Clinical aspects of immunologic monitoring.
Explore the source record for details and available documents.
Humans↗
Biomedical subjects
C Dubray
Publications and source records attributed to C Dubray.
Assessment of postoperative pain after laryngeal surgery for cancer.
OBJECTIVES: To assess the intensity of postoperative pain after laryngeal surgery for cancer and the efficacy of analgesic injections at fixed hours. DESIGN: A prospective clinical study performed during the 3 days following laryngeal cancer surgery. SETTING: A university medical center. PATIENTS: Fifteen men (age range, 38-74 years) having just undergone a partial or total laryngectomy for epidermoid carcinoma. INTERVENTIONS: The analgesic treatment consisted of intravenous administrations at fixed hours (propacetamol or nalbuphine hydrochloride), with the possibility of rescue doses on demand. Pain and anxiety were assessed by means of visual analog scales (graduated from 0-10) every 3 hours on postoperative day 1, then every 6 hours on postoperative days 2 and 3. Objective criteria, ie, heart and respiratory rates and mean blood pressure, were measured with the same schedule. MAIN OUTCOME MEASURES: Postoperative pain and anxiety intensities and their variations were analyzed. Correlations between postoperative pain and other criteria were researched. RESULTS: Postoperative pain had a high initial level (maximum median, 7), then decreased and reached a score of 3 at the 30th hour. Unpredictable individual peaks of pain were reported. Anxiety was never high (maximum median, 4). No individual correlation was found between pain and objective parameters. CONCLUSIONS: After laryngeal surgery for cancer, pain can reach high levels, particularly in the first hours following recovery. Analgesic administrations at fixed hours are not effective enough. Postoperative analgesic treatment should aim to prevent the high initial pain and be individually adapted.
Acetaminophen↗
Evidence for a role for bulbospinal pathways in the spinal antinociceptive effect of systemically administered vapreotide in normal rats.
Numerous neurotransmitters are involved in nociceptive transmission or regulation. Several reports have shown the analgesic effects of somatostatin and its analogues. Somatostatin, when given intrathecally, markedly reduced pain in cancer patients. Somatostatin analogues that possess a longer half-life time are more convenient for therapeutic use. Vapreotide, a somatostatin analogue, was shown to induce a long-lasting antinociceptive effect in rats. We studied the site and the mechanism of action of vapreotide in rats using the paw pressure test. Intrathecal administration of vapreotide induced no antinociception. Systemically administered vapreotide-induced antinociception was inhibited by several intrathecal (i.t.) administered antagonists (yohimbine, naloxone and to a lesser degree tropisetron). These results show a lack of spinal effect and suggest a supraspinal site of action with an involvement of noradrenergic and to a lesser degree serotonergic bulbospinal pathways. In addition, spinal opioid receptors also seen to be involved.
Adrenergic alpha-Antagonists↗
Magnesium deficiency induces an hyperalgesia reversed by the NMDA receptor antagonist MK801.
The aim of this study was to determine the changes of the nociceptive thresholds in response to an acute mechanical stimulus (paw pressure) in magnesium (Mg)-deficient rats, and the involvement of the NMDA receptor in these changes. Changes in vocalization thresholds was determined after 7 days of feeding with a Mg-depleted diet. Compared with the control group, Mg-deficient rats showed a significant decrease in the vocalization thresholds (-35.8 +/- 2.5%, p < 0.001) reflecting hyperalgesia. In Mg-deprived rats, three doses (0.06, 0.12 and 0.24 mg/kg s.c.) of dizocilpine (MK801), a non-competitive NMDA receptor antagonist, significantly reversed the hyperalgesia in a dose-dependent manner for at least 48 h. No effect of MK801 was observed in the control group. These data provide evidence that Mg deficiency could constitute a new model of hyperalgesia involving NMDA receptors.
Analysis of Variance↗
Decrease of ciliary beat frequency by platelet activating factor: protective effect of ketotifen.
