Efficacy and safety of a T-type calcium channel blocker in patients with neuropathic pain: A proof-of-concept, randomized, double-blind and controlled trial.

BACKGROUND: T-type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T-type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. METHODS: This proof-of-concept, multicentre, double-blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add-on therapy) to an inactive control (IC) in 114 patients with non-diabetic peripheral neuropathic pain. After a 7-day run-in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention-to-treat population. This study is registered with EudraCT (2013-004801-26) and ClinicalTrials.gov (NCT02100046). RESULTS: The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per-protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI -25.8; -5.4) from baseline compared to IC (-7.8%, 95% CI -14.3; -1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. CONCLUSION: Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. SIGNIFICANCE: This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per-protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T-type calcium channel inhibition for the treatment of neuropathic pain.

Effects of scFOS on the composition of fecal microbiota and anxiety in patients with irritable bowel syndrome: a randomized, double blind, placebo controlled study.

BACKGROUND: Short-chain fructooligosaccharides (scFOS) have beneficial effects in subjects with minor digestive complaints, but the potential mechanisms involved have not been elucidated. The aim of the study was to evaluate changes in rectal sensitivity related to the clinical effects of scFOS in a selected group of patients with irritable bowel syndrome (IBS) and rectal hypersensitivity. METHODS: In 79 IBS patients (defined by Rome III criteria) with rectal hypersensitivity (defined as discomfort threshold ≤44 g) a parallel, placebo-controlled, randomized, and double-blind study was performed to assess the effects of dietary supplementation (5 g d-1 ) with scFOS vs placebo for 4 weeks on rectal sensitivity (primary outcome: tolerance to increasing wall tension applied by a tensostat), clinical outcomes (IBS, anxiety/depression and quality of life scores) and composition of fecal microbiota. KEY RESULTS: Rectal discomfort threshold, and IBS and quality of life scores, significantly improved during treatment, but in a similar manner in both scFOS and placebo groups; a post-hoc analysis showed that the effect of scFOS on rectal sensitivity was more pronounced in constipation-predominant-IBS patients (P=.051 vs placebo). Contrary with placebo, scFOS significantly reduced anxiety scores and increased fecal Bifidobacteria (P<.05 for both) without modifying other bacterial groups. CONCLUSIONS & INTERFENCES: The effect of scFOS on anxiety may be related to modulation of the gut microbiota; demonstration of effects of scFOS on rectal sensitivity may require higher doses and may depend on the IBS subgroup.

Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome.

BACKGROUND: The role of the gut microbiota in patho-physiology of irritable bowel syndrome (IBS) is suggested by several studies. However, standard cultural and molecular methods used to date have not revealed specific and consistent IBS-related groups of microbes. AIM: To explore the constipated-IBS (C-IBS) gut microbiota using a function-based approach. METHODS: The faecal microbiota from 14 C-IBS women and 12 sex-match healthy subjects were examined through a combined strictly anaerobic cultural evaluation of functional groups of microbes and fluorescent in situ hybridisation (16S rDNA gene targeting probes) to quantify main groups of bacteria. Starch fermentation by C-IBS and healthy faecal samples was evaluated in vitro. RESULTS: In C-IBS, the numbers of lactate-producing and lactate-utilising bacteria and the number of H(2) -consuming populations, methanogens and reductive acetogens, were at least 10-fold lower (P < 0.05) compared with control subjects. Concomitantly, the number of lactate- and H(2) -utilising sulphate-reducing population was 10 to 100 fold increased in C-IBS compared with healthy subjects. The butyrate-producing Roseburia - E. rectale group was in lower number (0.01 < P < 0.05) in C-IBS than in control. C-IBS faecal microbiota produced more sulphides and H(2) and less butyrate from starch fermentation than healthy ones. CONCLUSIONS: A major functional dysbiosis was observed in constipated-irritable bowel syndrome gut microbiota, reflecting altered intestinal fermentation. Sulphate-reducing population increased in the gut of C-IBS and were accompanied by alterations in other microbial groups. This could be responsible for changes in the metabolic output and enhancement in toxic sulphide production which could in turn influence gut physiology and contribute to IBS pathogenesis.

Plasma levels and systemic safety of 0.1% unpreserved timolol maleate gel, 0.5% timolol aqueous solution and 0.5% timolol maleate gel.

