The QcrB Inhibitors TB47 and Telacebec Do Not Potentiate the Activity of Clofazimine in Mycobacterium abscessus.

The antituberculosis drug telacebec is ineffective against Mycobacterium abscessus. A recent study suggested that TB47, a telacebec analogue, potentiated the efficacy of clofazimine against M. abscessus. Here, we report that TB47 not only is ineffective against M. abscessus in vitro but also does not potentiate the activity of clofazimine.

Nationwide survey on training and device utilization during tracheal intubation in French intensive care units.

BACKGROUND: Intubation is a lifesaving procedure that is often performed in intensive care unit (ICU) patients, but leads to serious adverse events in 20-40% of cases. Recent trials aimed to provide guidance about which medications, devices, and modalities maximize patient safety. Videolaryngoscopes are being offered in an increasing range of options and used in broadening indications (from difficult to unremarkable intubation). The objective of this study was to describe intubation practices and device availability in French ICUs. MATERIALS AND METHODS: We conducted an online nationwide survey by emailing an anonymous 26-item questionnaire to physicians in French ICUs. A single questionnaire was sent to either the head or the intubation expert at each ICU. RESULTS: Of 257 ICUs, 180 (70%) returned the completed questionnaire. The results showed that 43% of intubators were not fully proficient in intubation; among them, 18.8% had no intubation training or had received only basic training (lectures and observation at the bedside). Among the participating ICUs, 94.4% had a difficult intubation trolley, 74.5% an intubation protocol, 92.2% a capnography device (used routinely to check tube position in 69.3% of ICUs having the device), 91.6% a laryngeal mask, 97.2% front-of-neck access capabilities, and 76.6% a videolaryngoscope. In case of difficult intubation, 85.6% of ICUs used a bougie (154/180) and 7.8% switched to a videolaryngoscope (14/180). Use of a videolaryngoscope was reserved for difficult intubation in 84% of ICUs (154/180). Having a videolaryngoscope was significantly associated with having an intubation protocol (P = 0.043) and using capnography (P = 0.02). Airtraq® was the most often used videolaryngoscope (39.3%), followed by McGrath®Mac (36.9%) then by Glidescope® (14.5%). CONCLUSION: Nearly half the intubators in French ICUs are not fully proficient with OTI. Access to modern training methods such as simulation is inadequate. Most ICUs own a videolaryngoscope, but reserve it for difficult intubations.

Numerical analysis of aeroacoustic-structural interaction of a flexible panel in uniform duct flow.

Accurate prediction of the acoustics of fluid-structure interaction is important in devising quieting designs for engineering systems equipped with extensive flow duct networks where the thin duct wall panels are in contact with the flowing fluid. The flow unsteadiness generates acoustic waves that propagate back to the source region to modify the flow process generating them. Meanwhile the unsteady flow pressure excites the thin panels to vibrate, which in turn modifies the flow processes. Evidently a strong coupling between the fluid aeroacoustics and the panel structural dynamics exists. Such coupled physical processes have to be thoroughly understood; otherwise, effective quieting design is never achieved. This paper reports an analysis, using a time-domain numerical methodology the authors have recently developed, of the nonlinear aeroacoustic-structural interaction experienced by a flexible panel in a duct carrying a uniform mean flow. With no mean flow, the numerical results agree well with existing theories and reveal the physics of duct transmission loss. Four regimes of aeroacoustic-structural interaction are identified when the duct flow velocity increases from low subsonic to low supersonic values. Insight in the underlying physics of duct transmission loss at different velocities are highlighted and discussed.

Potential probiotic Bifidobacterium animalis ssp. lactis 420 prevents weight gain and glucose intolerance in diet-induced obese mice.

