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Biomedical subjects

M K James

Publications and source records attributed to M K James.

At least 37 records · Page 2Linked to original sources
PubMed1996

3-[2-(N-phenylacetamide)]-1,5-benzodiazepines: orally active, binding selective CCK-A agonists.

A series of modifications were made to the C-3 substituent of the 1,5-benzodiazepine CCK-A agonist 1. Replacement of the inner urea NH and addition of a methyl group to generate a C-3 quaternary carbon resulted in acetamide 6, which showed CCK-A receptor binding selectivity and sub-micromolar agonist activity in vitro. Benzodiazepine 6 was active in an in vivo mouse gallbladder emptying assay and represents a novel orally active, binding selective CCK-A agonist.

Acetanilides↗
PubMed1996

Some techniques for the analysis of work sampling data.

Work sampling is an observational technique that produces counts representing the number of times that an individual has been observed performing each of several tasks. These data are collected using either systematic or random times of observation, and typically exhibit correlation between repeated observations on the same individual, with the degree of correlation being a function of the amount of time elapsed between measurements. Using several recently developed statistical techniques, we illustrate how it is possible to carry out analyses of these nominal outcomes that account for the correlation between repeated outcomes. We use description of a work sampling study to motivate the techniques and we compare empirically results from analyses based on several different underlying assumptions.

Adult↗
PubMed1996

Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger".

Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.

Amino Acid Sequence↗
PubMed1995

Modification of receptor selectivity and functional activity in cholecystokinin peptoid ligands.

Hybrid analogs of the cholecystokinin A (CCK-A) receptor selective tetrapeptide agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (1,A-71623) and the CCK-B receptor selective antagonists PD-135118 (2) and CI-988 (3) were prepared. Incorporation of the Lys(Tac) side chain into 2 produced a moderately potent antagonist of CCK-8 in the isolated guinea pig gallbladder (GPGB). Incorporation of the Lys(Tac) side chain into 3 produced the novel agonist analog 7 (EC50 = 28 nM in the GPGB) with excellent affinity for both human CCK-A (IC50 = 12 nM) and CCK-B (IC50 = 17 nM) receptors. Analog 7 was a full agonist (EC50 = 3.5 nM) for calcium mobilization on CHO-K1 cells expressing hCCK-A receptors but a partial agonist on CHO-K1 cells expressing hCCK-B receptors, eliciting a weak agonist response (EC50 = 2800 nM) and antagonizing CCK-8-induced calcium mobilization (KB = 20 nM). Despite this unusual in vitro profile, analog 7 was a potent anorectic agent in rats (ED50 = 30 nmol/kg) following intraperitoneal administration.

Adamantane↗
PubMed1995

Predicting inpatient costs with admitting clinical data.

Hospital cost-containment programs should themselves be cost-effective, targeting high-cost physicians (which requires adjusting for case mix) and patients (which requires early identification). In this study, clinical data available within 24 hours of admission from an electronic medical record system were used to develop statistical models to predict hospital costs. In this retrospective analysis of clinical data and diagnosis-related groups (DRGs), study subjects were 2,355 patients admitted for at least 1 day to the medicine service at an urban teaching hospital with sophisticated electronic medical records. Of these 2,355 patients, 1,663 (71%) had one of the 41 most common DRGs. Predictive models were derived on a random subset of two thirds of the patients and were validated on the remaining third. The following patient data were obtained: admission and prior diagnostic test results, diagnoses, vital signs; demographic data; prior inpatient and outpatient visits; tests and treatments ordered within 24 hours of admission (discretionary data); DRGs; and total inpatient costs (estimated from charges). Diagnosis-related groups explained 24% of the variance in total costs in the derivation patient set and 16% in the validation set. When only nondiscretionary data were used, the models retained only clinical laboratory results and prior diagnoses, explaining 20% of the derivation set variance in total costs and 16% in the validation set. Adding DRGs increased the variance explained in the derivation set to 34%, but decreased to 24% in the validation set. Adding discretionary data substantially increased the explained variance in the derivation and validation patient sets. The models' median predicted costs underestimated true costs by 10% to 13%, with the lowest error in the models using all types of variables. Clinical data gathered during routine clinical care can be used to adjust for case mix and identify high-cost patients early in their hospital stays, when they could be targeted by cost-containment interventions.

Cost Control↗
PubMed1995

Etiology of iliotibial band friction syndrome in distance runners.