The ciliary beat frequency (CBF) of the tracheal epithelial cells controls in part the respiratory tract mucociliary transport efficiency. We investigated the effects on CBF of PAF-acether (PAF) and its metabolite/precursor lyso-PAF. Guinea-pig tracheal rings were incubated for 3 to 6h with 1 microM PAF (C16, C18, C16/C18: 80/20%), lyso-PAF C16 or lyso-phosphatidylcholine (LPC). CBF changes were assessed by microphotooscillography (mean number of measures per ring = 14). We also examined the effect on PAF-induced CBF changes of the PAF receptor-antagonist WEB 2086, the anti-asthmatic/anti-anaphylactic drug ketotifen and the anti-histamine H1 pyribenzamine. CBF of control rings exposed to vehicle only from 0 to 6h showed no significant statistical variations (hertz, mean +/- SEM): 10.8 +/- 0.1 (n of measures = 890). By contrast, 1 microM C16, C18, and C16/C18 PAF significantly inhibited CBF after 3 to 6h incubation. C16 and C16/C18 PAF were more potent than C18 PAF (8.8 +/- 0.2, n = 112, 8.7 +/- 0.2, n = 64, and 9.6 +/- 0.1, n = 537 respectively; ANOVA analysis, p < 0.001 from control). At the same concentration, lyso-PAF also inhibited CBF, 9.5 +/- 0.1 (n = 197, p < 0.001) but not LPC, 10.5 +/- 0.2 (n = 127). WEB 2086 inhibited lyso-PAF and C16/18 PAF-induced CBF decrease. Preincubation (20 min) with ketotifen but not with pyribenzamine (1 microM) also suppressed the CBF inhibitory effect of PAF and lyso-PAF. Incubation of [3H]PAF with tracheal rings from 10 min to 6h resulted in its partial metabolism (25%) into [3H]lyso-PAF and a compound with a short retention time (10 min). [3H]lyso-PAF incubated for 3h with tracheal rings was partially metabolized (10%) into [3H]PAF and a compound with a short retention time. The PAF-induced decrease of CBF is congruent with its influence on pulmonary clearance, possibly via a specific receptor, since WEB 2086 abolished the effect of PAF. The inhibition of the PAF-induced CBF decrease by ketotifen may contribute to the therapeutic properties of this antiallergic drug.
Animals↗
Human pharmacokinetics of dihydroergotamine administered by nasal spray.
OBJECTIVES: A nasal spray of dihydroergotamine was developed for the treatment of migraine headaches, and pharmacokinetic studies were scheduled to evaluate the bioavailability of dihydroergotamine by this new route of administration. METHODS: Nine studies were performed with dihydroergotamine administered by nasal spray to evaluate the bioavailability of the nasal route versus the intramuscular route, the linearity of the kinetics, the interindividual and intraindividual variations, and the influence of different factors. RESULTS: Nasally administered dihydroergotamine (1 mg) becomes rapidly available to the systemic circulation, with peak plasma levels of 1 ng/ml achieved in 0.9 hour. The relative bioavailability versus intramuscular route is 38.4%. Dihydroergotamine administered by the nasal route exhibits linear dose proportionality (1 to 4 mg). Intraindividual variations of bioavailability evaluated for a 1-year period were higher (29%) than those found for the intramuscular route (20%) but comparable to the oral route. Interindividual variations for bioavailability were greater (25% versus 14% by the intramuscular route) but comparable to the oral route. Caffeine contained in the nasal solution (1%) had no effect on the absorption. Vasomotor phenomena, which could also affect the nasal mucosa during a migraine headache, do not modify the bioavailability. The constriction of the nasal mucosa by fenoxazoline leads to a slight decrease (-15%) in the bioavailability. The presence of acute viral rhinitis did not result in any change in dihydroergotamine nasal absorption compared with the normal state of the nasal mucosa. From a pharmacokinetic point of view, nasally administered dihydroergotamine can be given, without risk of overdose, to patients receiving long-term oral dihydroergotamine medication. CONCLUSION: These results show the reliability and reproducibility of this route of dihydroergotamine administration adapted for the treatment of migraine headaches.
Acute Disease↗
Tropisetron inhibits the antinociceptive effect of intrathecally administered paracetamol and serotonin.
Explore the source record for details and available documents.
Acetaminophen↗
Paracetamol exerts a spinal antinociceptive effect involving an indirect interaction with 5-hydroxytryptamine3 receptors: in vivo and in vitro evidence.
