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At least 721 records · Page 40Linked to original sources
PubMed1995

(+/-)-(Z)-2-(aminomethyl)-1-phenylcyclopropanecarboxamide derivatives as a new prototype of NMDA receptor antagonists.

(+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarbo xamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 microM; 7, 13 +/- 2.1 microM; 8, 88 +/- 1.4 microM; 12, 10 +/- 1.2 microM). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.

Animals↗
PubMed1989

Metabolism of 3-(p-chlorophenyl)pyrrolidine. Structural effects in conversion of a prototype gamma-aminobutyric acid prodrug to lactam and gamma-aminobutyric acid type metabolites.

By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1)] underwent a series of alpha-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5 greater than 10 and 6 greater than 11) with the exception of the liver homogenate mitochondrial fraction (6 less than 11). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.

Amino Acids↗
PubMed1986

Bioisosteric prototype design of biaryl imidazolyl and triazolyl competitive histamine H2-receptor antagonists.

The structural relationship of the competitive histamine H2-receptor antagonist 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole (1) to the agonist histamine and to antagonists of the cimetidine type was explored by the design and synthesis of four series of bioisosterically designed prototypes. Biological data from these series was best interpreted as indicating a similarity between the imidazole moiety of histamine and cimetidine and the 2-amino-4-pyridyl moiety of 1. On the basis of this data, sequential replacement of 2-amino-4-pyridyl by 2-[(dimethylamino)methyl]-5-furyl and 2-guanidino-4-triazolyl moieties led to a structurally more potent series of biaryl histamine H2-receptor antagonists. The best of these, 2-methyl-4-(2-guanidino-4-thiazolyl)imidazole (29, CP-57,361-1) was 120 times more potent as a histamine H2-receptor antagonist than 1.

Animals↗
PubMed1999

High-resolution NMR and computer modeling studies of the cannabimimetic aminoalkylindole prototype WIN-55212-2.

Aminoalkylindoles (AAIs), although structurally dissimilar from the classical cannabinoids (CCs), are known to be capable of binding to cannabinoid receptors and of evoking cannabimimetic responses. However, their mode of binding remains unknown. In this communication, we have carried out further studies on the AAI prototype (R)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN-55212-2, 1) by the combined use of high-resolution 2D NMR and computer modeling. Our results suggest that the minimum energy conformations of the molecule 1 have distinct pharmacophoric features: (i) The naphthyl ring is oriented off the plane of the benzoxazine ring by approximately 59 degrees with the carbonyl C=O group pointing toward the C2-CH(3) group. (ii) At the C10-position the axial morpholinomethyl conformation is preferred over the equatorial in order to relieve a steric interaction with the C2-methyl group. The preferred conformer as defined by the three key pharmacophores, naphthyl, morpholino, and 3-keto groups, shows that the morpholinyl ring of the molecule 1 deviates from the plane of the benzoxazine ring by about 32 degrees and orients in the left molecular quadrant. This model supports the hypothesis that a certain deviation of the morpholino group from the plane of the indole ring in compound 1 is essential for cannabimimetic activity. We postulate that such an alignment by the respective pharmacophores allows them to interact optimally with the receptor. The results should help us to better understand the pharmacophoric requirements of the AAIs and serve as a basis for future SAR studies and drug design.

Benzoxazines↗
PubMed2006

Energy transfer at a gas-liquid interface: kinematics in a prototypical system.

A detailed characterization of collisional energy transfer at a liquid surface not only provides a framework for the interpretation of experimental studies but also affords insight into energy feedback mechanisms that may be important in multiphase combustion processes. We address this problem by performing simulations of a prototypical Lennard-Jones system, investigating the dependence of the energy transfer and incident-atom trapping probability on the liquid temperature, on the mass and angle of incidence of the impinging atom, and on the strength of the gas-liquid interaction. In general, in agreement with the results of experiments, these calculations point to the dominance of kinematic effects in determining the gross energy transfer, but they also attest to the important role played by surface roughening in the enhancement of energy transfer that accompanies an increase in the liquid temperature.

Journal Article↗
PubMed2006

High-level ab initio studies of hydrogen abstraction from prototype hydrocarbon systems.