The objectives of our study were: 1) to examine differences between a noninjured cohort of runners (N = 70) and runners afflicted with iliotibial band friction syndrome (ITBFS) (N = 56) according to selected anthropometric, biomechanical, muscular strength, and training measures; 2) to explore multivariate relationships among these measures in both the well and injured groups; and 3) to develop specific hypotheses concerning risk factors for injury that will later be tested in a prospective observational study. High speed videography (200 fps), a force platform (500 Hz), and a Cybex II+ isokinetic dynamometer were used to assess rearfoot motion, ground reaction forces, and knee muscular strength and endurance, respectively. A linear discriminant function analysis of the training data revealed weekly mileage, training pace, number of months using current training protocol, % time spent swimming, and % time spent running on a track to be significant (P < 0.10). Height was a significant anthropometric discriminator, while seven isokinetic strength and endurance measures were found to discriminate significantly between the groups. Calcaneal to vertical touchdown angle, and maximum supination velocity were significant rearfoot movement discriminators. Maximum braking force was the only significant kinetic discriminator. A combined discriminant analysis using those variables found to be significant in the previous analyses revealed weekly mileage, and maximum normalized braking force to be the best discriminators (model P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics.

A simple mathematical model of analgesia in the rat is developed and utilized to determine quantitative structure-activity relationships for a series of novel 4-anilidopiperidine opioids. The compounds tested (selected alkyl carboxyethyl esters attached at the one position of the piperidine ring) were designed for rapid inactivation by blood and tissue esterases. Model parameters included potency and rate constants for loss of pharmacodynamic effect by hydrolysis dependent and independent processes. A significant correlation is observed between duration of pharmacological effect in vivo and the rate constant for hydrolysis in human blood (r = 0.89). In vivo potency shows a moderate correlation with log P2 (r = -0.77). The validity of the model is shown by comparing model-based parameters which characterize potency and duration of effect in vivo with graphically derived parameters. Significant correlations are observed between model and graphically based estimates of potency (r = 0.75) and between model and graphically based estimates of duration of effect (r = 0.70). This model has potential application in studies of other classes of compounds in which hydrolytic cleavage limits duration of pharmacologic effect.

Analgesia↗
PubMed1993

Effects of remifentanil, a new short-acting opioid, on cerebral blood flow, brain electrical activity, and intracranial pressure in dogs anesthetized with isoflurane and nitrous oxide.

BACKGROUND: A new short-acting opioid, remifentanil, is metabolized by esterase activity in blood and tissue. It is important to know whether remifentanil may decrease the time to recovery of opioid-induced cardiovascular and cerebral effects compared to that of other short-acting agents such as alfentanil. METHODS: Baseline measures were made during 1% end-tidal isoflurane and 50% N2O in oxygen in dogs. Approximately equipotent low- and high-dose remifentanil (0.5 and 1.0 micrograms.kg-1.min-1) or alfentanil (1.6 and 3.2 micrograms.kg-1.min-1) were infused for 30 min each (total infusion time 60 min) followed by a 30-min recovery period. Blood pressure, heart rate, and intracranial pressure were recorded continuously. Electroencephalogram measurements were made using aperiodic analysis, and regional cerebral blood flow using radioactive microspheres. RESULTS: Both remifentanil and alfentanil decreased blood pressure and heart rate 25-30%. Cortex, hippocampus, and caudate blood flow decreased 40-50% during opioid infusion, but flow changes in lower brain regions were modest or absent. The electroencephalogram showed a shift from low-amplitude, high-frequency activity during baseline to high-amplitude, low-frequency activity during opioid infusion. During a 30-min recovery period, heart rate, electroencephalogram, and regional cerebral blood flow recovered to baseline levels in remifentanil--but not in alfentanil--treated dogs. Blood pressure and intracranial pressure decreased during opioid infusion and increased above baseline levels during the recovery period in remifentanil-treated dogs. CONCLUSIONS: These results show that the cardiovascular and cerebral effects of remifentanil and alfentanil are similar but that recovery of these parameters occurs sooner following remifentanil.

Alfentanil↗
PubMed1993

Exit-site care--is it time for a change?