Rats (Sprague-Dawley), submitted to a mechanical noxious stimulus (paw pressure), were tested to determine 1) the antinociceptive effects of p.o. (200, 400 and 800 mg/kg), i.v. (50, 100, 200 and 300 mg/kg) and intrathecal (i.t.) (100 and 200 micrograms/rat) administrations of paracetamol; 2) the influence of i.t. administered tropisetron, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist (0.5, 1 or 10 micrograms/rat) on paracetamol-induced antinociception; 3) the influence of indomethacin (25 mg/kg s.c.), naloxone (10 micrograms/rat i.t.) and yohimbine (1 mg/kg i.v.) on the effect of paracetamol (200 mg/kg i.v.) to determine the involvement of prostaglandins, opioids and alpha-2 adrenoceptors. The displacement by paracetamol of radioligand binding to various receptors was also investigated. Paracetamol induced a significant antinociceptive effect after p.o., i.v. and i.t. administration. A total inhibition of the effect of paracetamol, administered p.o. or i.t., occurred at the dose of 0.5 microgram/rat of tropisetron, whereas 10 micrograms/rat of this antagonist was needed to totally inhibit the action of i.v. administered paracetamol. Indomethacin, naloxone and yohimbine failed to modify paracetamol antinociceptive action. In vitro studies failed to show any binding of paracetamol to 5-HT3 and several other receptors and to 5-HT uptake sites. It is concluded that paracetamol has a central antinociceptive effect, based on an indirect involvement of spinal 5-HT3 receptors.
Acetaminophen↗
[Postoperative pain evaluation in the surgery of head and neck cancers].
UNLABELLED: Postoperative pain has rarely been assessed after ENT surgery for cancer. Its evaluation is difficult because of the frequent lack of speech after this type of surgery. OBJECTIVES: to assess postoperative pain after pharyngeal and laryngeal surgery for cancer. PATIENTS AND METHOD: prospective study in 13 men (38-71 ans) operated on by total laryngectomy with or without partial pharyngectomy. A standardised treatment using propacetamol and nalbuphine was systematically prescribed. Pain, anxiety and relief were assessed with the help of visual analogue scales (VAS). Heart rate, mean blood pressure and respiratory rate were evaluated too. RESULTS: mean postoperative pain was maximal just after recovery (6,64 +/- 2,14 cm) then decreased regularly. Initial mean score of anxiety was 3,14 +/- 3 cm and then was decreasing too. Anxiety and pain did not correlate except in 2 cases. None of the 3 objective parameters correlated with pain. CONCLUSION: postoperative pain can be assessed reliably after pharyngolaryngeal cancer surgery and is probably underrated. Its high initial score indicates that efforts must be focused on pre-emotive analgesia. Its high individual variability let us hypothesise that PCA systems should be effective.
Adult↗
[Cardiovascular effects of a calcium channel blocker in hypoxia caused by altitude].
OBJECTIVE: High altitude pulmonary oedema can be successfully treated and prevented by calcium channel blockers. Moreover, calcium entering in the cells could explain the congestive phenomena of acute mountain sickness (AMS). These findings led us to study the action of a calcium channel blocker, isradipine, in the prevention of non-complicated AMS. METHODS: In a double blind randomized study, 20 healthy volunteers received 5 mg of isradipine (n = 6) or placebo (n = 6) for 8 days. After 5 days of treatment in normoxia, the subjects were rapidly transported to an altitude of 4350 m. The efficiency of the treatment was then estimated by the AMS symptom score, haemodynamic parameters and renal function. RESULTS: The administration of isradipine did not significantly modify AMS symptom score nor most of other parameters measured in high altitude hypoxia. Heart rate was an average of 15 b/min lower in the isradipine group, probably because of a direct action of isradipine on the sinus node. Otherwise, the effects of hypoxia were similar in both groups and were in accordance with the literature. There was no clear explanation for the increase in cardiac output and stroke volume when the subjects moved from supine to standing position. Renal blood flow, measured by Doppler or para-aminohippuric acid clearance was not modified by hypoxia. Cerebral blood flow was elevated, due to the direct vasodilator effect of hypoxia. However this increase did not seem to be the main mechanism responsible for the congestive phenomena. On the other hand, the increase in capillary permeability (demonstrated by the increased transcapillary escape rate of albumin, and albuminuria) appeared to play a major role in the pathogenesis of AMS and high altitude cerebral oedema. Isradipine had no protective effect on these phenomena and its use should be restricted to the treatment of high altitude pulmonary oedema.