PURPOSE: To compare systemic absorption of three formulations of timolol eye drops: 0.1% timolol maleate gel, 0.5% timolol aqueous solution, and 0.5% timolol maleate gel. METHODS: This was a double cross-over phase I study. Cross-over 1: two weeks of 0.1% timolol gel once daily, followed by a 3-week wash-out period and then two weeks of 0.5% timolol aqueous solution twice a day (group 1) or the reverse (group 2). Cross-over 2: two weeks of 0.1% timolol gel once daily, followed by a 3-week wash-out period, and then two weeks of 0.5% timolol gel once daily (group 3) or the reverse (group 4). Subjects underwent tonometry, blood sampling, and heart rate and blood pressure assessments (during bicycle exercise and head-up tilt tests) before and after instillation at the beginning and end of each treatment period. RESULTS: Forty-three healthy volunteers were randomized: 11 subjects in groups 1, 2, and 3, and 10 subjects in group 4. Areas under the concentration-time curve (AUC) values after administration of timolol 0.5% formulations were 15- to 38-fold higher than those seen after administration of timolol 0.1% gel. Maximum timolol concentrations after instillation of 0.1% gel are reduced by almost 90% compared to concentrations obtained after both 0.5% aqueous solution and 0.5% gel instillation. The AUC between 0 and 12 h post-administration were also reduced by up to 93 to 98%. CONCLUSIONS: After treatment with a timolol 0.1% gel formulation, systemic concentrations found were considerably lower than after administration of timolol 0.5% gel or in aqueous solution.

Acetaminophen metabolism after major surgery: a greater challenge with increasing age.

Patients undergoing major surgery represent a good model for the study of the hepatic metabolism of acetaminophen (APAP) after surgery and for the evaluation of how the detoxification process is influenced by aging. Thirty patients received intravenous APAP (1 g/6 h) for 4 days (D1-D4). Daily 24-h urinary metabolites-cysteine-APAP, mercapturate-APAP, APAP, and glucuronide and sulfate conjugates-as well as blood glutathione levels were compared with repeated-measures analysis of variance (significance, P<0.05). Between D1 and D4, cysteine-APAP increased (308±308 mg vs. 570±512 mg, P=0.005), and sulfate and glucuronide conjugates decreased (1,365±1,084 mg vs. 694±600 mg, P<0.0001 and 2,418±817 mg vs. 1,513±1,076 mg, P=0.011, respectively). Blood glutathione decreased (790±125 vs. 623±132 µmol/l, P<0.0001. These changes increased with aging. APAP disposition after major surgery shifts toward the oxidative pathways of metabolism, and this is enhanced with aging. Supplementation with sulfur-containing amino acids should be investigated further as it might minimize the effect on antioxidant defenses, especially in older persons undergoing more extensive surgical procedures.

Clinical and microcirculatory effects of transcutaneous CO2 therapy in intermittent claudication. Randomized double-blind clinical trial with a parallel design.

BACKGROUND: This randomized, double blind trial determined the short and long-term clinical and hemodynamic vasodilator effects induced by percutaneous applications of natural CO2 gas in patients with moderate Fontaine stage II. PATIENTS AND METHODS: 62 patients with intermittent claudication (100-500 meters) were randomized to 18 consecutive days of CO2 treatment or placebo (air). The gas fluids were applied at a constant temperature of 30 degrees C on pre-humidified skin. The effects of the treatment were evaluated by total distance walked (primary criterion) and hemodynamic and microcirculatory findings. Patients also answered a quality of life questionnaire. RESULTS: The Strandness test showed a significant increase in total distance walked (+ 131 meters, 66%; p = 0.001) and pain-free distance (+ 81 meters, 73%; p = 0.02) after 18 days of CO2 treatment. The improvement was maintained 3 and 12 months later. The systolic pressure index (ABI) increased by 37% (p = 0.001) 1 minute after treadmill walking and ABI recovery time decreased significantly by 38% (p = 0.002). Microcirculatory findings showed an increase in systolic pressure of the great toe (13%; p < 0.0001), in baseline pO2 (20%; p = 0.01) and in vasomotion (78%; p = 0.001) in the treatment group. The improvement in total walking distance was correlated with the increase in ABI and peripheral cutaneous oxygenation. Patients' subjective assessments corroborated the benefits. No significant change was observed in the placebo group. CONCLUSIONS: This study demonstrates that 18 consecutive days of percutaneous CO2 treatment significantly increases walking distance in patients with moderate intermittent claudication. This effect, which was associated with an increase in peripheral systolic pressure and pO2, is evidence of a better ability to withstand effort.

