献
OBJECTIVE The purpose of this report was to define parameters that achieve single-pass purpura-free telangiectasia reduction.
MATERIALS Thirty patients between the ages of 23 and 78 years were treated with a pulsed dye laser with a 10-mm spot and fluences ranging from 9 to 10 J/cm
RESULTS Smaller telangiectases (<600 μm) showed transient bluing followed by stenosis. Larger vessels (600–10,000 μm) showed bluing but inconsistent closure. A second pass typically resulted in closure.
CONCLUSION A modified pulsed dye laser was capable of single-pass purpura-free reduction with a 10-mm spot size. 相似文献
7.
NOEL S. STURM ANN MARIE HUTZLER CLINTON S. DAVID BASSEM Y. AZIZEH DEV TRIVEDI VICTOR J. HRUBY 《Chemical biology & drug design》1997,49(4):293-299
We have designed and synthesized eight compounds 2-9 which incorporate neutral, hydrophobic amino acid residues in positions 9, 11 and 16 of the glucagon molecule: (2) [desHis1,Va19,11e11,16] glucagon amide, (3) [desHis1,Val9,11,16]glucagon amide, (4) [desHis1,Va19,Leu11,16]glucagon amide, (5) [desHis1,Nle9,11e11,16]glucagon amide, (6) [desHis1,Nle9,Val11,16]glucagon amide, (7) [desHis1,Nle9,Leu11,16]glucagon amide, (8) [desHis1,Val9,Leu11,16,Lys17,18,Glu21]glucagon amide and (9) [desHis1,Nle9,Leu11,16,Lys17,18,Glu21]glucagon amide. The effect of neutral, hydrophobic residues at positions 9, 11 and 16 led to good binding to the glucagon receptor. Compared to glucagon (IC50= 1.5 nM), analogues 2-9 were found to have IC50 values of 6.0, 6.0, 11.0, 9.0, 2.5, 2.8, 6.5 and 7.0 nM, respectively. When these compounds were tested for their ability to block adenylate cyclase (AC) activity, they were found to be antagonists having no stimulation of adenyl cyclase, with PA2, values of 6.15, 6.20, 6.30, 7.25, 6.10, 7.30, 6.25 and 7.25, respectively. © Munksgaard 1997. 相似文献
8.
BUCCI THOMAS J.; WUSTENBERG WILLIAM; PERMAN VICTOR; WEISS DOUGLAS J.; DACRE JACK C.; BAUMEL IRWIN P.; PARKER ROBERT M. 《Toxicological sciences》1994,22(2):220-230
Diisopropyl methylphosphonate (DIMP), produced during manufactureof the chemical agent GB (Sarin), is a groundwater contaminantat Rocky Mountain Arsenal, Colorado. DIMP was fed for 90 daysto dark brown "Ranch Wild" mink housed under controlled indoorconditions. One-year-old mink, 10 of each sex, were fed 0, 50,450, 2700, 5400, or 8000 ppm in standard ranch diet. ActualDIMP consumption was 0, 8, 73, 400, 827, and 1136 mg/kg bodywt/day, respectively. Two additional groups of 10 served as"pair-fed" controls. Body weight and food intake were recordedweekly. Complete blood count and 15 chemical analytes were measuredat Weeks 0, 3, 7, and 13. Necropsy and microscopic examinationwere performed on all mink. No clinical morbidity or deathsoccurred. Both sexes fed 8000 ppm ate approximately 20% lessand weighed approximately 20% less than the controls; 5400 ppmfemales had a 10% weight decrement. Plasma cholinesterase (ChE)decreased in the top three dose groups starting at Week 3. At13 weeks, decrements were approximately 50% but returned tonormal after 1 week without DIMP. Erythrocyte ChE was not reduced.Heinz bodies occurred in 1015% of RBCs in 50% of 8000ppm mink at 13 weeks, and 0.12.0% of RBCs in 25% at 2700ppm. There were mild decreases in RBC count, hematocrit, andhemoglobin, and increases in reticulocyte count, at the 5400and 8000 ppm doses. All recovered within 3 weeks after DIMPwas with drawn. The 8000 ppm group had marginal splenic hematopoiesis,histologically. No other treatment-related changes were noted.The 450 ppm dose was a clear no-effect level (approximately73 mg DIMP/kg body wt/day). Compared to reports of similar studiesof DIMP in rats and dogs, these mink displayed no unique speciessusceptibility. 相似文献
9.
VICTOR PARSONNET M.D. 《Pacing and clinical electrophysiology : PACE》2012,35(10):1280-1280
10.