Pretreatment Intervals Research Articles

Outcomes of Cognitive-Behavioral Treatment for Insomnia on Insomnia, Depression, and Fatigue for Individuals with Multiple Sclerosis: A Case Series.

This clinical case series examined outcomes of cognitive-behavioral therapy for insomnia (CBT-I) in individuals with multiple sclerosis (MS). Current literature links insomnia with higher rates of depression and fatigue in individuals with MS. However, no research to date evaluates a targeted psychotherapeutic intervention for insomnia in this population. Eleven individuals with a diagnosis of MS and insomnia participated in individual or group-based CBT-I sessions at the Cleveland Clinic Sleep Disorders Center between 2008 and 2013. A medical record review examined these individuals' self-reported experiences of insomnia, depression, and fatigue at the preintervention and postintervention levels using the Insomnia Severity Index, nine-item Patient Health Questionnaire, and Fatigue Severity Scale. Total sleep time was also reported at pretreatment and posttreatment intervals. Overall, participants reported improvements regarding insomnia, fatigue, and depression after CBT-I. Total sleep time also increased by an average of 1.5 hours. Despite overall improvement, symptoms of fatigue, insomnia, and depression persisted, at varying levels, for most participants. These results strongly suggest that CBT-I may serve as an effective clinical intervention for individuals with MS who report symptoms of insomnia. Given the considerable overlap of experiences of insomnia, depression, and fatigue in people with MS, CBT-I may also be helpful in identifying areas that may require additional clinical intervention for persistent symptoms of depression and fatigue. Further research is necessary.

Pretreatment changes in drinking: relationship to treatment outcomes.

Pretreatment changes in alcohol use challenges the assumption that the major portion of the change process occurs after treatment entry. Greater understanding of the behavior change process prior to treatment has the potential to improve our understanding of behavioral changes during treatment. In this study, participants (N = 45) were recruited for a clinical trial examining multiple mechanisms of change in cognitive-behavioral treatment for alcohol dependence. Using data from both baseline and end of treatment assessments, several pretreatment intervals were created (e.g., a 2-week pre-phone call interval, phone call to baseline assessment, baseline assessment to first treatment). To examine pretreatment changes in drinking, percent days abstinent and drinks per drinking day were analyzed using multilevel growth curve modeling and repeated-measures ANOVAs. Initial examination of the data revealed significant increases in percent days abstinent and decreases in drinks per drinking day during the pretreatment intervals. Follow-up analyses also suggested that the majority of change in drinking occurs between the phone call and baseline assessment. Further examination of the data revealed two distinct patterns of pretreatment change: (a) rapid changers who maintained changes during the course of treatment and (b) gradual changers who changed more gradually during the course of treatment. Analyses revealed that rapid changers had significantly higher rates of abstinence and lower drinks per drinking day at 90 days posttreatment compared with gradual changers. Overall, the data suggest that a more systematic investigation of pretreatment changes in alcohol use is warranted. Future studies may yield insights resulting in more efficient treatment delivery and adaptations to treatment based on an individual's pretreatment change status.

Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self-administration in rats

Despite the high prevalence of use of methamphetamine (METH), there is no FDA-approved pharmacological treatment available currently for METH addiction. The vesicular monoamine transporter (VMAT2) has been proposed as a novel target to treat METH abuse. GZ-793A, a lobelane analog and selective VMAT2 inhibitor, has been shown previously to decrease METH self-administration specifically when administered via the subcutaneous route in rats. Since oral administration is the preferred clinical route, the present experiments determined if oral administration of GZ-793A would decrease specifically METH self-administration. Experiments 1 and 2 assessed the dose-effect functions of oral administration of GZ-793A (30–240mg/kg) on intravenous METH self-administration and food-maintained responding, respectively. Experiments 3 and 4 assessed the time-course (20–180min pretreatment) of oral administration of GZ-793A on METH self-administration and food-maintained responding, respectively. Oral administration of GZ-793A dose-dependently decreased METH self-administration, with the highest dose (240mg/kg) producing an 85% decrease compared to control baseline. The decrease in METH self-administration produced by GZ-793A (120mg/kg) lasted at least 180min. In contrast, GZ-793A failed to alter food-maintained responding at any of the doses or pretreatment intervals tested. The oral effectiveness and the specificity of GZ-793A to decrease methamphetamine self-administration support the feasibility of developing VMAT2 inhibitors as treatments for METH abuse.