Adult↗
Heterogeneity in migration of smooth muscle cells from normal and injured rat thoracic aorta in primary culture.
OBJECTIVE: Aside from proliferation, migration of smooth muscle cells is an essential component of the arterial sclerotic reaction. The aim of this study was to define a model to study migration. METHODS: Primary cultures of smooth muscle cells were derived from normal or injured rat thoracic aorta. An image analysis system was used to track cells migrating out of the explants and measure the displacement of their centre of gravity. RESULTS: Migration speeds for smooth muscle cells randomly sampled from the normal whole media were very heterogeneous. The media were therefore separated into three vertical segments. Cells from the middle third migrated faster than those from the upper and lower thirds, regardless of whether they originated from the anterior and posterior parts of the segment (P = 0.001). Heparin (10 micrograms.ml-1) only inhibited smooth muscle cell migration from the middle segment (P < 0.001). Migration of smooth muscle cells from explants of aorta 3 and 14 d after injury was also studied using a balloon catheter. Three days after injury, cell velocity varied widely among the segments of the same media. In contrast, 14 d after injury cells from neointimal explants migrated homogeneously and at a slower rate than those obtained from normal media. CONCLUSIONS: These experiments show migratory variations among smooth muscle cells depending upon their position in the normal aorta and their state of activation after arterial injury. This variability must be taken into account when planning experiments to study smooth muscle cell migration.
Animals↗
Ca(2+)-dependent protein kinase C isoforms in rat pituitary hyperplasia: effect of in vivo treatment with quinagolide.
Ca(2+)-dependent protein kinase C (PKC) activity, diacylglycerol levels and PKC alpha, beta I, beta II and gamma expression were analyzed in the pituitary of female rats treated with estradiol alone (2 months) or in combination with quinagolide in the second month. Polymerase chain reaction (PCR) and Western blot analysis revealed the presence of PKC alpha, beta I and beta II isoenzymes in the rat pituitary gland but not of PKC gamma isoenzymes. Increases in pituitary weight and plasma prolactin levels induced by estradiol were associated with an increase in diacylglycerol pituitary content (1.55 +/- 0.06 versus 1.12 +/- 0.17 nmol diacylglycerol/mg protein in controls, P < 0.01). Cotreatment with quinagolide reversed these effects. Changes in PKC activity were accompanied by parallel changes in PKC alpha and beta I expressions. Estradiol treatment increased the expression of these isoforms whereas cotreatment with quinagolide antagonized these effects. PKC beta II expression was not affected. In conclusion, Ca(2+)-dependent PKC activity and protein expression are increased in hyperplastic pituitary cells, suggesting the involvement of this class of PKCs in the rat pituitary cell proliferation and/or hormonal secretion. This is further assessed by the fact that the dopamine receptor agonist treatment decreases activity and expression of these PKCs in parallel with the decrease in hormonal secretion and cell proliferation.
Aminoquinolines↗
Adrenergic status of humans during prolonged exposure to the altitude of 6,542 m.