Alterations of the gut microbiota and mucosal barrier are linked with metabolic diseases. Our aim was to investigate the potential benefit of the potential probiotic Bifidobacterium animalis ssp. lactis 420 in reducing high-fat diet-induced body weight gain and diabetes in mice. In the obesity model, C57Bl/6J mice were fed a high-fat diet (60 energy %) for 12 weeks, and gavaged daily with B. lactis 420 (109 cfu) or vehicle. In the diabetes model, mice were fed a high-fat, ketogenic diet (72 energy % fat) for 4 weeks, with a 6-week subsequent treatment with B. lactis 420 (108-1010 cfu/day) or vehicle, after which they were analysed for body composition. We also analysed glucose tolerance, plasma lipopolysaccharide and target tissue inflammation using only one of the B. lactis 420 groups (109 cfu/day). Intestinal bacterial translocation and adhesion were analysed in a separate experiment using an Escherichia coli gavage. Body fat mass was increased in both obese (10.7 ± 0.8 g (mean ± standard error of mean) vs. 1.86 ± 0.21 g, P<0.001) and diabetic mice (3.01 ± 0.4 g vs. 1.14 ± 0.15 g, P<0.001) compared to healthy controls. Treatment with B. lactis 420 significantly decreased fat mass in obese (7.83 ± 0.67 g, P=0.007 compared to obese with vehicle) and diabetic mice (1.89 ± 0.16 g, P=0.02 for highest dose). This was reflected as reduced weight gain and improved glucose tolerance. Furthermore, B. lactis 420 decreased plasma lipopolysaccharide levels (P<0.001), liver inflammation (P=0.04), and E. coli adhesion in the distal gut (P<0.05). In conclusion, B. lactis 420 reduces fat mass and glucose intolerance in both obese and diabetic mice. Reduced intestinal mucosal adherence and plasma lipopolysaccharide suggest a mechanism related to reduced translocation of gut microbes.

High-frequency rheological characterization of homogeneous polymer films with the quartz crystal microbalance.

We utilize quartz crystal resonators operating at multiple resonant harmonics to measure the high-frequency rheological properties of materials with a broad range of viscoelastic properties. The technique is demonstrated with poly(t-butyl acrylate) films in the vicinity of the calorimetrically determined glass transition and with rubbery polyisoprene films. The technique is a noncontact technique that can be used to quantify the temperature or time-dependent viscoelastic response in homogeneous films with thicknesses in the micrometer range. This work complements the ability of the resonators to quantify the viscoelastic behavior of viscoelastic polymer solutions and simple Newtonian liquids. For each material we obtain the density-shear modulus product and the viscoelastic phase angle at frequencies of 5 and 15 MHz. A standardized analysis protocol is described that enables this information to be obtained reliably and accurately. The polyisoprene data are found to be in good agreement with measurements obtained by dynamic mechanical analysis using extrapolated temperature shift factors.

High frequency rheometry of viscoelastic coatings with the quartz crystal microbalance.

We describe a quantitative method for using the quartz crystal microbalance (QCM) to characterize the high frequency viscoelastic response of glassy polymer coatings with thicknesses in the 5-10 µm regime. By measuring the frequency and dissipation at the fundamental resonant frequency (5 MHz) and at the third harmonic (15 MHz), we obtain three independent quantities. For coatings with a predominantly elastic response, characterized by relatively low phase angles, these quantities are the mass per unit area of the coating, the density-shear modulus product, and the phase angle itself. The approach was demonstrated with a model polyurethane coating, where the evolution of these properties as a function of cure time was investigated. For fully cured films, data obtained from the QCM are in good agreement with results obtained from traditional dynamic mechanical analysis.

An enhanced hydrogen adsorption enthalpy for fluoride intercalated graphite compounds.

We present a combined theoretical and experimental study on H(2) physisorption in partially fluorinated graphite. This material, first predicted computationally using ab initio molecular dynamics simulation and subsequently synthesized and characterized experimentally, represents a novel class of "acceptor type" graphite intercalated compounds that exhibit significantly higher isosteric heat of adsorption for H(2) at near ambient temperatures than previously demonstrated for commonly available porous carbon-based materials. The unusually strong interaction arises from the semi-ionic nature of the C-F bonds. Although a high H(2) storage capacity (>4 wt %) at room temperature is predicted not to be feasible due to the low heat of adsorption, enhanced storage properties can be envisaged by doping the graphitic host with appropriate species to promote higher levels of charge transfer from graphene to F(-) anions.