How Substance Abuse Recovery Skills, Readiness to Change and Symptom Reduction Impact Change Processes in Wilderness Therapy Participants

Previous research has demonstrated that wilderness therapy is effective, yet very few studies have attempted to discern quantitative factors responsible for change that occur during wilderness therapy. This study aimed to tease apart specific factors that impact client progress and outcome. A sample of 189 adolescent clients in a wilderness therapy program completed the Youth Outcome Questionnaire Self-Report, the University of Rhode Island Change Assessment (URICA), and the Adolescent Relapse Coping Questionnaire (ARCQ) at pre-treatment, post-treatment, and follow-up intervals. Analysis of the complete data sets of 41 adolescents indicated that client Y-OQ scores improved significantly at post and follow-up assessments. URICA scores were not significantly related to such changes, while the ARCQ subscale of abstinence-focused coping strategies accounted for a significant proportion of the variance in Y-OQ change. These results indicate that clients in wilderness therapy do not necessarily need to want to change in order to do so. Furthermore, helping adolescents in wilderness therapy settings gain abstinence-focused coping strategies may be the most effective tool to improve treatment outcomes.

Does Hormone Therapy Exacerbate the Adverse Effects of Radiotherapy in Men With Prostate Cancer? A Quality of Life Study

We examined whether short course androgen deprivation therapy as an adjunct to radiotherapy would impact health related quality of life outcomes in patients with localized prostate cancer treated definitively with external beam radiation therapy or permanent brachytherapy. From 1999 to 2003 patients were enrolled in a prospective study at our institution and completed validated health related quality of life surveys at defined pretreatment and posttreatment intervals. A total of 81 men received radiotherapy alone and 67 received radiotherapy plus androgen deprivation therapy. Median androgen deprivation therapy duration was 4 months. Univariate and multivariate analysis was done to compare time to return to baseline in 6 distinct health related quality of life domains. On univariate analysis the radiotherapy plus androgen deprivation therapy group achieved baseline urinary symptoms more rapidly than the radiotherapy group (5 months, p = 0.002). On multivariate analysis time to return to baseline in any of the 6 health related quality of life domains was not significantly affected by adding androgen deprivation therapy. Factors associated with longer time to return to baseline mental composite scores on multivariate analysis included nonwhite ethnicity, cerebrovascular disease history and alcohol abuse history. Men treated with permanent brachytherapy monotherapy experienced longer time to return to baseline for urinary function and symptoms. Baseline sexual function and lack of a partner were associated with longer time to sexual recovery. Adding androgen deprivation therapy to definitive radiotherapy does not significantly impact the time to return to baseline health related quality of life. These data may be valuable for patients and physicians when weighing the toxicity and benefits of androgen deprivation therapy when added to definitive radiotherapy.

Corticosterone pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis activity via multiple actions that vary with time, site of action and de novo protein synthesis

Glucocorticoid regulation of the hypothalamic-pituitary-adrenal (HPA) axis is believed to depend on multiple actions operative within discrete time domains. However, the underlying cellular and molecular mechanisms for those glucocorticoid actions remain undetermined. Moreover, there is absence of in vivo studies examining whether there are multiple glucocorticoid effects on HPA axis-related function within an intermediate feedback time frame (1-3 h after glucocorticoid elevation), and whether those effects depend on de novo protein synthesis. We examined in rats the effects of protein synthesis inhibition on HPA axis response to restraint (15 min) after 1 and 3 h phasic corticosterone (CORT) pretreatment. We measured HPA axis hormones (ACTH and CORT) and gene expression in the paraventricular nucleus (c-fos and crh genes), as well as gene expression in the anterior and intermediate pituitaries (c-fos and pomc genes). Both CORT pretreatment intervals produced inhibition of stress-induced ACTH secretion, but no inhibition was observed in the presence of protein synthesis inhibition. CORT pretreatment produced inhibitory effects on stress-induced gene expression that varied for each gene depending on the anatomical site, pretreatment time, and protein synthesis dependency. Taken together, the ACTH and gene expression patterns support the presence of multiple independent glucocorticoid actions initiated during the intermediate glucocorticoid negative feedback phase. Moreover, we conclude that those effects are exerted predominantly on the intrinsic anatomical elements of the HPA axis, and some of those effects depend on CORT induction of the expression of one or more regulatory gene products.