Hematopoietic progenitor cell mobilization and harvesting in children with malignancies: do the advantages of pegfilgrastim really translate into clinical benefit?

Our purpose was to assess success rates in children of achieving optimal hematopoietic progenitor cells (HPCs) harvest after mobilization with 300 microg/kg pegfilgrastim. Between January 2005 and January 2007, 26 children with solid malignancies who were referred for HPC collection were consecutively included. Hematopoietic progenitor cell mobilization consisted of one s.c. injection of 300 microg/kg body weight (BW) of pegfilgrastim. The success criterion was defined as at least 5 x 10(6) CD34+ cells/kg during the first standard apheresis (less than 3 blood volumes processed (BVP)). After 26 inclusions, the Bayesian analysis gave a mean estimated success rate of 60.7% (95% credibility interval: 42.0-78.0%). The first apheresis allowed the collection of 8.3 x 10(6) CD34+ cells/kg BW (range 0.6-37.8), with a median of 2.8 BVP (range 1.4-3.0). Overall, the median of CD34+ cells collected was 12.4 x 10(6)/kg (range 2.7-37.8). The cumulative dose of anthracyclin was the only variable associated with the total number of CD34+ collected cells (P<0.05). Mobilization was clinically well tolerated in 20 patients. No drug-related adverse events of grade > or =3 occurred. We conclude that a single injection of 300 microg/kg pegfilgrastim in the hematological steady state is an efficient and well-tolerated method of HPC mobilization in children with solid malignancies.

Tear concentrations of azithromycin following topical administration of a single dose of azithromycin 0.5%, 1.0%, and 1.5% eyedrops (T1225) in healthy volunteers.

PURPOSE: To evaluate azithromycin tear concentrations after one drop of T1225 0.5%, 1.0%, and 1.5% eyedrops. METHODS: In this randomized, double-masked study, 91 healthy volunteers received one drop into each eye of T1225 0.5% (n=23), T1225 1.0% (n=38), or T1225 1.5% (n=38). Azithromycin tear concentrations were measured by HPLC-MS at seven time points for 24 hours. Tolerability was evaluated. RESULTS: T1225 1.0% and 1.5% had similar pharmacokinetic profiles. After a post-instillation peak (167 to 178 mg/L after 10 minutes), mean concentrations remained above 7 mg/L for 24 hours (except for T1225 1% at H24). A delayed increase of the azithromycin mean tear concentration might be explained by the known late azithromycin release from tissues after storage in cells. Areas under inhibitory curve (AUICs) of T1225 1.0% and 1.5% were higher than AUICs of T1225 0.5% and ranged between 47 and 90. The three T1225 concentrations were safe for the ocular surface. CONCLUSIONS: Once daily instillation of T1225 1.0% and 1.5% was shown to reach an AUIC markedly above the required threshold for an antibacterial activity against Gram-positive bacteria (25-35). These results suggest that a BID instillation is more likely to ensure antimicrobial activity against Gram-negative bacteria (threshold >100).

Acetaminophen reinforces descending inhibitory pain pathways.

The mechanism of the analgesic action of acetaminophen involves the serotonergic system. This study explores how acetaminophen interferes with serotonergic descending pain pathways. Eighteen rapid metabolizers of tropisetron were included in this double-blind cross-over study. After ethical approval, the healthy volunteers took 1 g oral acetaminophen (A) or placebo (p) combined with either the 5-HT3 antagonist tropisetron (T) (5 mg) or saline, intravenously, at weekly intervals. Mechanical pain thresholds, determined before and after a cold pressor test (CPT), were repeated seven times during the three post-dosing hours, and area under the concentration-time curves (AUCs) of the three treatments were compared. After CPT, AUC (%*min) of Ap (1,561+/-429) was larger than before CPT (393+/-382, P<0.05); these effects were totally inhibited by tropisetron. Acetaminophen reinforces descending inhibitory pain pathways; it suggests a supraspinal target for acetaminophen's antinociceptive action. This study also confirmed that there is a central serotonergic mechanism of action for acetaminophen that is not stimulus-dependent.

Safety and immunogenicity of subcutaneous or intramuscular administration of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae in healthy volunteers.