Symmetric and nonsymmetric hydrogen abstraction reactions are studied using state-of-the-art ab initio electronic structure methods. Second-order Møller-Plesset perturbation theory (MP2) and the coupled-cluster singles, doubles, and perturbative triples [CCSD(T)] methods with large correlation consistent basis sets (cc-pVXZ, where X = D,T,Q) are used in determining the transition-state geometries, activation barriers, and thermodynamic properties of several representative hydrogen abstraction reactions. The importance of basis set, electron correlation, and choice of zeroth-order reference wave function in the accurate prediction of activation barriers and reaction enthalpies are also investigated. The ethynyl radical (*CCH), which has a very high affinity for hydrogen atoms, is studied as a prototype hydrogen abstraction agent. Our high-level quantum mechanical computations indicate that hydrogen abstraction using the ethynyl radical has an activation energy of less than 3 kcal mol(-1) for hydrogens bonded to an sp(2) or sp(3) carbon. These low activation barriers further corroborate previous studies suggesting that ethynyl-type radicals would make good tooltips for abstracting hydrogens from diamondoid surfaces during mechanosynthesis. Modeling the diamond C(111) surface with isobutane and treating the ethynyl radical as a tooltip, hydrogen abstraction in this reaction is predicted to be barrierless.

Computer Simulation↗
PubMed2006

Slow manifold structure in explosive kinetics. 1. Bifurcations of points-at-infinity in prototypical models.

This article analyzes in detail the global geometric properties (structure of the slow and fast manifolds) of prototypical models of explosive kinetics (the Semenov model for thermal explosion and the chain-branching model). The concepts of global or generalized slow manifolds and the notions of heterogeneity and alpha-omega inversion for invariant manifolds are introduced in order to classify the different geometric features exhibited by two-dimensional kinetic schemes by varying model parameters and to explain the phenomena that may occur in model reduction practice. This classification stems from the definition of suitable Lyapunov-type numbers and from the analysis of normal-to-tangent stretching rates. In the case of the Semenov model, we show that the existence of a global slow manifold and its properties are controlled by a transcritical bifurcation of the points-at-infinity, which can be readily identified by analyzing the Poincaré projected system. The issue of slow manifold uniqueness and the implications of the theory with regard to the practical definition of explosion limits are thoroughly addressed.

Journal Article↗
PubMed1999

Clustering of CD spectral data as a prototype QSAR model for neuropeptides.

An analytical method that might eventually qualify as a general quality control assay procedure for polypeptide drug forms was described in the companion article to this paper. The detector is visible range circular dichroism spectroscopy. Multivariate data analysis reduced the spectral data to essentially four principal components (or factors) that are characteristic of each analyte. The level of analytical selectivity achieved among 51 analytes is very high. Using an alternative factor analysis algorithm, the selectivity is even more conveniently accomplished in the form of a 2-D cluster diagram presentation that has the potential of being a prototypical predictive in vitro model for correlating experimental data with structure-activity or structure-function relationships. Clustering of the analytes is a consequence not only of the chiral interactions associated with ligand exchange in the immediate primary coordination sphere of the host derivatizing reagent, but also of long-range intermolecular interactions between the coordination architecture of the host and the chiral polypeptides.

Circular Dichroism↗
PubMed2005

Biological assembly of nanocircuit prototypes from protein-modified CdTe nanowires.

CdTe nanowires made by self-organization of CdTe nanoparticles in aqueous media were separately conjugated with complementary biological connectors, such as antigen-antibody and biotin-streptavidin. Transmission electron microscopy images and Forster resonance energy transfer measurements in nanowire superstructures with different diameters indicate that biological affinity of the attached proteins results in the formation of crossbar and end-to-side connections between the nanowires. A prototype of a logical circuit made from a triangular arrangement of the nanowires spontaneously assembled on a Si substrate was examined by conducting atomic force microscopy. While diode-like behavior was observed in the sides of the triangle, the nanowire junction points were found to be nonconductive. It was attributed to high tunneling barrier created by protein molecules wedged between the nanowires. Suggestions are made how to reduce it or use the insulating gap between the nanowires as a framework for single-electron devices.

Antigen-Antibody Complex↗
PubMed2000

Herbacic acid, a simple prototype of 5,5,5-trichloroleucine metabolites from the sponge Dysidea herbacea.

Dysidea herbacea, collected at Harrier Reef on the Great Barrier Reef, contains the novel metabolite herbacic acid as the major trichloroleucine metabolite. Herbacic acid appears to be an early product of direct free-radical chlorination of leucine and is a prototype for further transformation of the free carboxylic acid group and generation of complex trichloromethyl metabolites, including natural products of the dysidenin family.

Amino Acids↗
PubMed1997

Safety, functionality and acceptability of a prototype polyurethane condom.

Male condoms made from synthetic materials offer an alternative to latex condoms that may be more acceptable to users, thereby potentially resulting in more protected acts of intercourse. A prospective, noncomparative clinical study was conducted to evaluate the safety of using certain polyurethane materials to make condoms. Fifty-one healthy, contracepting, mutually monogamous couples were recruited between June 30 and November 24, 1993 to use a prototype roll-on polyurethane condom developed by Family Health International. Couples were to use the condoms for 10 consecutive acts of vaginal intercourse over a 4-week period. Baseline and postexposure genital examinations, including colposcopy for female participants, were performed. Fifty couples completed the study requirements and 517 acts of intercourse occurred using the condoms. Two adverse events were reported: irritation of introitus in a female participant and a small irritated erythematous lesion on a male participant's penis. Neither event was considered to be serious and both were resolved without treatment. Breakage and slippage rates were similar to those reported for latex condoms. These results suggest that polyurethane condoms represent a safe, functional and acceptable alternative to latex condoms.