Heart Rate Variability Modulation After Manipulation in Pain-Free Patients vs Patients in Pain

Background The purpose of this study was to examine heart rate variability (HRV) in the presence or the absence of pain in the lower back, while receiving one chiropractic treatment at L5 from either a manually assisted mechanical force (Activator) or a traditional diversified technique spinal manipulation. Methods A total of 51 participants were randomly assigned to a control (n = 11), 2 treatment, or 2 sham groups (n = 10 per group). Participants underwent an 8-minute acclimatizing period. The HRV tachygram (RR interval) data were recorded directly into a Suunto watch (model T6; FitzWright Company Ltd, Langley, British Columbia, Canada). We analyzed the 5-minute pretreatment and posttreatment intervals. The spectral analysis of the tachygram was performed with Kubios software. Results All groups decreased in value except the control group that reacted in the opposite direction, when comparing the pretests and posttests for the high-frequency component. The very low frequency increased in all groups except the control group. The low frequency decreased in all groups except the sham pain-free group. The low frequency-high frequency ratio decreased in the treatment pain group by 0.46 and in the sham pain-free group by 0.26. The low frequency-high frequency ratio increase was 0.13 for the sham pain group, 0.04 for the control group, and 0.34 for the treatment pain-free group. The mean RR increased by 11.89 milliseconds in the sham pain-free group, 18.65 milliseconds in the treatment pain group, and 13.14 milliseconds in the control group. The mean RR decreased in the treatment pain-free group by 1.75 milliseconds and by 0.01 milliseconds in the sham pain group. Conclusion Adjusting the lumbar vertebrae affected the lumbar parasympathetic nervous system output for this group of participants. Adaptation in the parasympathetic output, reflected by changes in high frequency, low frequency, and very low frequency, may be independent of type of adjustment. Therefore, the group differences found in the modulation of the HRV would seem to be related to the presence or absence of pain. The autonomic nervous system response may be specific and sensitive to its effectors organ.

Effect of R3487/MEM3454, a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats

It is well established that nicotinic systems in the brain are critically involved in attentional processes in both animals and humans. The current study assessed the effects of a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist, R3487/MEM3454 (also referred to as R3487 or MEM 3454) on sustained attention in rats performing an operant visual signal detection task. The effects of R3487/MEM3454 were compared to those of the acetylcholinesterase inhibitor/nicotinic α7 allosteric positive modulator galanthamine. Adult female Sprague–Dawley rats were injected subcutaneously with R3487/MEM3454 (0.03, 0.1, 0.15, 0.3 and 0.6 mg/kg), galanthamine (0.25, 0.5, 1, 2 mg/kg) or vehicle 30 min before the attentional test. In the second study, the time-dependent effects of R3487/MEM3454 were assessed by injecting the compound (0.6 mg/kg, s.c.) at different pretreatment intervals (30, 60 or 90 min) before the start of the attentional task. Our results show a significant dose-effect for R3487/MEM3454 on percent hit accuracy performance without any significant alteration on percent correct rejection performance. In the time-dependent test, R3487/MEM3454 significantly increased the percent hit accuracy performance when animals were injected 60 min before the start of the attentional task. Administration of galanthamine failed to significantly increase percent hit accuracy performance and increasing the dose of galanthamine produced a decrease in percent correct rejection performance. The present findings with R3487/MEM3454 suggest that nicotinic α7 receptors and/or 5-HT3 receptors may play an important role in modulating sustained attention and that R3487/MEM3454 may have therapeutic potential in improving sustained attention in humans.

Muscarinic receptor antagonism causes a functional alteration in nucleus accumbens μ-opiate-mediated feeding behavior

Intra-nucleus accumbens (Acb) infusion of cholinergic muscarinic antagonist, scopolamine (10 μg/0.5 μl), markedly reduced fat intake elicited by intra-Acb treatment of the μ-opioid receptor agonist, DAMGO, with 30 min and 4 h pretreatment intervals. Intra-Acb scopolamine infusions also reduced food intake in food-deprived rats, but not water intake in water-deprived rats. Hence, Acb muscarinic manipulations exhibit some specificity for feeding, perhaps via interactions with the striatal opioid system.