The safety and immunogenicity of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae was evaluated in 84 volunteers according to the route of administration, i.e., subcutaneous (SC) or intramuscular (IM), in a double-blind randomised trial. The volunteers were randomised into four groups: SC vaccine; IM vaccine; SC placebo; and IM placebo. Primary vaccination comprised two injections on day 0 and day 14, with a booster after 6 months. A second booster was given 30 months after primary vaccination. Local reactions within 1 h of injections were rare, with no difference between vaccine groups. Local reactions within 3 h were more frequent after the second, third and fourth SC injections than after IM injections. Systemic reactions never occurred within 1 h of vaccination and were rare within 3 days; the rates were comparable for the different vaccine groups. Evolution of the antibody responses, as assessed by microscopic agglutination tests and specific IgG and IgM ELISAs, were similar for both injection routes. IgG seroconversion rates after the first booster were 97% (95% CI 80-100%) for the SC vaccine group, and 96% (95% CI 80-100%) for the IM vaccine group, and both reached 100% for IgG after the second booster. The safety and immunogenicity of the anti-leptospiral vaccine were both good. Monitoring of antibody levels established that a booster dose triggered a strong antibody response in fully vaccinated subjects at 30 months after primary vaccination.

Unacceptably high mortality related to measles epidemics in Niger, Nigeria, and Chad.

BACKGROUND: Despite the comprehensive World Health Organization (WHO)/United Nations Children's Fund (UNICEF) measles mortality-reduction strategy and the Measles Initiative, a partnership of international organizations supporting measles mortality reduction in Africa, certain high-burden countries continue to face recurrent epidemics. To our knowledge, few recent studies have documented measles mortality in sub-Saharan Africa. The objective of our study was to investigate measles mortality in three recent epidemics in Niamey (Niger), N'Djamena (Chad), and Adamawa State (Nigeria). METHODS AND FINDINGS: We conducted three exhaustive household retrospective mortality surveys in one neighbourhood of each of the three affected areas: Boukoki, Niamey, Niger (April 2004, n = 26,795); Moursal, N'Djamena, Chad (June 2005, n = 21,812); and Dong District, Adamawa State, Nigeria (April 2005, n = 16,249), where n is the total surveyed population in each of the respective areas. Study populations included all persons resident for at least 2 wk prior to the study, a duration encompassing the measles incubation period. Heads of households provided information on measles cases, clinical outcomes up to 30 d after rash onset, and health-seeking behaviour during the epidemic. Measles cases and deaths were ascertained using standard WHO surveillance-case definitions. Our main outcome measures were measles attack rates (ARs) and case fatality ratios (CFRs) by age group, and descriptions of measles complications and health-seeking behaviour. Measles ARs were the highest in children under 5 y old (under 5 y): 17.1% in Boukoki, 17.2% in Moursal, and 24.3% in Dong District. CFRs in under 5-y-olds were 4.6%, 4.0%, and 10.8% in Boukoki, Moursal, and Dong District, respectively. In all sites, more than half of measles cases in children aged under 5 y experienced acute respiratory infection and/or diarrhoea in the 30 d following rash onset. Of measles cases, it was reported that 85.7% (979/1,142) of patients visited a health-care facility within 30 d after rash onset in Boukoki, 73.5% (519/706) in Moursal, and 52.8% (603/1,142) in Dong District. CONCLUSIONS: Children in these countries still face unacceptably high mortality from a completely preventable disease. While the successes of measles mortality-reduction strategies and progress observed in measles control in other countries of the region are laudable and evident, they should not overshadow the need for intensive efforts in countries that have just begun implementation of the WHO/UNICEF comprehensive strategy.

Estimating transmission intensity for a measles epidemic in Niamey, Niger: lessons for intervention.

The objective of this study is to estimate the effective reproductive ratio for the 2003-2004 measles epidemic in Niamey, Niger. Using the results of a retrospective and prospective study of reported cases within Niamey during the 2003-2004 epidemic, we estimate the basic reproductive ratio, effective reproductive ratio (RE) and minimal vaccination coverage necessary to avert future epidemics using a recent method allowing for estimation based on the epidemic case series. We provide these estimates for geographic areas within Niamey, thereby identifying neighbourhoods at high risk. The estimated citywide RE was 2.8, considerably lower than previous estimates, which may help explain the long duration of the epidemic. Transmission intensity varied during the course of the epidemic and within different neighbourhoods (RE range: 1.4-4.7). Our results indicate that vaccination coverage in currently susceptible children should be increased by at least 67% (vaccine efficacy 90%) to produce a citywide vaccine coverage of 90%. This research highlights the importance of local differences in vaccination coverage on the potential impact of epidemic control measures. The spatial-temporal spread of the epidemic from district to district in Niamey over 30 weeks suggests that targeted interventions within the city could have an impact.