Adult↗
PubMed1999

Performance of the frameless IUD (Flexigard prototype inserter) and the TCu380A after six years as part of a WHO multicenter randomized comparative clinical trial in parous women.

The clinical performance of the new Frameless IUD was compared with the TCu380A, the most widely used copper IUD in the world today. Insertions of the Frameless IUD were conducted with a prototype inserter (Flexigard). We report on the 6-year results from a randomized comparative clinical trial conducted at the Shanghai Institute of Planned Parenthood Research, as part of an international multicenter WHO clinical trial, involving 200 women, respectively recruited for use of each device. The cumulative 6-year pregnancy rates were 0.0 per 100 women for the Frameless IUD and 3.3 for TCu380A. Termination due to partial expulsion was significantly less for the Frameless IUD as compared with TCu380A (0.0 and 4.3 per hundred women, respectively). Complete expulsion, bleeding, pain, bleeding and pain and other medical reasons for termination did not differ significantly between the two devices. The net cumulative continuation rates at six years per 100 women were 80.8 for TCu380A, and 83.0 for the Frameless IUD. Both Frameless IUD and TCu380A are highly effective, safe and acceptable contraceptive devices, because of low pregnancy rates (per 100 women), and low termination rates due to expulsion, pain, bleeding, and bleeding and pain. Due to its anchoring, the Frameless IUD is significantly more effective than the TCu380A IUD as regards proper retention of the IUD in the uterine cavity. This may also explain its lower failure rate.

Adult↗
PubMed2000

A prototype device for standardized calibration of pulse oximeters.

OBJECTIVE: To develop and test a method for standardized calibration of pulse oximeters. METHODS: A novel pulse oximeter calibration technique capable of simulating the behavior of real patients is discussed. It is based on an artificial finger with a variable spectral-resolved light attenuator in conjunction with an extensive clinical database of time-resolved optical transmission spectra of patients fingers in the wavelength range 600-1000 nm. The arterial oxygen saturation of the patients at the time of recording was derived by analyzing a corresponding blood sample with a CO-oximeter. These spectra are used to compute the modulation of the light attenuator which is attached to the artificial finger. This calibration method was tested by arbitrarily playing back recorded spectra to pulse oximeters and comparing their display to the value they displayed when the spectra were recorded. RESULTS: We were able to demonstrate that the calibrator could generate physiological signals which are accepted by a pulse oximeter. We also present some experience of playing back recorded patient spectra. The mean difference between the original reading of the pulse oximeters and the display when attached to the calibrator is 1.2 saturation points (displayed oxygen saturation SpO2) with a standard deviation of 1.9 saturation points. CONCLUSIONS: The tests have shown the capabilities of a spectral light modulator for use as a possible calibration standard for pulse oximeters. If some improvements of the current prototype can be achieved we conclude from the experience with the device that this novel concept for the calibration of pulse oximeters is feasible and that it could become an important tool for assessing the performance of pulse oximeters.

Calibration↗
PubMed2001

Auto-sensuous shapes: prototypes for creative forms.

The author looks at some of the more normative, adaptive, and creative aspects of what have been called 'autistic' or 'auto-sensuous' shapes by Tustin and others. She explores the construct from several frameworks, including the literature on early sensory experience and that on the empathic attunement between infant and caretaker in which interpersonal rhythms and meanings are built. The views of Bion and Matte-Blanco are utilized to help explore the processes by which meaning is created from experience, while the works of Segal and Milner are used to focus more explicitly on the role of symbol formation in the creative process. Finally, it is suggested that these auto-sensuous shapes can become prototypes for creative endeavours, including the creative process we call psychoanalysis. The author uses examples from her own experience in deriving pattern from basic sensory experience, toward the creation of poetry, drawings, and the establishment of attunement and 'meaning-making' within the analytic setting.

Child↗
PubMed1993

Human transbuccal absorption of diclofenac sodium from a prototype hydrogel delivery device.

The buccal delivery of the nonsteroidal antiinflammatory drug, diclofenac sodium (Voltaren), from a prototype hydrogel was studied in man in a randomized crossover design of buccal delivery and i.v. infusion. After a 30-min delay, plasma levels of diclofenac increased to near steady-state levels of 100 ng/ml by 3 hr. With each subject serving as his own control, the i.v. infusion data facilitated the calculation of a mean steady-state flux of diclofenac sodium of 2.1 +/- 0.6 mg/cm2-hr across human buccal mucosa and a time lag of 1.0 +/- 0.5 hr. The large flux of this ionized species indicates that the traditional lipoidal model of buccal permeation based on the partition coefficient is inadequate.