Peritoneal catheter exit-site infections (ESI's) continue to impact significantly on morbidity and catheter longevity. The controversy concerning protocols for daily exit-site care continues for frequency, methodology, cleansing agent, and dressing. Routine daily exit-site care prior to January 1991 consisted of daily showers using liquid soap, povidone scrub, rinsing the shower, and drying with a 4 x 4-in. gauze pad. Catheters have always been immobilized, either with tape or an immobilizing device. Hydrogen peroxide was used only when needed to soften crust formation prior to showering. A light dressing, usually 2 x 2 in., was optional. A recent survey revealed that povidone iodine was the antiseptic of choice for catheter care in 75% of the respondents. However, povidone iodine irritates and dries the skin predisposing it to infection. ESI's are prospectively monitored as part of our quality improvement (QI) program. An incidence of 0.76 episodes/patient-year was noted between January 1989 and May 1991. Given the relative high frequency of ESI's, the protocol was modified and introduced during the January-May 1991 time frame. Routine care now consists of daily showers using only CC-500, a gentle antibacterial cleaner (Care-Tech Laboratories, Inc.), rinsing in the shower, and drying with a 4 x 4-in. gauze. Use of hydrogen peroxide and dressings has remained the same. Additionally, a protocol addressing the prophylaxis for traumatized exist sites was initiated. The incidence of ESI's has dropped significantly to 0.12 episodes/patient-year. Although our population size is small (n = 18), this study does point out the utility of prospectively monitoring trends for appropriate indicators within a QI program.(ABSTRACT TRUNCATED AT 250 WORDS)

Catheters, Indwelling↗
PubMed1992

Hemodynamic effects of GI 87084B, an ultra-short acting mu-opioid analgesic, in anesthetized dogs.

Hemodynamic effects of GI 87084B, a novel ultra-short acting mu-opioid agonist, were studied in anesthetized dogs. In these studies, GI 87084B (0.3-20 nmol/kg/min i.v.) produced dose-dependent decreases in heart rate, arterial blood pressure, +dP/dt and cardiac output. Alfentanil produced similar effects but was less potent. After termination of the infusions (397 nmol/kg cumulative dose), the hemodynamic effects of GI 87084B dissipated over 30 to 40 min. The effects of alfentanil, however, persisted throughout the 60-min recovery period. Infusion of GI 87084B at lower dose rates (0.001-0.3 nmol/kg/min) in barbiturate-anesthetized dogs showed a threshold dose of 0.1 to 0.3 nmol/kg/min for effects on hemodynamic variables. After infusing 0.3 nmol/kg/min of GI 87084B for 10 min, hemodynamic variables recovered rapidly (10-20 min). Boli of GI 87084B (0.3-100 nmol/kg i.v.) produced dose-dependent decreases in the same hemodynamic variables. The duration of these effects increased from 5 to 20 min at 3 nmol/kg to 15 to 45 min at 100 nmol/kg. Naloxone (0.063 mg/kg/hr) decreased the magnitude and duration of the effects of GI 87084B, suggesting that these effects are mediated through opioid receptors. In summary, GI 87084B produced hemodynamic effects consistent with mu-opioid agonism when administered by infusion or bolus, but these effects were brief in duration compared to other opioids.

Alfentanil↗
PubMed1991

Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.

In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

Analgesics↗
PubMed1991

Opioid receptor activity of GI 87084B, a novel ultra-short acting analgesic, in isolated tissues.

GI 87084B (3-[4-methoxycarbonyl-4-[(1-oxopropyl) phenylamino]1-piperidine]propanoic acid, methyl ester, hydrochloride) was found to be a potent opioid agonist in the guinea pig ileum (EC50 = 2.4 +/- 0.6 nM), the rat vas deferens (EC50 = 387 +/- 44 nM) and the mouse vas deferens (EC50 = 39.5 +/- 7.4 nM). In the guinea pig ileum, GI 87084B, was roughly equivalent in potency to fentanyl (EC50 = 1.8 +/- 0.4 nM). GI 87084B was more potent in this tissue than alfentanil (EC50 = 20.1 +/- 1.2 nM) and less potent than sufentanil (EC50 = 0.3 +/- 0.09 nM). Schild analyses of antagonism of GI 87084B by naloxone yielded pKB values of 8.2 and slopes indistinguishable from unity in the guinea pig ileum and the mouse vas deferens. Insurmountable antagonism of GI 87084B by naloxone was observed in the rat vas deferens. However, an empirical measure of antagonist potency could be made: apparent pA2 = 8.1. The agonist dissociation constant (KA) for GI 87084B (220 +/- 90 nM) was determined by receptor alkylation with beta-chlornaltrexamine in the guinea pig ileum. Calculation of receptor occupancy suggested poor receptor-effector coupling and limited receptor reserve in the rat vas deferens, which could explain the insurmountable antagonism seen with higher concentrations of naloxone. These data suggest that GI 87084B acted through the mu class of opioid receptors to inhibit contraction induced by field stimulation in these tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗
PubMed1989

A new method for estimation of agonist dissociation constants (KA): directly fitting the postinactivation concentration-response curve to a nested hyperbolic equation.