Incapacidad y calidad de vida del paciente afectado por un accidente vascular cerebral: evaluación nueve meses después del alta hospitalaria / Disability and quality of life of stroke survivors: evaluation nine months after discharge

Introducción y objetivos. Tras el episodio agudo de accidentevascular cerebral (AVC), un gran número de supervivientesse ve afectado por secuelas que impiden llevar a cabo diversas actividadesbásicas o instrumentales de la vida diaria. Junto con laevaluación clínica, la percepción del paciente relativa a su estadode salud constituye una información útil en su proceso de recuperación.El objetivo de este estudio se centró en evaluar la capacidadfuncional y la calidad de vida tras el AVC. Pacientes y métodos.Tras la identificación de una cohorte de pacientes atendidos en unhospital general, se contactó con ellos nueve meses después del altahospitalaria. El instrumento de recogida de datos, enviado porcorreo, integraba la escala de COOP WONCA, el índice de actividadesde Frenchay, el índice de Barthel y la escala de Rankin, ademásde un conjunto de variables sociodemográficas. Resultados. Latasa de supervivencia de los participantes fue del 81%. La aptitudfísica y la capacidad para ejecutar actividades diarias son lasdimensiones físicas más afectadas, que impiden a los pacientes realizarun conjunto de actividades básicas e instrumentales diarias.El estado afectivo-emocional y la autopercepción del estado generalde salud se correlacionan igualmente con la incapacidad física.Conclusiones. Los resultados apuntan a un porcentaje significativode individuos que tras el AVC mantienen una incapacidad moderadao grave (47,8%), lo cual determina la presencia de una segundapersona para colaborar en las actividades de autocuidado. Los datosencontrados son decisivos en cuanto a que los individuos presentandisfunciones físicas graves asociadas a alteraciones emocionalesy psicológicas

Introduction and aim. After acute episode, a great number of individuals who survive a stroke have impairmentsthat impede them to carry out with autonomy a set of basic activities of daily life and instrumental activities of daily life. Theclinical evaluation health self perception is a useful element on patient’s recovering process. The purpose of this study was toevaluate post-stroke functional health status and quality of life. Patients and methods. After identification of a cohort ofadmitted patients at a general hospital, those were contacted by phone nine months after discharge. The collected tool sent bymail included the COOP WONCA charts, Frenchay Activities Index, Barthel Index, Rankin scale and a set of sociodemographicvariables. Results. Participants survival rate was of 81%. The physical functioning and the capacity to performdaily activities were the most affected ones, impairing the patients of making a set of basic and instrumental daily activities.The emotional state and health self-perception are also correlated to disability. Conclusions. The results suggest asignificative percentage of stroke survivors maintaining a moderate or severe disability (47.8%) requiring the presence ofcaregiver helping self-care. Collected data enhances that stroke survivors have severe physical dysfunction associated toemotional and psychological disturbances

Influence of cirrhosis on lamotrigine pharmacokinetics.

AIMS: Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. METHODS: Thirty-six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. RESULTS: The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child-Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child-Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half-life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). CONCLUSIONS: Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child-Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.

A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia.

BACKGROUND & AIMS: : At least half of patients with chronic hepatitis C virus (HCV) fail to respond to interferon or interferon/ribavirin therapy. Histological improvement is observed in some nonresponders. We conducted a randomized, controlled trial to determine if maintenance interferon therapy could prevent histological progression in this subset of nonresponders. METHODS: Fifty-three patients with chronic HCV were enrolled. All were HCV-RNA positive after 6 months of treatment with interferon alfa-2b but had a histological response. Twenty-seven of the patients were randomly assigned to continue interferon (3 MU 3 times weekly) for 24 months; 26 patients discontinued treatment and were observed prospectively. Alanine aminotransferase (ALT) level and HCV-RNA titer were monitored, and liver biopsy was repeated every 12 months. RESULTS: Before interferon therapy, the 2 groups were well matched for all demographic factors, serum ALT (94.0 +/- 15.6), log HCV-RNA titer (5. 85 +/- 0.15 copies/mL), histology score (9.5 +/- 0.2), and percentage with cirrhosis (25%). After 6 months of treatment, significant reductions (P < 0.05) in serum ALT level (62.6 +/- 9.6), log HCV-RNA titer (4.79 +/- 0.13 copies/mL), and hepatic inflammation (4.0 +/- 0.2) were observed. These improvements were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, log HCV-RNA, and hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement (P < 0.03). Discontinuation of interferon was associated with an increase in mean fibrosis score from 2.2 to 2.4 and worsening of hepatic histology in 30% of patients (P < 0.01). CONCLUSIONS: These data support the hypothesis that maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic.

Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey.

Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17beta-estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 microg/kg) to long-term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration. These levels are in agreement with the experimentally determined IC50 value of the antagonist. The most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate-induced LH and FSH surges, which suggests that endogenous SP normally has an inhibitory role during this time. The enhancement of LH release is approximately 50%, regardless of the amount of the NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 receptor with the smaller dose of the antagonist leads to a small, but significant, increase in plasma levels of SP, indicating that blockade of SP receptors leads to an increased release of SP. Collectively, these results further substantiate the link which exists between the ovarian steroid 17beta-estradiol and SP systems. Also, for the first time, these results demonstrate an inhibitory involvement of the human NK1 receptor in the 17beta-estradiol-induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.

Linkage analysis in 16 families with incontinentia pigmenti.

A locus for the X-linked dominant genodermatosis incontinentia pigmenti (IP) has been linked to markers in Xq28. Here we report high lod scores for markers spanning the interval DXS52-DXYS154 using 16 families, providing further evidence for a single major X-linked IP locus.

Correlations between p21 expression and clinicopathological findings, p53 gene and protein alterations, and survival in patients with endometrial carcinoma.

The p21 protein inhibits cyclin-dependent kinases and mediates cell-cycle arrest and cell differentiation. It is induced by wild-type p53, but not by mutant p53. This study of 75 patients with endometrial carcinoma investigates the relationship between p21 expression and the functional status of p53, and the usefulness of p21 as a prognostic marker. Correlations were determined between p21 immunoreactivity, p53 overexpression as examined by immunohistochemistry, p53 DNA mutations as examined by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) analysis, and clinicopathological features, including the clinical outcome. Immunoreactivity for p21 and p53 mutations were detected in 47 (62.7 per cent), 37 (49 per cent), and 23 (31 per cent) patients, respectively. There were no significant correlations between the presence or absence of p21 immunoreactivity and p53 overexpression and DNA mutations. Survival curves revealed that patients with p53 overexpression tended to have a poorer prognosis than those without p53 overexpression (P = 0.104), that patients with p53 mutations had a significantly worse prognosis than those without mutations (P = 0.035), and that patients with p21 expression tended to have a better prognosis than those without p21 expression (P = 0.074). Immunohistochemical analysis of p21 was not useful for evaluating the functional status of p53 in patients with endometrial carcinoma. Both p21 expression and p53 abnormalities were considered as prognostic indicators in patients with endometrioid endometrial carcinoma.

CGRP in the trigeminal nucleus, spinal cord and hypothalamus: effect of gonadal steroids.

Calcitonin gene-related peptide (CGRP) contents were assayed in cervical spinal cord, trigeminal nucleus and hypothalamus throughout the estrous cycle and in male and ovariectomized rats. In the trigeminal nucleus, neither testosterone nor 17 beta-estradiol seem to affect CGRP accumulation, but progesterone seems to decrease it. In the cervical spinal cord, ovarian steroids seem to decrease CGRP while testosterone does not seem to influence it. In the hypothalamus, CGRP was only detectable in the male rat suggesting a positive effect of testosterone. It had marked circadian rhythm. In conclusion, CGRP content appears to be affected by gonadal steroids in the hypothalamus, the cervical spinal cord and the trigeminal nucleus in the rat.

Substance P and neurokinin A variations throughout the rat estrous cycle; comparison with ovariectomized and male rats: I. Plasma, hypothalamus, anterior and posterior pituitary.

The concentrations of Substance P and Neurokinin A were measured in plasma, and the hypothalamo-pituitary complex of 4-day-cycling female, ovariectomized and male rats. Estrous cycle-related fluctuations were recorded for these two neurokinins. The patterns of plasma concentrations of Substance P and Neurokinin A, however, were not similar throughout the rat estrous cycle. The plasma concentration of Substance P increased on proestrus at 19.00 hr, while Neurokinin A decreased. The plasma concentration of Substance P was positively correlated with plasma 17 beta-estradiol levels. In the ovariectomized rat, the absence of ovarian steroids led to low levels of plasma Neurokinin A, but the plasma concentration of Substance P did not show any change as compared to the estrous cycle. In the male rat, a similar observation was made in the presence of a testosterone environment. The largest variations in tissue concentration of both peptides were observed in the anterior pituitary. Substance P and Neurokinin A contents were higher throughout the proestrous day than the 3 other days. However, the level fell at 18.00 hr on proestrus, and there were similar falls in the hypothalamic contents of Substance P and Neurokinin A at 19.00 hr. In the ovariectomized rat, with no gonadal steroids, the hypothalamic and/or anterior pituitary levels of Substance P were in the same range as during the estrous cycle. However, the hypothalamic levels of Neurokinin A were lower and Neurokinin A was undetectable in the anterior pituitary. Substance P and Neurokinin A concentrations in the posterior pituitary were stable throughout the estrous cycle, with the exception of rises for both peptides on estrous day. Substance P levels were much lower in ovariectomized and male rats. These results describe large fluctuations in hypothalamic and pituitary Substance P and Neurokinin A contents through the estrous cycle in the female rat. They also strongly suggest the involvement of gonadal steroids in the differential regulation of Substance P and Neurokinin A in the female and male rat.