Plasma norepinephrine (NE) concentration increases with altitude exposure while maximal heart rate (HR) and chronotropic response to isoproterenol (IP) are blunted. Downregulation of cardiac beta-adrenergic receptors (beta-AR) has been evoked to explain this phenomenon. Chronotropic response was studied at extreme altitude in 10 subjects (4 women, 6 men; aged 35 +/- 6 yr). Observations were made in normoxia (N) and after 1 (H1) and 3 (H3) wk at 6,542 m. Acclimatization was accomplished by gradual climbing from 4,000 to 6,542 m over 10 days. Plasma NE was obtained at rest and during submaximal exercise. Successive doses of IP (0.02, 0.04, and 0.06 microgram/kg-1.min-1) were infused for 5 min each. Density and affinity of lymphocyte beta 2-AR were also measured. Increase in HR for maximal dose of IP decreased from 57 +/- 12 to 34 +/- 7 and 37 +/- 10 min-1 in H1 and H3, respectively (P < 0.001 for both). IP dose for which HR rises by 25 min-1 (I25) increased from 27 +/- 5 in N to 42 +/- 10 and 43 +/- 17 ng.kg-1.min-1 in H1 and H3, respectively (P < 0.001 for both). Arterial O2 saturation at rest was 98 +/- 2% in N, 72 +/- 6% in H1 (P < 0.001), and 79 +/- 5% in H3 (P < 0.001). The chronotropic response was neither restored nor further attenuated after 3 wk at 6,542 m. Plasma NE levels at rest and during exercise were higher at 6,542 m than values obtained in previous studies at 4,350 and 4,800 m.(ABSTRACT TRUNCATED AT 250 WORDS)
Acclimatization↗
Albuminuria and overall capillary permeability of albumin in acute altitude hypoxia.
The mechanism of proteinuria at high altitude is unclear. Renal function and urinary excretion rate of albumin (Ualb) at rest and during submaximal exercise and transcapillary escape rate of 125I-labeled albumin (TERalb) were investigated in 12 normal volunteers at sea level and after rapid and passive ascent to 4,350 m. The calcium antagonist isradipine (5 mg/day; n = 6) or placebo (n = 6) was administered to abolish hypoxia-induced rises in blood pressure. Lithium clearance and urinary excretion of beta 2-microglobulin were used to evaluate renal tubular function. High altitude increased Ualb from 2.8 to > 5.0 micrograms/min in both groups (P < 0.05). In the placebo group, high altitude significantly increased filtration fraction (P < 0.05), but this response was abolished by isradipine. Lithium clearance and urinary excretion of beta 2-microglobulin remained unchanged by hypoxia in both groups. Exercise did not reveal any further renal dysfunction. In both groups, high altitude increased TERalb from 4.8 to > 6.7%/h (P < 0.05). In conclusion, acute altitude hypoxia increases Ualb despite unchanged tubular function and independent of effects of isradipine on filtration fraction. The elevated TERalb suggests an overall increase in capillary permeability, including the glomerular endothelium, as the critical factor in high-altitude induced albuminuria.
Adult↗
Inhibitory effects of the dopamine agonists quinagolide (CV 205-502) and bromocriptine on prolactin secretion and growth of SMtTW pituitary tumors in the rat.
The SMtTW tumor, a spontaneous PRL-secreting transplantable tumor, is the only available animal model sensitive to dopamine agonists. This model has been used to compare the long term in vivo effects of CV 205-502 (CV) and bromocriptine (BR) on PRL secretion and tumor growth. These two drugs were given for 2 months to female Wistar-Furth rats bearing either small or large tumors 4 and 6 months after the graft. Untreated grafted rats served as control. In all rats treated with 5 or 10 mg/kg.day BR or 0.3 mg/kg.day CV, a normalization of plasma PRL levels was observed whatever the pretreatment levels (plasma PRL or CV or BR-treated rats, < 15 ng/ml vs. 28253 ng/ml in control rats 8 months after graft). An inhibition of tumor growth was found for both small and large tumors, but the tumors never disappeared completely (mean tumor weights at autopsy, 440 and 660 mg in BR and CV groups vs. 5270 mg in control group 8 months after graft). Experiments performed with increasing doses of BR (0.15-5 mg/kg.day) or CV (0.03-0.6 mg/kg.day) indicated that CV is effective at doses 5-10 times lower than those of BR. A shrinkage under treatment and a regrowth after drug withdrawal were demonstrated for large tumors by in vivo ultrasonographic measurements of tumor size. Histological and ultrastructural effects were similar for the two drugs: decrease in hemorrhage, reduction of the cell size and secretory activity, increase in immunoreactive PRL cellular content, and inhibition of exocytosis. There was no difference in the PRL mRNA content of treated and untreated tumors, as assessed by in situ hybridization. In conclusion, CV and BR exhibit similar inhibitory effects on tumor growth and PRL secretion. These effects are rapidly and fully reversible after drug withdrawal. The present results give a complete account of the actions of the two dopamine agonists under conditions comparable to those used in the treatment of human prolactinomas.