The common method for estimating agonist dissociation constants (KA) is the method proposed separately by Furchgott and Mackay. Concentrations of the given agonist producing the same response before ([A]) and after ([A']) irreversible inactivation of a fraction of the receptors (1-q) are described by the equation: 1/[A] = 1/(q*[A']) + (1-q)/(q*KA) and plotted on axes of 1/[A] vs. 1/[A']. The double reciprocal method suffers from the disadvantage that undue weight may be placed on values generated from the smallest observed responses. Our new method of estimating KA and q uses hyperbolic functions to directly fit both concentration-response curves. The control curve is fit to the logistic equation: response = (M* [A]n)/(kn + [A]n); where M is the maximal tissue response, n is the apparent kinetic order of the response at low [A] and k is [A] required for a half-maximal response. The postinactivation concentration-response curve is simultaneously fit to the following equation: response' = M/(((k/(q*KA*[A']))*(KA + [A']* (1-q)))n + 1). This new method was shown to determine KA and q more accurately and precisely than other methods when applied to an artificial data set. In experiments with the rat anococcygeus muscle, the nested hyperbolic method gave estimates of KA with less variance and less range than the double reciprocal method. The nested hyperbolic method was shown to be a valid method of estimating KA and q that has advantages over the other methods.

Animals↗
PubMed1987

Acute cardiovascular and pulmonary effects of intravenous and aerosolized amiloride in the dog.

Active Na+ absorption by the epithelia that line the airways can drive volume from the airway surface. Exposure of the lumen-facing surface of airway epithelia to amiloride inhibits Na+ transport. Consequently, aerosolized amiloride may help hydrate the desiccated surface liquid that characterizes lung diseases such as cystic fibrosis. We studied the acute cardiovascular and pulmonary effects of amiloride in anesthetized dogs. Intravenous amiloride reduced blood pressure and increased ventilation frequency and airways resistance of the dog. The effects were dose-related (ED50 = 1.3 X 10(-6) mol/kg), resembled those of injected histamine, and were antagonized by methapyrilene. These results were compatible with the release of endogenous histamine by amiloride, but the graded dose-effect relationship for amiloride differed from the quantal relationship induced by the prototypical releaser, 48/80. Aerosolization of a Ringer's solution that was nearly saturated with amiloride deposited, in upper airway surface liquid, drug concentrations which in previous studies, were sufficient to inhibit Na+ transport by canine airways (ED50 approximately 10(-6) M). Cardiovascular function, airways resistance, and indices of pulmonary tissue water, gas exchange, and perfusion were not affected. Since circulating amiloride after aerosolization was estimated to fall below the concentration that induced vasodepression and correct circled bronchoconstriction after intravenous injection, we conclude that the potency of aerosolized amiloride to induce acute effects in tissues other than airway epithelia is no greater than that of intravenous drug.

Administration, Inhalation↗
PubMed1987

Analysis of putative alpha-1s adrenoceptor agonism by Sgd 101/75 in the rat anococcygeus muscle.

