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Biomedical subjects

R Paul

Publications and source records attributed to R Paul.

At least 127 records · Page 7Linked to original sources
PubMed1994

Allosteric modulation of peripheral sigma binding sites by a new selective ligand: SR 31747.

The interactions of a new compound SR 31747 with sigma sites were examined in rat spleen membranes and in human peripheral blood leukocytes (PBL). Nanomolar concentrations of SR 31747 selectively inhibited in a non-competitive manner the binding of the prototypic sigma ligands [3H](+)-pentazocine, [3H](+)-3PPP and [3H]DTG on rat spleen membranes. Characterization of SR 31747 binding sites using [3H]SR 31747 as a ligand showed that this compound binds reversibly, with high affinity to one class of sites on rat spleen membranes (Kd 0.66 nM, Bmax 5646 fmol/mg protein). The pharmacological profile of [3H]SR 31747 binding sites was consistent with the presence of specific sites distinct from classical sigma 1 and sigma 2 receptor subtypes strongly suggesting an allosteric modulation of sigma sites by SR 31747. Similarly, [3H]SR 31747 binding sites were demonstrated on human PBL and also on purified subpopulations of human mononuclear cells (granulocytes, NK cells, T4, T8 and B lymphocytes). Administered to mice by i.p. or oral route 30 min before sacrifice, SR 31747 strongly inhibited the binding of [3H](+)-3PPP to mice spleen membranes with ED50 values of 0.18 and 1.43 mg/kg, respectively. Taken together these results could suggest a potential immunological activity of SR 31747 either directly or through allosteric modulation of peripheral sigma sites.

Allosteric Site↗
PubMed1994

Immunopharmacological profile of SR 31747: in vitro and in vivo studies on humoral and cellular responses.

In our preceding paper, we demonstrated that both human and rat lymphocytes possess saturable high-affinity binding sites for the new sigma ligand SR 31747. Here we investigate the potential activity of this ligand on immune responses. In vitro, our study shows that SR 31747 exerts a concentration- and time-dependent inhibition of proliferative response to mitogens on mouse and human lymphocytes without affecting cell viability. This suppressive effect elicited by SR 31747 occurs over a concentration range which correlates with the pharmacological profile of the molecule in binding assays, strongly suggesting that SR 31747 acts through a receptor-mediated process. We showed that the SR 31747 effect, which was observed on purified T lymphocytes, affects a late event in the activation process which occurs after the G1 during the S phase of the cell cycle. Interestingly, no anti-proliferative effect was observed in a variety of tumor cell lines, supporting a specific effect limited to normal immune cells. In vivo, in mice, treatment with SR 31747 prevented both graft-versus-host disease and delayed-type hypersensitivity granuloma formation, while antibody response to sheep red blood cells was not affected. These results strongly suggest that the sigma-related receptor recognized by SR 31747 is very likely coupled to a biological function of lymphocytes.

Animals↗
PubMed1994

The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human.

OBJECTIVE: The purpose of this study was to test the hypothesis that infusion of the oxytocin antagonist atosiban results in decreased preterm uterine activity in the human. STUDY DESIGN: A randomized, double-blind, placebo-controlled trial was performed. One hundred twenty women from 20 to 36 weeks' gestation with a complaint of labor who had more than four uterine contractions per hour after intravenous hydration but no evidence of cervical changes were randomized to receive a 2-hour intravenous infusion of atosiban at a rate of 300 micrograms/min or placebo. Ond hundred-twelve subjects (56 in each arm) were suitable for analysis of efficacy. Both groups remained at bed rest and received hydration. RESULTS: The mean percent decrease in contraction frequency was greater in atosiban subjects compared with controls (55.3% +/- 36.3% vs 26.7% +/- 40.4%, mean +/- SD, p < 0.001). A minimal (< 20%) decrease or an increase in contraction frequency was noted in 25 placebo subjects (45%) and seven atosiban subjects (13%). There was no clinically or statistically significant change in maternal blood pressure or heart rate during the infusion. The only adverse experiences possibly related to the drug were nausea and vomiting in one atosiban patient. CONCLUSION: A 2-hour infusion of the oxytocin antagonist atosiban resulted in a significantly greater decline in contraction frequency compared with controls. Oxytocin appears to play a role in the maintenance of preterm uterine activity in the human.

Adult↗
PubMed1994

Clinical experience with the Hewlett-Packard M-1350A fetal monitor: correlation of Doppler-detected fetal body movements with fetal heart rate parameters and perinatal outcome.