Aminoquinolines↗
A mathematical model for dynamics of cardiovascular drug action: application to intravenous dihydropyridines in healthy volunteers.
A physiologically based mathematical model was built to describe the pharmacodynamic effects in response to the administration of intravenous (iv) dihydropyridine drugs in healthy volunteers. This model incorporates a limited number of hemodynamic variables, namely, mean arterial blood pressure (MAP), cardiac output (CO) or heart rate (HR), stroke volume (SV), and total peripheral resistance (TPR), into a closed-loop system supposed to represent essential features of the cardiovascular regulation. We also defined an additional auxiliary control variable (U) which is thought to represent primarily the role of the baroreceptor reflex. It was assumed that the variable U was related to MAP changes through both deviation- and rate-sensitive mechanisms. Other model parameters are the baseline levels for MAP, CO (or HR), and TPR, as well as time constants to account for further temporal aspects of the regulation. Finally, TPR was assumed to be linked to the plasma concentrations of dihydropyridine drugs via a conventional pharmacokinetic/pharmacodynamic (PK/PD) model, relying upon an effect compartment and a linear, hyperbolic, or sigmoidal relationship between the reduction in TPR and the drug concentrations at the effect site. The model characteristics were explored by studying the influence of various parameters, including baseline levels and deviation- and rate-sensitive control parameters, on the hemodynamic responses to a fictive constant rate i.v. infusion of a vasodilator drug. Attempts were also made to mimic literature data with nifedipine, following i.v. administration under both constant and exponentially decreasing infusion rates. The applicability of the model was demonstrated by fitting hemodynamic data following i.v. infusion of nicardipine to healthy volunteers, under experimental conditions similar to those described above for nifedipine. The effect model for the action of nicardipine on TPR, combined with the physiological model including a feedback control loop, allowed an adequate quantitative description of time profiles for both cardiac output and mean arterial pressure. The suggested model is a useful tool for integrated data analysis of hemodynamic responses to vasodilator drugs in healthy volunteers. Computer simulations suggest that a graded variation of a few model parameters--including baseline levels of TPR and MAP and the deviation-sensitive parameter of the arterial pressure control--would also be able to account for the pattern of hemodynamic response observed in hypertensive patients, which is qualitatively different to that seen in normotensive subjects. Extrapolation of drug response from the healthy volunteer to the hypertensive patient is allowed by our model. Its usefulness for an early evaluation of drug efficacy during drug development is under current investigation.
Adult↗
Invasive human pituitary tumors express a point-mutated alpha-protein kinase-C.
Protein kinase-C (PKC) is a ubiquitous eukaryotic kinase that plays a key role in transmembrane signaling and influences important cellular processes, such as proliferation. Increases in its activity and expression have been demonstrated in adenomatous human pituitaries, with protein expression being the highest in invasive tumors (1). Moreover, in these same invasive tumors, the mean increase in expression (8.9-fold) does not correlate with the mean increase in activity (2.6-fold), suggesting a dysfunction in PKC in these tumors. Here, we show that the PKC alpha-isoform (alpha PKC) is overexpressed in human pituitary tumors. The complete sequencing of the PKC cDNA from four invasive tumors has revealed a point mutation that is absent in the noninvasive tumors analyzed. The point mutation is located at position 294 of the protein, in the V3 region, leading to a substitution of a negatively charged aspartic acid by an apolar glycine. Thus, not only is alpha PKC overexpressed in human pituitary tumors, but it is also structurally altered in the invasive subpopulation of these tumors.
Amino Acid Sequence↗
Absence of a direct coupling of a G protein to dihydropyridine binding sites in rat heart.
In rat heart membranes, the addition of guanine 5'-O-(3-thiotriphosphate) (GTP-gamma-S), a stable GTP analogue, did not significantly modify the displacement of [3H]PN 200-110 binding by the 1,4-dihydropyridine (DHP) agonist Bay K 8644 and antagonists, nifedipine and nicardipine. These results are in agreement with some previously reported electrophysiological and pharmacological data, and they suggest that there is no direct involvement of a G protein in the modulation of DHP sensitive Ca channels in cardiac cells.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