Sgd 101/75 [2-(2-methylindazol-4-imino)-imidazolidine hydrochloride] is an alpha 1 adrenoceptor agonist that shows a greater sensitivity to receptor alkylation with phenoxybenzamine (POB) than norepinephrine (NE) (present study). J. Coates, D.G. Weetman and their co-workers have concluded that Sgd 101/75 is selective for a subtype of alpha-1 receptors, i.e., alpha-1s. The present studies have shown that Sgd 101/75 was a full agonist in the rat anococcygeus muscle and acts at alpha-1 adrenoceptors, as determined by Schild analysis of prazosin antagonism (pKB = 9.24 +/- 0.21, slope = 0.87 +/- 0.13). Alkylation experiments showed that the contractile effects of Sgd 101/75 were more sensitive to POB than the effects of NE. These experiments also allowed the determination of KA values for these agonists (Sgd 101/75 KA = 1.5 +/- 0.6 X 10(-5) M, NE KA = 2.6 +/- 1.0 X 10(-6) M). At 3 X 10(-8) M POB (10 min), the contractile effect of Sgd 101/75 was eliminated, whereas the concentration-effect curve for NE was shifted approximately one log unit to the right with a 20% decrease in maximal response. After similar POB treatment, incubation with Sgd 101/75 (60 min, 3 X 10(-6) to 3 X 10(-4) M) shifted the NE curve to the right in a concentration-dependent manner. Schild regression of these data yielded a pKB = 5.22 +/- 0.09 and slope = 0.87 +/- 0.08. This pKB (-log KB) showed that Sgd 101/75 was competing for the same receptor after POB treatment and before POB treatment (mean of -log KA = 4.92 +/- 0.12).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1987

Naloxazone treatment in the guinea pig ileum in vitro reveals second functional opioid receptor site.

Guinea pig ilea were incubated in vitro with naloxazone, an irreversible opioid receptor antagonist, in an attempt to determine a dissociation constant (KA) value for the opioid agonist, BW 942C, by the method of partial receptor alkylation. However, concentrations of naloxazone up to 3 X 10(-4) M (120 min incubation-60 min washout) did not depress the maximal response or the slope of the concentration-response curve for BW 942C and, therefore, did not allow calculation of KA value. To analyze the residual activity of BW 942C, tissues were incubated with naloxone for 60 min after naloxazone treatment. Schild analysis of naloxone antagonism after 3 X 10(-6) M naloxazone produced a pKB of 8.0 +/- 0.06 and a slope of 0.88 +/- 0.03, suggesting simple competitive antagonism at a single site. In the absence of naloxazone treatment, naloxone 10(-8) to 10(-5) M antagonized the effects of BW 942C yielding a pKB value and slope of 8.34 +/- 0.08 and 1.0 +/- 0.04, respectively. Schild analysis of naloxone antagonism after 10(-4) M naloxazone yielded a pA2 of 6.23 +/- 0.20 and a slope of 0.55 +/- 0.08. These values were not consistent with simple competitive antagonism at a single receptor site. Modeled curves showed that the data for naloxone antagonism after 10(-4) M naloxazone were consistent with action at two receptor sites with naloxone pKB values of approximately 8.3 (experimentally determined) and approximately 6.0. An alternative explanation of altered affinity for BW 942C and naloxone at a single site produced by naloxazone treatment cannot be excluded.

Alkylation↗
PubMed1987

Ionic mechanism of dopaminergic and muscarinic auto- and heteroreceptor activation in superfused striatal slices: role of extracellular chloride.

The Cl dependency of agonist-induced ionic mechanisms involved in the receptor-mediated modulation of electrically stimulated release of dopamine (DA) and acetylcholine (ACh) was examined in superfused rabbit striatal slices prelabeled with [3H] DA (3,4-[8-3H]dihydroxyphenylethylamine) and [14C]choline ([ methyl-14C]choline Cl). Cl- was substituted in the superfusion medium to varying degrees with the impermeant anions isethionate, methanesulfonate or gluconate. The sodium concentration was held constant. Apomorphine (30 nM), a DA receptor agonist, inhibited the stimulation-evoked (1 Hz, 2 min) release of both DA and ACh in Krebs-Ringer-bicarbonate medium (KRB; 125.4 mM Cl-). The inhibitory effects of the agonist were not altered significantly in media containing 66.4 mM Cl-. In 7.4 mM Cl- medium (isethionate replacement), apomorphine-induced inhibition of DA release was reduced (40% inhibition vs. 67% inhibition in KRB). Similarly, apomorphine inhibition of ACh release was lowered from 38% in KRB to 25% in 7.4 mM Cl-. The muscarinic receptor agonist carbachol (10 microM) inhibited the stimulation-evoked release of ACh while enhancing the evoked release of DA in normal Cl- (125.4 mM) medium. Inhibition of ACh release was not altered in 66.4 mM Cl- media but was increased in 7.4 mM Cl- (63% inhibition in low Cl- vs. 50% in KRB). The enhancing effects of carbachol on stimulated DA release were potentiated in 66.4 mM Cl- (88% enhancement vs. 57% in KRB), whereas no change in the agonist effect was observed in the lower Cl- medium (7.4 mM Cl-).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