OBJECTIVE: Our purpose was to correlate measures of Doppler-detected fetal movements with standard fetal heart rate parameters and perinatal outcomes. STUDY DESIGN: This prospective, multiinstitutional trial used the Hewlett-Packard M1350A monitor to record simultaneous fetal heart rate baseline, variability, accelerations, decelerations, and number of fetal movements, and duration and percent of total time. These data were compared at 10- and 30-minute intervals during nonstress tests and were correlated with fetal heart rate baseline parameters and maternally perceived fetal movements and with outcomes of infants delivered within 7 days of the last test. RESULTS: At six centers 1704 actocardiograms from 884 third-trimester patients were analyzed. Doppler-detected fetal movement counts, durations, and percent of total time correlated weakly with all baseline fetal heart rate parameters (all values < 0.20). All fetal movement parameters increased significantly in successive 10-minute blocks and in periods of increased or normal fetal heart rate variability compared with those with fetal heart rate variability. The sensitivity, specificity, and predictive values of the percent of total movement time were comparable to those of standard nonstress test parameters. The risk of poor perinatal outcomes after nonreactive nonstress tests was lower in cases with fetal movements than in those without. CONCLUSIONS: Doppler actocardiography may help to discriminate fetal states during antepartum testing. It may prevent inappropriate diagnosis of fetal compromise when the nonstress test is nonreactive or nonreassuring.

Female↗
PubMed1994

Lack of evidence of neurotoxicity following 8 weeks of treatment with tripotassium dicitrato bismuthate.

OBJECTIVE: To search for evidence of subclinical neurotoxicity in patients treated with tripotassium dicitrato bismuthate. DESIGN: Prospective, controlled, triplicate study using urinary bismuth concentration, magnetic resonance imaging (MRI), nerve conduction studies, visual evoked response and a battery of 10 neuropsychological screening tests. SETTING: Out-patient clinics, Walsgrave Hospital, Coventry, UK. SUBJECTS: Fourteen dyspeptic patients; 8 (treatment group) treated with tripotassium dicitrato bismuthate one tablet q.d.s and 6 (control group) treated with ranitidine 150 mg b.d. for 8 weeks. MAIN OUTCOME MEASURES: Changes in urinary bismuth, MRI, nerve conduction studies, visual evoked response, and neuropsychological tests performed before, immediately after and 8 weeks after the cessation of treatment. RESULTS: In the treatment group the median (range) urinary bismuth concentration was 1 (1-12) ng/ml before treatment, increased to 560 (140-1300) immediately after treatment (P < 0.01, Wilcoxon Rank Sum test) and was still significantly elevated (23 (7-53) ng/ml) 8 weeks after the cessation of treatment. In the patient who recorded the highest urinary bismuth, a high intensity signal appeared in the globus pallidus immediately after treatment and was still present (though diminished in intensity) 8 weeks after the cessation of treatment. This isolated MRI finding was not associated with evidence of subclinical neurotoxicity. No changes in the MRI, nerve conduction studies, visual evoked response and neuropsychological tests were observed among the other patients studied. CONCLUSIONS: Bismuth accumulation occurs in patients receiving a conventional course of treatment with tripotassium dicitrato bismuthate but this is not associated with significant changes in the nervous system.

Administration, Oral↗
PubMed1994

Spontaneous remission in acute myeloid leukaemia.

A summary of the literature of adult patients with acute myeloid leukaemia (AML) who have undergone spontaneous remission (SR) is presented together with a report of a patient whose SR was accompanied by cytogenetic remission. There are less than 20 reports of SR since the 1980s. SR is by no means synonymous with cure, since the average duration of the remission is only 7.1 +/- 9.2 months. Neither infections nor transfusions are absolute requirements of SR.

Adult↗
PubMed1994

Transdermal fentanyl disposition in elderly subjects.

The pharmacokinetic characteristics of a 20-cm2 fentanyl 24-hour transdermal patch were compared between 10 healthy elderly subjects 67-87 years and 6 young subjects 19-27 years. All 10 elderly subjects required patch removal prior to 24 h due to adverse effects versus none of the young subjects. The mean patch duration (PD) in elderly subjects was 11.7 +/- 4.9 h, yielding a mean area under the curve from 0 to 60 h (AUC0-60) of 20.4 +/- 10.3 ng h/ml versus a mean AUC0-60 of 21.0 +/- 10.4 ng h/ml in young subjects. Correcting AUC0-60 for PD (AUC0-60/PD) gave a mean value of 2.05 +/- 1.10 ng/ml for elderly subjects, which was significantly greater than the AUC0-60/PD of 0.88 +/- 0.44 ng/ml in young subjects (p = 0.034, Student's t test). The higher serum concentrations reflect increased absorption and/or decreased clearance in the elderly.