Substance P and neurokinin A variations throughout the rat estrous cycle; comparison with ovariectomized and male rats: II. Trigeminal nucleus and cervical spinal cord.

Substance P and neurokinin A were assayed in the trigeminal nucleus and cervical spinal cord of 4-day cycling female, ovariectomized, and male rats. During the estrous cycle, levels were largely stable in the trigeminal nucleus. In ovariectomized rats, the levels differed from those on any day of the estrous cycle suggesting a weak effect of ovarian steroids. In males, the variations in the substance P and neurokinin A contents in the trigeminal nucleus were not similar to those in either cyclic or ovariectomized rats. The levels fluctuated substantially in the cervical spinal cord. During the first 3 days of the estrous cycle, the substance P and neurokinin A contents fell concomitant with the 17 beta-estradiol surge, suggesting a downregulation of substance P and neurokinin A contents by 17 beta-estradiol. Furthermore, on estrus, progesterone seemed to inhibit the accumulation of both neurokinins. Testosterone may stimulate accumulation of substance P and neurokinin A in the cervical spinal cord, with a marked circadian rhythm. These results are in favor of the neurokinin content of the spinal cord being regulated by the gonadal steroids. In the trigeminal nucleus, only testosterone has an effect.

Reduction of the amplitude of preovulatory LH and FSH surges and of the amplitude of the in vitro GnRH-induced LH release by substance P. Reversal of the effect by RP 67580.

The effects of Substance P (SP) and of a specific nonpeptide antagonist of the NK1 receptor (RP 67580) on preovulatory gonadotropin surges and on the in vitro GnRH induced LH surge were investigated in cycling female rats. A subcutaneous injection of SP (0.5 mg/kg body weight) at 12.00 h on the proestrous day significantly decreased the LH preovulatory surge. RP 67580 (1.5 mg/kg) significantly increased this LH surge. However, when SP and its antagonist were administered together, LH preovulatory surge was normal. The FSH preovulatory surge at 18.00 h and also at 19.00 h was significantly inhibited by SP administration. RP 67580 alone had no effect on the FSH preovulatory surge. When SP and RP 67580 were both administered, there was no diminution of FSH plasma levels at 18.00 h and 19.00 h. In vitro perifusions of anterior pituitaries showed that SP inhibits GnRH-induced LH release via a NK1 receptor. Thus, SP inhibits the LH preovulatory surge via NK1 receptors and SP modulation of gonadotropin surges is at least partly exerted at the pituitary.

Comparative behavioural profile of centrally administered tachykinin NK1, NK2 and NK3 receptor agonists in the guinea-pig.

1. The NK1 tachykinin receptor agonists, septide, [Sar9,Met(O2)11]SP and [Pro9]SP produced locomotor hyperactivity (10-20 min) when injected intracerebroventricularly (i.c.v.) in the guinea-pig. The most potent in eliciting this hyperactivity was septide (from 0.63 to 5 micrograms), compared to [Sar9,Met(O2)11]SP, which was active at 2.5 and 5 micrograms and [Pro9]SP which induced a non-significant increase even at 10 micrograms. 2. Wet-dog shakes were elicited by septide, [Sar9,Met(O2)11]SP and [Pro9]SP injected by the i.c.v. route in the guinea-pig. [Sar9,Met(O2)11]SP, active from 0.16 to 2.5 micrograms was more potent than septide (active at 1.25 micrograms) and [Pro9]SP (active at 0.63 micrograms) in eliciting such behaviour. To a lesser extent, grooming was also observed after injection of these agonists. 3. The NK2 tachykinin receptor agonist, [Lys5,MeLeu9,Nle10]NKA(4-10), up to the dose of 10 micrograms i.c.v. had no effect in the guinea-pig. It neither modified locomotor activity nor induced a characteristic behavioural response. At higher doses (20 micrograms), some toxic effects were noted. 4. The NK3 tachykinin receptor agonist, senktide, contrasts with the NK1 receptor agonists in that it elicited only wet-dog shakes, at doses ranging from 0.32 to 1.25 micrograms. It neither modified locomotor activity (1 microgram) nor induced grooming (up to 5 micrograms) in the guinea-pig. 5. To our knowledge, these results are the first demonstration that the guinea-pig could be useful to differentiate tachykinin agonists on the basis of their behavioural profile, distinct from those obtained in mice and rats.