Exploring the time to intervene with a reactive mass vaccination campaign in measles epidemics.

The current WHO policy during measles outbreaks focuses on case management rather than reactive vaccination campaigns in urban areas of resource-poor countries having low vaccine coverage. Vaccination campaigns may be costly, or not timely enough to impact significantly on morbidity and mortality. We explored the time available for intervention during two recent epidemics. Our analysis suggests that the spread of measles in African urban settings may not be as fast as expected. Examining measles epidemic spread in Kinshasa (DRC), and Niamey (Niger) reveals a progression of smaller epidemics. Intervening with a mass campaign or in areas where cases have not yet been reported could slow the epidemic spread. The results of this preliminary analysis illustrate the importance of revisiting outbreak response plans.

[Ocular tolerance of a new formulation of nonpreserved diclofenac]. / Intérêt d'une nouvelle formulation de diclofénac sans conservateur pour la surface oculaire.

AIM: To compare the ocular tolerance of nonpreserved diclofenac versus thiomersal-preserved diclofenac in healthy volunteers. MATERIALS AND METHODS: Forty healthy volunteers instilled Dicloabak in the randomised eye and thiomersal-preserved diclofenac in the other eye, according to a strictly identical dosing regimen, for 28 days. Each volunteer thus served as his or her own control. The dose regimen was five drops/day for 7 days followed by three drops/day for 20 days. Ocular tolerance was assessed by the discomfort upon instillation (measured on a visual analogue scale [VAS]), subjective ocular symptoms following instillation (irritation/burning/stinging, eye dryness and foreign body sensation) and finally by an objective examination of the ocular surface. These criteria were evaluated on days 0, 14, 21 and 28. RESULTS: The subjective ocular symptoms following instillation were significantly lower in the nonpreserved group at Day 7 and nearly significantly lower until the end of the study. The biomicroscopy exam confirmed that there was better tolerance without thiomersal. There was less follicular-papillary conjunctivitis and a significantly better lissamine green score in the Dicloabak group. CONCLUSION: The results of this study demonstrate that the nonpreserved formulation of diclofenac is better tolerated by the ocular surface and thus constitutes a therapeutic benefit.

Comparison of the pharmacokinetics of miconazole after administration via a bioadhesive slow release tablet and an oral gel to healthy male and female subjects.

AIMS: The aim of this study was to compare salivary miconazole pharmacokinetics following once daily application of bioadhesive tablets (50 or 100 mg), vs the current treatment with a gel (3 times a day, 375 mg day(-1)). METHODS: A three way cross over study was carried out in 18 healthy subjects (nine males, nine females) with a 1 week washout period between each treatment. Plasma and salivary pharmacokinetics of miconazole were assessed over a 24-h period. RESULTS: In all subjects the tablets gave higher and more prolonged salivary miconazole concentrations than the gel. Thus salivary miconazole AUC(0,24 h) was 37.2 times greater for the 100 mg tablet (90% confidence interval [CI] 22.9, 60.5) and 18.9 times greater for the 50 mg tablet (CI 11.7, 30.6) compared with the gel. Similarly, Cmax was 17.2 times greater (CI 11.8, 25.2) and 7.8 times greater (CI 5.3, 11.4) for the 100 mg tablet and 50 mg tablet, respectively. Comparison of the 100 mg and 50 mg tablets gave ratios of 2.2 and 2.0 for Cmax and AUC(0,24 h), respectively (CI 1.5, 3.2 and 1.2, 3.2). The mean time that salivary miconazole concentrations were above 0.4 micro g ml(-1) (the concentration reached 3 h after application of the oral gel according to published data) or above 1.0 microg ml(-1) (the MIC of some Candida species) was greater for both bioadhesive tablets than for the oral gel (10-14 h vs 1.5 h and 7 h vs 0.6 h). Only 19 plasma samples from eight subjects had concentrations of miconazole above 0.4 micro g ml(-1). Ten of these were taken from five subjects after administration of the gel and nine from three subjects after administration of the tablets. CONCLUSIONS: These data strongly support the further development of miconazole bioadhesive tablets as a sustained release formulation leading to improved antifungal exposure in the buccal cavity. A single daily application should improve compliance, whereas the low systemic absorption of miconazole will alleviate concerns regarding drug interactions and adverse effects.