Administration, Cutaneous↗
PubMed1994

GAS TRANSPORT IN THE HAEMOLYMPH OF ARACHNIDS - OXYGEN TRANSPORT AND THE PHYSIOLOGICAL ROLE OF HAEMOCYANIN

Oxygen equilibrium curves and the relationships between the partial pressure of CO2 and pH were determined for the haemolymph of the arachnids Eurypelma californicum, Pandinus imperator and Cupiennius salei. A new type of experimental apparatus was constructed, tested and used to make these measurements on small undiluted cell-free haemolymph samples. Most of its components were made in our workshop and were inexpensive. The apparatus proved to be very reliable as demonstrated by control (oxygen concentration) experiments. In previous reports on O2 equilibrium curves of E. californicum haemocyanin, Tris&shy;HCl buffer was used to set the pH, whereas in our experiments, pH was adjusted by altering the partial pressure of CO2. The O2 concentration measurements demonstrate an increase in oxygen affinity of E. californicum haemocyanin when using Tris&shy;HCl buffer. The position and shape of the O2 equilibrium curves of E. californicum and P. imperator haemocyanin show a distinct dependency on pH. Oxygen affinity is lower in E. californicum and cooperativity changes with pH in E. californicum, but not in P. imperator. Oxygen transport in the haemolymph of E. californicum during rest, activity and recovery was calculated on the basis of the O2 equilibrium curves of undiluted haemolymph. Apart from oxygen transport, there are indications that haemocyanin is also involved in other physiological processes. For example, it may function as a storage protein.

Journal Article↗
PubMed1994

GAS TRANSPORT IN THE HAEMOLYMPH OF ARACHNIDS - CARBON DIOXIDE TRANSPORT AND ACID-BASE BALANCE

The relationships between PCO2 and pH were determined in cell-free undiluted haemolymph of the arachnids Eurypelma californicum, Pandinus imperator and Cupiennius salei. The pH/bicarbonate diagrams and the CO2 equilibrium curves were calculated, using the Henderson&shy;Hasselbalch equation, for haemolymph sampled at rest and during recovery from exercise. The calculations of solubility (alphaCO2) and dissociation constant (pK"') were based on additional ion concentration measurements. Blood gas analyses corroborate these results: after locomotor activity, there is a metabolic acidosis linked to the accumulation of lactate in the haemolymph. The concentration of bicarbonate in the haemolymph of resting individuals is quite different in the three species and is related to the extent of post-exercise bicarbonate depletion. During early recovery, buffering in the haemolymph strongly depends upon CO2 release. Potassium and magnesium concentrations in the haemolymph increase after exercise. During cold-acclimation (to 10 &deg;C), there is a metabolic acidosis in the tarantula's haemolymph that is linked to the accumulation of acetate.

Journal Article↗
PubMed1993

Preparation of substituted N-phenyl-4-aryl-2-pyrimidinamines as mediator release inhibitors.

The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.

Animals↗
PubMed1993

Antibiotic treatment of preterm labor with intact membranes: a multicenter, randomized, double-blinded, placebo-controlled trial.

OBJECTIVE: Although an association between subclinical intrauterine infection and preterm birth is well established, there is conflicting evidence regarding the benefits of antibiotic administration to women in preterm labor with intact membranes. We attempted to determine the effect of ampicillin-amoxicillin and erythromycin treatment on prolongation of pregnancy, the rate of preterm birth, and neonatal morbidity in patients with preterm labor and intact membranes. STUDY DESIGN: A multicenter, randomized, double-blinded, placebo-controlled trial was designed and implemented by the Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development. Two hundred seventy-seven women with singleton pregnancies and preterm labor with intact membranes (24 to 34 weeks) were randomly allocated to receive either antibiotics or placebos. RESULTS: Of the 2373 patients screened for participation in this study in six medical centers, 277 women were enrolled (n = 133 for antibiotics group vs n = 144 for placebo group). In each study group, 60% of patients completed all the study medications. The overall prevalence of microbial invasion of the amniotic cavity was 5.8% (14/239). No significant difference between the antibiotic group and the placebo group was found in maternal outcomes, including duration of randomization-to-delivery interval, frequency of preterm delivery (< 37 weeks), frequency of preterm premature rupture of membranes, clinical chorioamnionitis, endometritis, and number of subsequent admissions for preterm labor. Similarly, no significant difference in neonatal outcomes could be detected between the two groups including respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, sepsis, and admission and duration of newborn intensive special care unit hospitalization. CONCLUSION: The results of this study do not support the routine use of antibiotic administration to women in preterm labor with intact membranes.