Absorption↗
PubMed2000

Light-guided intubation via the intubating laryngeal mask using a prototype illuminated flexible catheter. Clinical experience in 400 patients.

BACKGROUND: The transillumination of the soft tissues of the neck using lighted stylets has been used as an aid for tracheal intubation. We evaluated the efficacy and safety of a prototype illuminated flexible catheter to facilitate light-guided intubation through the intubating laryngeal mask. METHODS: The illuminated flexible catheter consists of a completely flexible thin plastic catheter with a bulb attached to its distal end. The device was placed into a silicone tracheal tube in such a way that the bulb was adjusted at the distal end of the tracheal tube. The tracheal tube preloaded with the device was inserted through the intubating laryngeal mask and, by observing the glow on the neck, was advanced into the trachea. We report our experience with light-guided intubation through the intubating laryngeal mask in 400 ASA grade 1-3 patients undergoing general anaesthesia. RESULTS: The intubating laryngeal mask was inserted successfully in all patients. The overall intubating success rate was 99.8% (399/400); in 367 (91.8%) cases at the first attempt, in 28 (7%) at the second, in 4 (1%) at the third and in one case (0.2%) at the fifth attempt. There were 27 patients with potentially difficult airways. All these cases were intubated successfully; in 23 of 27 (85.2%) at the first attempt, in 3 of 27 (11.1%) at the second and one of 27 patients (3.7%) at the third attempt. CONCLUSION: We conclude that the use of the illuminated flexible catheter facilitates the intubation through the intubating laryngeal mask. The suggested light-guided intubating method proved to be a simple, safe and effective technique.

Adolescent↗
PubMed2000

Comparison of a double-textured prototype manual toothbrush with 3 branded products. A professional brushing study.

BACKGROUND: The consensus has been that there is no one superior design of manual toothbrush for plaque removal, despite, in some cases, encouraging findings from laboratory studies. The user appears the major variable and may mask differences in brush efficacy. AIMS: The aim of this study was to compare 2 new double-filament texture brushes with 3 established brands for plaque removal, under standardised conditions of professional brushing. METHOD: The study was a blind, randomised crossover design, balanced for residual effects. A panel of 15 subjects suspended tooth cleaning for 3 days. On day 4, plaque was scored from 6 sites per tooth before and after a 2-min professional toothbrushing. A washout period of at least 3 days was allowed between study periods. RESULTS: Overall plaque removal was 50% with no significant differences between brushes, a 3% absolute difference in average total mouth plaque separating brushes. However, at upper- and mid-buccal sites, a not significant 8% and a significant 9% difference, respectively, in plaque removal were recorded in favour of one of the prototype brushes, and at the mid-lingual site, there was a non-significant 10% difference in favour of one branded brush. Other sites were cleaned similarly by all brushes except for reduced plaque removal from buccal compared to lingual surfaces and interproximal compared to mid-surface sites. Highly significant subject differences in plaque removal were noted which may be relevant to inherent anatomical difficulties in tooth cleaning for some individuals. Period effects were not significant, supporting the consistency in brushing by the professional brusher. CONCLUSION: The method appeared capable of detecting small benefits of brush design. However, the benefits reported must be taken within the context of an overall lack of difference between brushes. The method could be used to set and record a minimum level of efficacy for toothbrushes.

Adult↗
PubMed2001

Clinical application of computer-aided rapid prototyping for tooth transplantation.

The maintenance of healthy periodontal ligament cells in the donor tooth is one of the most important factors for successful tooth transplantation. This is achieved by minimizing the extraoral time during the surgical procedure. If a duplicate form of donor tooth could be obtained before extraction, it would be possible to precontour the recipient alveolar bone compatible with the donor tooth, and thereby reduce the extra-oral time of the donor tooth. We obtained a three-dimensional image with the real dimensions of the donor tooth from a CT Highspeed Advantage, allowing a life-sized resin model of the tooth to be fabricated. From 22 clinical cases, we achieved an average total transplantation time of 7.7 min. The average distance between the transplanted root surface and the alveolar bone from 12 available cases was 0.87 mm at the mesial cervix, 0.91 mm at the mesial apex, 0.98 mm at the distal cervix and 1.16 mm at the distal apex on the postoperative radiographs. Clinical data indicate that computer-aided rapid prototyping may be of value in minimizing the extra-oral time and possible injury to transplanted tooth during the process of autotransplantation.

Adult↗