[Interest of the use of pindolol in the treatment of depression: review]. / Intérêt de l'utilisation du pindolol dans le traitement des dépressions: revue de la littérature.

The principal stakes of depression treatment are to accelerate and enhance the clinical effects of antidepressant drug. The onset of antidepressant action of Serotonin (5HT) selective reuptake inhibitors (SSRIs) was attributed in part to the decrease in firing activity of serotonin neurons produced by the activation of raphe 5HT1A autoreceptors at the time of treatment initiation. Pindolol, an antagonist at somatodendritic pre-synaptic 5HT1A receptors has been investigated as a potential accelerator or potentialisator of antidepressant response. Six open label studies and 12 controlled studies were identified for revue. The first open-label pilot study was conducted by Artigas et al. They showed promising results with pindolol, both in the acceleration of antidepressant response and in improving the efficacy of antidepressant. On the basis of these results five open-label studies were conducted. The open label studies suggest that pindolol accelerate the antidepressant response of serotoninergics therapeutics. The augmentation of antidepressant response was not clearly demonstrated by these studies particularly in the treatment of refractory depression. For example, Dinan et Scott that found the addition of pindolol in association with SSRI therapy had a poor efficacy. In the twelve controlled studies, 4 tried to underscore the shortening of the onset and the augmentation of efficacy of SSRI by pindolol [Berman et al., Maes et al., Perez et al., Tome et al. ], 3 tried to underscore shortening of the onset [Bordet, Zanardi ] and 3 tried to underscore the augmentation of efficacy [Maes et al., Moreno et al., Perez et al. ]. One study tried to underscore the augmentation of efficacy of sleep deprivation by pindolol and another one the shortening of the onset of ECT. Six studies included depressive resistant patients. Three studies were carried out with fluoxetine, 1 with fluvoxamine, 3 with paroxetine, 1 with trazodone. Two -studies were investigated with several antidepressant treatments. The results of the studies indicate one acceleration of antidepressant response in 6 studies, one augmentation of efficacy in 5 studies. Two studies clearly demonstrate that pindolol may -augment and accelerate antidepressant response. Three studies did not confirm these observations. Several points can be examined. For pindolol: 3 authors have demonstrated that the effect of pindolol did not rely upon small antidepressant effect mediated by b-blockers properties, because anxiety was not predominantly improved by pindolol plus SSRI while depressive symptoms were clearly improved. On the basis of data issues from recent positron emission tomography (PET) studies, several authors suggested that the dose of pindolol used in most clinical trials (3 yen 2,5 mg day-1) might be insufficient to induce a substantial occupancy of 5-HTA receptors (Rabiner et al. It is possible that higher doses will show a more evident benefit. On the whole, pindolol seemed to be well tolerated. Adverse effects most commonly reported were increased irritability, insomnia and nausea. Pindolol had poor adverse effects in cardiovascular functions. The variation of the results of the controlled studies can be explained by different points: Firstly by difficulty to determine good criterion of resistance. The most simplistic definition of treatment resistance is the failure to achieve and sustain euthymia with adequate antidepressant treatment. Secondly by the fact that depressive patients who present antecedents of depressive illness seem to be worst responders to the association pindolol/serotoninergic antidepressant than patients suffering of first episode of depression. We observed one antecedent of depression in the group of resistant patients who were good responders to the association pindolol/antidepressant therapy. We observed three anterior episodes of depression in negatives studies of the association pindolol/antidepressant therapy. Thirdly by the fact that the failure of the antidepressant treatment at the time of earlier (or actual) episode seems to be a criterion for less responsiveness to the association of this antidepressant treatment with pindolol. In fact, the open label studies who demonstrated efficacy of the association between pindolol and serotoninergic therapy in major resistant depression were realized with new antidepressant molecule for the episode. Other controlled trials could confirm these facts. Most of the studies failed to retrace clearly the historicity of depression, and it may be interesting in future investigations to analyze the response of the association -compared to the status of the patient with the antidepressant therapy. Further perspective could be envisaged especially in the utilization of pindolol for the treatment of pathologies which are usually treated with a serotoninergic antidepressant -therapy. For example, the antagonist 5HT(1A) Way 100635 was experimented with success in animals in order to augment the efficacy of clomipramine in the treatment of chronic pain. In other respects several psychopharmacogenetics studies could be investigated to examine, for instance, the role of the 5-HT transporter and its implication in the response to pindolol and antidepressant association. In summary, pindolol accele-rates, and in some cases enhances the clinical action of antidepressant drugs. It appears that this augmentation strategy has more limited effect on treatment resistant patient but there is experimental evidence for using higher doses in future augmentation trial.

