A comparison of putative 5-HT2 receptors in two different arterial tissues.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
A R Martin
Publications and source records attributed to A R Martin.
Molecular determinants for recognition of RU 24969 analogs at central 5-hydroxytryptamine recognition sites: use of a bilinear function and substituent volumes to describe steric fit.
The putative serotonin (5-HT) agonist RU 24969 [5-methoxy-3-1,2,3,6-tetrahydropyridin-4-yl)indole; 5-MeO-THPI] has been extensively used in the study and classification of 5-HT receptors. In order to study molecular determinants for recognition of THPIs at central 5-HT recognition sites, about 25 additional THPI derivatives were synthesized, incorporating, among others, 16 different indole-5-substituents and three different pyridine-N substituents in various combinations. Two saturated derivatives (piperidin-4-ylindoles) and two 2-methyl analogs were also included. Binding affinities at 5-HT1A, 5-HT2, and total 5-HT1 sites were obtained and the data were incorporated in quantitative structure-activity relationships (QSARs) using a combined linear free energy/molecular modeling approach. The QSAR analyses suggest distinct differences in the structural features that determine optimal potency at 5-HT1A sites versus those directing optimal potency for 5-HT2 sites. The parameter of the indole-5 substituent that almost exclusively determines potency for 5-HT1A sites is volume, the optimal size being about 24 cubic angstroms (calculated by fitting the activity versus volume data to a bilinear function). This is approximately the size of a carboxamide group. In contrast, at the 5-HT2 site both volume and hydrophobicity play major but opposing roles for the 5-substituent. A balance between the smallest possible volume and the greatest possible hydrophobicity is required for maximal 5-HT2 potency. Benzyl groups on the indole-1 or pyridyl-1 positions also favor potency at the 5-HT2 site (probably largely due to increased hydrophobic binding) while decreasing potency at the 5-HT1A site. A minor electronic contribution to the QSARs involving the charge on the indole 5-carbon is of opposite sign for 5-HT1A versus 5-HT2 sites and thus may also be useful for selective drug design. The data are consistent with the possibility that the indole and pyridyl rings are in a coplanar configuration when binding at both 5-HT1A and 5-HT2 sites, because the indole-2-methyl substituent, which provides a large energy barrier to the coplanar configuration, greatly reduces the potency of THPIs at both binding sites. Similarities in analog selectivity patterns suggest that the indolic portion of these compounds binds similarly to that of other indole derivatives such as tryptamines; thus, it is possible that optimally selective substituents predicted by these QSARs may be extrapolated to tryptamines and other indoles.
Animals↗
Structure-anticonvulsant activity relationships of cannabidiol analogs.
Cannabidiol (CBD) exhibits anticonvulsant activity in experimental animals and in man. As part of a structure-activity study, analogs were prepared wherein the terpene unit, the aryl unit, and/or the side chain were modified. Thus, several pinenyl and carenyl derivatives, aryl ethers and acetates, and a variety of 1",1"-dialkylhexyl and 1",1"-dialkylheptyl analogs were synthesized. The compounds were evaluated for anti-convulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rat rotorod (ROT) test. Comparisons of stereoisomers of CBD and several analogs revealed a general lack of stereoselectivity for anticonvulsant and other CNS properties of this class of compounds.
Animals↗
A clinician's guide to helping patients change behavior.
Explore the source record for details and available documents.
Aged↗
Contribution of the Na(+)-K+ pump to membrane potential in familial periodic paralysis.
The possibility has been raised that in familial periodic paralysis, the relatively large depolarization of the muscle fiber membrane seen during periods of paralysis might be attributable to a reduction in activity of the electrogenic Na(+)-K+ pump. The theoretical analysis presented here shows that although such hypotheses are qualitatively correct, the quantitative contribution of the electrogenic pump is too small to account entirely for the changes in membrane potential observed between the paralytic and interictal states.
Cations↗
Stress and medical training.
Explore the source record for details and available documents.
Adaptation, Psychological↗
Which hospital services are most overused? Results from a medical audit.
When we assessed the extent of unnecessary ordering of clinical services by medical house staff at a large university hospital, 21% of services were judged to be unwarranted. Most overordered were nuclear medicine services, followed by laboratory tests. Because of their large volume, clinical laboratory services accounted for 78% of all unwarranted orders. Unwarranted use of hospital services is substantial and variable among physicians and services. This study confirms the value of medical record reviews for documenting the need for and guiding the course of hospital cost-containment programs.
California↗
Single-dose amoxicillin therapy of acute uncomplicated urinary tract infections in women.