Administration, Oral↗
PubMed1993

Neuropharmacological profile of a novel and selective ligand of the sigma site: SR 31742A.

The biochemical, electrophysiological and behavioural effects of SR 31742A, a novel and selective ligand of sigma sites in brain, labelled with (+)-[3H]3PPP (Ki = 5.3 +/- 0.3 nM), were investigated in rodents and compared with those of DA antagonists having (haloperidol) or not (spiroperidol) a high affinity for sigma sites. Like haloperidol but unlike spiroperidol, SR 31742A, (ED50 = 0.065 mg/kg, i.p., and 0.21 mg/kg, p.o.) antagonized sigma-dependent turning behaviour in mice and inhibited (0.5 mg/kg, i.v.) the spontaneous firing of hippocampal (CA3) neurones in urethane-anaesthetized rats. In chloral hydrate-anaesthetized rats, like classical antipsychotic compounds, SR 31742A (0.625-5 mg/kg, i.p.) increased the number of spontaneously active A9 and A10 DA cells after single administration and produced an opposite effect after repeated injections. The drug SR 31742A reduced (2.5, 5, 10 mg/kg, i.p.) the hyperactivity elicited by various drugs including that produced by injection of (+)-amphetamine into the nucleus accumbens and impaired avoidance responses at doses (5, 10 mg/kg, i.p.), sparing escape behaviour. SR 31742A lacked affinity for DA receptors and neither did the compound induce catalepsy nor antagonize such effects elicited by apomorphine as climbing, hypothermia, stereotypy or the inhibition of firing of DA neurones. SR 31742A did not affect the basal metabolism of DA but at 10 mg/kg (i.p.) it significantly reduced the amphetamine-induced rise in levels of 3-MT in the striatum of mice. Together, these results indicate a modulatory role for sigma sites upon the activity of hippocampal and DA systems and that sigma ligands exert effects, which suggest antipsychotic potential.

Animals↗
PubMed1993

Narrative skills in 4-year-olds with normal, impaired, and late-developing language.

Two groups of children who were slow in expressive language development (SELD) at age 2 and a matched group of toddlers with normal language were re-evaluated at age 4. Assessment included measures of productive syntactic skills in spontaneous speech and narrative abilities in a standard story retelling task. Four-year-olds who continued to perform below the normal range in sentence structure production scored significantly lower than their normally speaking peers on all measures of narrative skill. Children who were slow to begin talking at age 2 but who, by age 4, had moved into the normal range in basic sentence structure production showed no statistically significant differences, in terms of several of the measures of narrative ability, from either normally speaking 4-year-olds or from the group with persistent delay. The implications of these findings for the management of early language delay and its relation to school learning disability are discussed.

Age Factors↗
PubMed1993

History of middle ear involvement and speech/language development in late talkers.

Late-talking and normally speaking toddlers with and without histories of middle ear involvement were followed for 2 years to assess speech and expressive language outcomes. Results revealed no differences in expressive language outcome that could be attributed to history of middle ear involvement in either group. There did seem to be differences in outcome on measures of articulation that were associated with history of middle ear involvement. The implications of these findings for treatment of otitis media and for referral of late-talking toddlers for speech and language services are discussed.

Analysis of Variance↗
PubMed1993

Grammatical morpheme acquisition in 4-year-olds with normal, impaired, and late-developing language.

The production of the grammatical morphemes studied by Brown and his colleagues was examined in free speech samples from a cohort of 4-year-olds with a history of slow expressive language development (SELD) and a control group of normal speakers. Results suggest that children with SELD acquire morphemes in an order very similar to that shown in previous acquisition research. Children who were slow to begin talking at age 2 and who continued to evidence delayed expressive language development by age 4 showed mastery of the four earliest acquired grammatical morphemes, as would be expected, based on their MLUs, which fell at Early Stage IV. Four-year-olds with normal language histories produced all but one of the grammatical morphemes with more than 90% accuracy, as would be expected based on their late Stage V MLUs. Children who were slow to acquire expressive language as toddlers, but who "caught up" in terms of sentence length by age 4 did not differ in MLU from their peers with normal language histories. However, they had acquired fewer of the grammatical morphemes. The implications of these findings for understanding the phenomenon of slow expressive language development are discussed.

Child Language↗