A human oral capsaicin pain model to assess topical anesthetic-analgesic drugs.

Repeated application of capsaicin on the tongue has been used as a human oral pain model to assess topical anesthetic-analgesic drugs. The reliability of the model was evaluated by observing the variability of the response to repeated applications of capsaicin after three successive sessions at 1 day intervals. No session effect was observed for the time course of the visual analogue scale (VAS) scores and the area under the curve, but a significant decrease of VAS peak scores was noted from the first to the third session. The sensitivity of the model was assessed by mouth rinses with three doses of lidocaine (0.25, 0.5 and 1%). Lidocaine significantly reduced the burning pain. This effect was rapid, reversible and dose dependent. It is concluded that the oral capsaicin pain model displays good reliability and sensitivity and allows safe evaluation of candidate topical analgesic and anesthetic drugs.

Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats.

1. Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg-deficient rats. 2. Hyperalgesic Mg-deficient rats were administered intrathecally (10 microl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h. 3. Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 micromol) as well as NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 micromol x kg(-1), i.p.) induced an anti-hyperalgesic effect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold. 4. These results demonstrate that Mg-deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non-NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.

[Impact of age on pain perception and analgesic pharmacology]. / Influence de l'âge sur la perception de la douleur et la pharmacologie des antalgiques.

INFLUENCE OF AGING ON PAIN: Although pain affects a large majority of the elderly population living in the community and in institutions, our knowledge of the evolution of pain experience with age is poor. Results of clinical surveys and experimental pain studies are contradictory, showing no change, an increase, or a decrease of pain with age. Many results suggest a decrease of pain perception with age that could be explained by peripheral and central neuroanatomical aging and psychological changes of the aging patient towards pain. INFLUENCE OF AGE ON THE PHARMACOLOGY OF ANALGESICS: Biological aging added to multiple pathologies and polymedication explains the pharmacological changes of analgesics. Among pharmacokinetic changes that are globally well known, vigilance must focus on renal excretion of analgesics and their metabolites and on the increased risk of side-effects and drug interactions. Information on pharmacodynamic changes of analgesics are scarce in aging patients who are susceptible to drugs and which demographical trend increases. PERSPECTIVES: A better fundamental knowledge of the evolution of pain with age could help to improve care in the elderly with pain, especially in very old subjects with cognitive impairment and loss of communication skills, where pain evaluation is particularly difficult. Also, more research is needed on the pharmacodynamics of analgesics in older subjects, with a view of a decreased iatrogenic risk, a better pain treatment and quality of life of the elderly.

Effects of rapid eye movement (REM) sleep deprivation on pain sensitivity in the rat.

The relationship between pain and sleep seems to be reciprocal: if pain may interrupt or disturb sleep, poor sleep can also influence pain perception. However the influence of sleep disturbances on pain sensitivity remain poorly investigated. The aim of this study was to assess the effect of REM sleep deprivation on the reaction of rats subjected to different noxious stimuli. In each experiment 16 Wistar male rats were randomly assigned to two groups: controls (n=8), and REM sleep deprived rats (n=8). REM sleep deprivation was elicited using the 'inverted flower pot' technique. Four different experiments were performed to assess the sensitivity to mechanical (vocalization threshold in paw pressure), thermal (tail withdrawal latency in hot water immersion), electrical (envelope of 2nd peep in tail shock test) and chemical (analgesic behavior in formalin test) noxious stimuli. All experiments were performed over a 5-day period with baseline (day 1, day 2) in a dry environment and REM sleep deprivation (day 3, day 4 and day 5) in a wet environment. Under wet conditions, vocalization threshold in the paw pressure test (-20%, P=0.005), and tail withdrawal latency in the hot water immersion test (-21%, P=0.006) were significantly lower, and the envelope of 2nd peep in the tail electrical shock was significantly greater (+78%, P=0.009), in REM sleep deprived rats compared to controls. However, under wet conditions the mean duration of nociceptive behaviors in the formalin test did not differ between the two groups. In conclusion, REM sleep deprivation induces a significant increase in the behavioral responses to noxious mechanical, thermal and electrical stimuli in rats.