Of 210 women who were experiencing dysuria, frequent urination, pyuria, and significant bacteriuria and who were treated with a single 3-g dose of amoxicillin, 165 (79%) were cured of their original infections. Patients with infections that were negative by antibody-coated-bacteria assay were cured at a significantly higher rate than those with infections that were positive by antibody-coated-bacteria assay (90 versus 59%; P less than 0.001). Similarly, those with infections caused by amoxicillin-susceptible organisms were cured at a significantly higher rate than those with infections caused by resistant organisms (85 versus 50%; P less than 0.001). Of 27 patients who had infections caused by amoxicillin-susceptible organisms and who had relapses after single-dose therapy, 14 (52%) had relapses again after a conventional 10-day course of therapy, although all responded to a 6-week course. An additional 27 patients experiencing dysuria, frequent urination, and pyuria but who had a lower number of uropathogens in the urine (10(2) to 10(4.5)/ml of urine) were treated with single-dose therapy, with a 100% eradication of organisms and an 89% rate of symptomatic relief.
Acute Disease↗
Inhibitory conductance changes at synapses in the lamprey brainstem.
Although the conductance and kinetic behavior of inhibitory synaptic channels have been studied in a number of nerve and muscle cells, there has been little if any detailed study of such channels at synapses in the vertebrate central nervous system or of the relation of such channels to natural synaptic events. In the experiments reported here, current noise measurements were used to obtain such information at synapses on Müller cells in the lamprey brainstem. Application of glycine to the cells activated synaptic channels with large conductances and relaxation time constants (70 picosiemens and 33 milliseconds, respectively, at 3 degrees to 10 degrees C). Spontaneous inhibitory synaptic currents had a mean conductance of 107 nanosiemens and decayed with the same time constant. In addition, the glycine responses and the spontaneous currents had the same reversal potential and both were abolished by strychnine. These results support the idea that glycine is the natural inhibitory transmitter at these synapses and suggest that one quantum of transmitter activates about 1500 elementary conductance channels.
Animals↗
Exploring patient beliefs. Steps to enhancing physician-patient interaction.
Most physicians are skilled at collecting medical information important for clinical diagnosis. However, they obtain less information about the attitudes and beliefs patients have about their illnesses. Patients' beliefs determine their responses to an illness and the strategies they use for coping with it. Without knowing those beliefs, physicians may find themselves and their patients frustrated by misunderstandings and differing agenda. Beliefs can be explored fairly simply by careful listening and a few directed questions. Once recognized, they can be modified or incorporated into joint approaches to treatment. Learning patients' beliefs is an important early step in developing the physician-patient relationship.
Adolescent↗
A more reliable photometric technique for the measurement of scalp sebum excretion.
The objective assessment of antiseborrhoeic therapy for the scalp requires a reliable technique for the measurement of sebaceous gland activity. Previously published methods were tried but found to be unreliable. This paper describes a photometric technique which gave repeatable results and demonstrated a reduction of sebaceous gland activity on the scalp with both oral isotretinoin and topical II alpha-hydroxyprogesterone. The accuracy of the method was achieved by careful preparation of the scalp but was affected by recent shampooing.
Adult↗
Characteristics of inhibitory post-synaptic currents in brain-stem neurones of the lamprey.
Voltage-clamp techniques were used to record spontaneously occurring inhibitory post-synaptic currents (i.p.s.c.s) from Müller cells in the brain stem of the lamprey. In normal bathing solution, the i.p.s.c.s in most cells had unimodally distributed amplitudes with a mean corresponding to a peak conductance of 107 nS and a coefficient of variation of about 15%. About 20% of the cells displayed, in addition, events of approximately twice the modal amplitude. The falling phase of the i.p.s.c.s was exponential with a mean time constant of about 32 msec. This is the same as the relaxation time constant of glycine-activated channels in these cells under comparable conditions (Gold & Martin, 1983b). When tetrodotoxin (TTX) was added to the bathing solution the spontaneous i.p.s.c.s disappeared, suggesting that they were due to release of transmitter by action potentials in presynaptic terminals. Spontaneous activity was also abolished by removing Ca2+ from the bathing solution. When extracellular Ca2+ was increased, or 4-aminopyridine (4-AP) was added to the bathing solution, the mean amplitude of the i.p.s.c.s increased and the amplitude distribution showed two or more distinct peaks. Analysis of the amplitude distributions suggested that the peaks represented single and multiple quantal events and that the release process obeyed binomial statistics. In TTX-blocked preparations, spontaneous i.p.s.c.s could be induced by raising extracellular K+. These had the same time constant of decay as in normal solution and a unimodal amplitude distribution, with the mean corresponding to a peak conductance of 45 nS. In solutions with raised extracellular K+ and reduced extracellular Cl-, the mean i.p.s.c. amplitude corresponded to a peak conductance of 67 nS. These variations in conductance corresponded closely to variations in conductance with extracellular K+ and Cl- of single glycine-activated channels. It is concluded that the i.p.s.c.s are produced by activation of conductance channels identical to those activated by glycine, and that in normal bathing solution i.p.s.c.s produced by individual presynaptic action potentials are the result of the release of one or, at most, two quanta of transmitter. Each quantum activates approximately 1500 elementary channels.