Heart Rate Variability Modulation Produced by a Chiropractic Lumbar Adjustment

PURPOSE: The purpose of this study was to examine the heart rate variability (HRV) in the presence or the absence of pain in the lower back (L5), while receiving chiropractic care. METHODS: A total of 53 healthy subjects were randomly assigned to a control, 2 treatment or 2 sham groups (n = 10 per group). Subjects underwent an eight-minute acclimatizing period. The HRV tachygram (RR interval) data were recorded directly into a Suunto watch (model T6). We analyzed the five minute pre-treatment and post treatments intervals. The spectral analysis of the tachygram was performed with the Kubios Software (University of Kuopio, Finland). RESULTS: The HF component (0.15-0.40 Hz) in the pain-free group decreased significantly (p<0.05) from (Pre-treatment) 29.26 ± 17.16 Hz to (Post-treatment) 24.95 ± 19.73 Hz, and in the pain group increased significantly from 22.84 ± 16.7 Hz to 23.64 ± 19.44 Hz. The Mean R-R intervals in the pain-free grouping increased significantly from 822.32 ± 127.29 ms to 830.25 ± 127.82 ms and finally the VLF (0.0-0.04 Hz) of the pain grouping increased significantly from 46.71 ± 23.36 Hz to 49.43 ± 22.55 Hz. CONCLUSIONS: We found that pain is a factor in the directional change of the HF component of the HRV.

Effect of neck injection and handler visibility on behavioral reactivity of beef steers1

The use of the neck region as an injection site in cattle is becoming routine. Use of a blind may reduce aversive behavior caused by the presence of the person administering the injection. To evaluate whether cattle react to the proximity of the stockperson or to the actual injection, one hundred twenty 10-mo-old Angus steers (298 +/- 28 kg of BW; mean +/- SD) were assigned to 1 of 4 treatment groups using a partial crossover design (neck/sham injection x blind/no blind) replicated over 2 d (3 d apart). Steers were restrained for a total of 60 s in a squeeze chute, with treatment being administered 20 s after entry. Animal reactivity was rated using 2 scoring methods, including a visual and an electronic score, for three 20-s intervals (pre-treatment, treatment, and posttreatment intervals). Flight speed (m/s) was used as a measure of aversion to the treatments and was taken upon release from the chute. No interactions (P > 0.10) were observed between the blind and injection treatments for any of the measurements taken. No treatment or day effect on flight speed (2.7 vs. 2.6 m/s; P > 0.03) was observed; however, the correlation between days (r = 0.74; P < 0.001) was significant. Visual scores indicated that injected steers were more agitated during the treatment interval than were the sham injected steers (1.9 vs. 1.6, respectively; P = 0.01). However, no differences (P > 0.10) were found between injection and sham injection treatments for any of the electronic scores. Steers exposed to the blind had lower electronic reactivity scores (P < 0.05) than those not exposed to the blind, which was in contrast to the results obtained for the visual scores (P < 0.05). Discrepancies between reactivity scores may be due to the difficulty of accurately assessing minor animal responses using the visual method. The presence of a handler during an injection procedure could be a contributor to the aversion response observed in cattle undergoing routine neck injections, and use of a blind helped to reduce the reactivity of the steers.

Evaluation of Nd:YAG laser on partial oxygen saturation of pulpal blood in anterior hypersensitive teeth

Dentine hypersensitivity has of long been known to be a common clinical problem in dental practices. Lasers have recently come to play a prominent role in the treatment of this disorder. They might, however, cause dental pulp damage. This study was conducted to evaluate the effect of Nd:yttrium-aluminum-garnet (YAG) laser on partial oxygen saturation of pulpal blood in sensitive anterior teeth. In this clinical trial, 65 hypersensitive teeth were selected and randomly allocated to two groups. The study group involved Nd:YAG laser treatment, while no treatment was employed for the control group. Using a pulse oximetry system, evaluations were preformed of the partial oxygen saturation in the pulpal blood before, immediately after, 1 week after, and 1 month after the treatment. The results were analyzed using the SPSS software and repeated-measures analysis of variance and paired-samples t tests. The mean partial oxygen saturation of the blood was found to be 85.4% in the study group, which was not significantly different from that of the control group. No significant differences were observed in the control group between the means obtained from pretreatment and post-treatment intervals (P > 0.05). The Post-treatment partial oxygen saturation mean rose to 89.3% (P = 0.001) and remained constant throughout the following week after it. However, no significant differences were found between the pretreatment partial oxygen saturation mean and the same measurement 1 month after treatment (P = 0.702). Nd:YAG laser therapy for dentine desensitization of anterior teeth caused no persistent changes in the partial oxygen saturation of pulpal blood. It may, therefore, be concluded that the diffusion of heat induced by the Nd:YAG laser into the pulp within the limit of the desensitization parameters cause no irreversible damages in the dental pulp.