Electrographic studies of the effects of RP 60180, a novel kappa agonist, on the photosensitive baboon Papio papio.

1. The authors describe here the effects of intravenous administration of RP 60180, a novel kappa agonist, on conscious baboons of the species Papio papio, which spontaneously present photically induced epileptic responses. 2. Animals (n = 2) were chronically implanted with epidural recording electrodes and tested whilst seated in a primate chair. The electrocorticogram (ECoG) and electrocardiogram (ECG) were recorded during a control period of at least 30 minutes before the injection of RP 60180 (1 to 4.5 mg/kg i.v.) and immediately afterwards. 3. Qualitatively, up to the dose of 4.5 mg/kg i.v., RP 60180 did not modify ECoG background in term of paroxysmal activity in comparison with that observed during the control period. It did not cause any manifest focal or generalized seizure discharges, nor did it consistently enhance or reduce photically induced myoclonic responses. 4. From the dose of 1 mg/kg i.v., RP 60180 slowed ECG frequency. This effect, which lasted for about 30 minutes post-injection, was most often seen at the higher doses. 5. In another set of experiments, one baboon received the kappa agonist U-50488 (a benzacetamide derivative of spiradoline) at 1 and 3 mg/kg i.v. U-50488, at 3 and to a lesser degree at 1 mg/kg i.v., induced paroxysmal bursts of slow wave ECoG activity and a slowing of the ECG. These effects lasted about 1 hour post-drug administration. During this period, we observed spontaneous vocalization, as if the animal were complaining, as well as shaking.

The non-peptide neurokinin-1 antagonist, RPR 100893, decreases c-fos expression in trigeminal nucleus caudalis following noxious chemical meningeal stimulation.

The effect of RPR 100893, a selective and specific neurokinin-1 antagonist, or its enantiomer RPR 103253 was examined on c-fos antigen expression in brain stem and upper cervical cord 2 h after intracisternal capsaicin injection (30.5 micrograms/ml) in pentobarbital-anesthetized Hartley guinea-pigs. Positive cells were counted at three levels corresponding to obex, -2.25 mm and -6.75 mm in 18 sections (50 microns). Immunoreactivity was strongly expressed within laminae I and IIo of trigeminal nucleus caudalis, area postrema and the leptomeninges. Moderate labeling was present in the nucleus of the solitary tract and the medullary lateral reticular nucleus, whereas few positive cells were found in the ventral portion of the medullary reticular nucleus and Rexed laminae III-V and X. The distribution of labeled cells was consistent with previously reported results following subarachnoid placement of the noxious agents, blood or carrageenin. Pretreatment with RPR 100893 (1, 10 and 100 micrograms/kg, i.v.) but not its enantiomer (100 micrograms/kg, i.v.) 30 min prior to capsaicin injection significantly reduced the number of positive cells in the trigeminal nucleus caudalis (P < 0.01) in a dose-dependent manner, but not within area postrema or nucleus of the solitary tract. These results indicate that (i) the instillation of capsaicin into the subarachnoid space is an effective stimulus for the induction of c-fos antigen within trigeminal nucleus caudalis, presumably through activation of trigeminovascular afferents, and (ii) the neurokinin-1 antagonist RPR 100893 reduces the number of positive cells selectively within this nucleus. The findings are significant because drugs which alleviate vascular headaches decrease the number of c-fos-positive cells within trigeminal nucleus caudalis following noxious meningeal stimulation. Hence, strategies aimed at blocking the neurokinin-1 receptor may be useful for treating migraine and cluster headache.