4-Aminopyridine↗
Analysis of glycine-activated inhibitory post-synaptic channels in brain-stem neurones of the lamprey.
Voltage-clamp techniques were used to measure fluctuations in membrane current produced by the application of glycine to Müller cells in the brain stem of the lamprey. The power density spectrum of the glycine-induced current 'noise' was consistent with the hypothesis that glycine activated a single population of conductance channels with open times determined by first-order kinetics. In normal bathing solution the channel conductance was 73 +/- 12 pS (mean +/- S.D.) and the channel open time 34 +/- 6 msec at 5 degrees C. The reversal potential for the response was 66 +/- 5 mV. Neither channel conductance nor mean open time was voltage-dependent. Replacement of Cl- in the bathing solution by isethionate and sulphate reversibly abolished the response to glycine. Increasing intracellular Cl-, either by using Cl- -filled micropipettes or by raising extracellular K+, decreased channel conductance. This unexpected decrease was a direct effect of intracellular Cl- and was not related to coincident changes in reversal potential. Channel open time was unaffected by intracellular Cl- concentration. Reducing extracellular Cl- concentration from 126.5 to 31 mM reduced channel conductance at all levels of intracellular Cl- without affecting open time. Increasing the temperature of the preparation resulted in increase in channel conductance and a decrease in mean open time. Q10S for the effects were of the order of 1.3 and -2.3 respectively in the range 4-14 degrees C.
Animals↗
Intracellular Cl- accumulation reduces Cl- conductance in inhibitory synaptic channels.
Glycine increases Cl- conductance in neurones of the lamprey central nervous system and mimics the natural inhibitory transmitter pharmacologically. We have use current noise produce by glycine to examine in more detail the characteristics of inhibitory channels in Müller cells in the brain stem reticular formation. The channels have large conductances and mean open times consistent with large amplitudes and long durations of spontaneously occurring inhibitory synaptic currents. We now show that, unlike any post-junctional channels reported so far, their conductance decreases rapidly with increasing intracellular concentration of the permeant ion. This surprising behaviour is inconsistent with constant field theory and also with a single-site pore model such as proposed for cationic channels at the motor endplate, both of which predict an increase in conductance with concentration. In addition, the decrease in conductance cannot be explained quantitatively by a two-site, single-file pore model such as proposed for K+ channels and Na+ channels in nerve and for gramicidin channels. This property of the inhibitory channel may be functionally important in preventing intracellular Cl- accumulation during periods of intense synaptic activity when inhibition might otherwise convert progressively to excitation as the Cl- equilibrium potential became more and more positive.
Animals↗
Synthesis and pharmacological evaluation of conformationally restricted phenothiazine analogues.
The synthesis of 3-(dimethylamino)-2,3-dihydro-4-chloro-1H-pyrido[3,2,1-kl]phenothiazine, its 10-chloro analogue, and two chloro isomers of 2[(dimethylamino)methyl]-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine is described. In these compounds the side chain of chlorpromazine is fixed into a certain position in order to study the dopamine-overlap theory and the role of the substituents in the phenothiazine neuroleptics. The compounds were tested for their influence on dopamine metabolism, while for the second set their ability to displace [3H]spiroperidol from dopamine receptors was assessed. No neuroleptic activity was found from the pharmacological data. The results are discussed on the basis of conformational requirements for dopamine antagonistic activity.
Animals↗
Use of a potential rabbit model for structure--behavioral activity studies of cannabinoids.
Using the genetically unique tetrahydrocannabinol-seizure susceptible (THC-SS) rabbit, the behavioral effect of 14 cannabinoids or related structures were determined and compared to the effects of 11 previously tested cannabinoids. Relative potencies of the cannabinoid-induced convulsions in THC-SS rabbits were generally comparable to reported relative potencies of cannabinoid-produced psychoactivity in humans and other behavioral activity in monkeys or other species. These data suggest that the THC-SS rabbit may represent an experimentally convenient and reliable animal model for studies of structure--psychoactivity relationships of marijuana-like compounds.
Animals↗
Primary care training: how much, for whom?
Explore the source record for details and available documents.
Family Practice↗
Common and correctable errors in diagnostic test ordering.
Diagnostic tests represent a significant percentage of medical costs. Knowledge of test ordering principles and a few testing strategies can significantly reduce unnecessary testing and costs. Awareness of the limitations of screening, less frequent monitoring of known abnormalities, reduced utilization of stat. tests and test panels and better use of existing information will improve the efficiency and accuracy of diagnostic testing.
Diagnostic Services↗