Effects of the long-lasting kappa opioid 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl] acetamide in a drug discrimination and warm water tail-withdrawal procedure

Although studies suggest that 2-(3,4-dichlorophenyl-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl] acetamide (DIPPA) has transient kappa-opioid-mediated agonist effects followed by long-lasting kappa-antagonist effects, its behavioral and pharmacological actions have not been systematically examined and there is evidence suggesting that some of its effects are species dependent. The purpose of this investigation was to examine the actions of DIPPA in different behavioral procedures and in three species. In a pigeon drug discrimination procedure, DIPPA and the kappa-opioids U50,488 and ICI-199441 substituted fully for the stimulus effects produced by spiradoline. For DIPPA, this effect was observed between 0.25 and 4 h after administration. In a warm water tail-withdrawal procedure, DIPPA failed to produce antinociception in rats or mice even when relatively high doses were tested using pretreatment intervals ranging from 0.25 to 24 h. In this procedure, DIPPA antagonized the effects of spiradoline and U50,488 in mice. In rats, DIPPA antagonized the effects of U50,488 but not those of spiradoline. Taken together, these results suggest that DIPPA may function as a low-efficacy kappa-opioid and have a long duration of action, and there may be some species differences in its behavioral profile. This profile of action, however, differs from other low-efficacy kappa-opioids.

2-Bromoethylamine, a Suicide Inhibitor of Semicarbazide-Sensitive Amine Oxidase, Increases Hydralazine Hypotension in Rats

Previous work has shown that inhibitors of the predominantly vascular enzyme semicarbazide-sensitive amine oxidase (SSAO) potentiate the hypotensive response to hydralazine, itself a SSAO inhibitor, in anesthetized rats. The present study was carried out to determine whether the recently described suicide SSAO inhibitor 2-bromoethylamine shares this effect. Hypotensive responses to hydralazine, 0.1 mg/kg IV, were obtained in chloralose-urethane-anesthetized rats, either unpretreated or receiving bromoethylamine at different doses and pretreatment intervals. Parallel experiments were run with semicarbazide, the prototypical hydrazine SSAO inhibitor. Both inhibitors potentiated hydralazine hypotension, bromoethylamine having a longer latency and a shorter duration of action than semicarbazide. High doses of bromoethylamine did not produce potentiation, a phenomenon attributed to SSAO inactivation by excess substrate and decreased formation by the enzyme of the inhibitor product. Experiments with combined administration of both inhibitors were also carried out. When semicarbazide was administered before bromoethylamine, potentiaton was prevented, apparently by a mechanism similar to the above; when it was given after the amine, potentiation was increased. This was attributed to enzyme inhibition by interaction with 2 different active sites. The charactertistics of hydralazine potentiation by bromoethylamine were considered compatible with the mechanism of SSAO inhibition by the amine.

Areas of Capsaicin-Induced Secondary Hyperalgesia and Allodynia Are Reduced by a Single Chiropractic Adjustment: A Preliminary Study

Introduction The aim of the study was to investigate the hypoalgesic effects of a single spinal manipulation treatment on acute inflammatory reactions and pain induced by cutaneous application of capsaicin. Methods Twenty healthy subjects participated in the experiment, which consisted of 2 sessions. In both sessions, following control measurements, topical capsaicin was applied to the right or left forearm to induce cutaneous inflammatory reactions. The cream was removed after 20 minutes. Then subjects received either spinal manipulation treatment (SMT) or “nonspinal manipulation treatment” (N-SMT), respectively. In control as well as pretreatment and posttreatment intervals, the following tests were performed: measurement of the areas of mechanical hyperalgesia and stroking allodynia, assessment of spontaneous pain, and measurement of blood flow. Results The results confirmed that topical capsaicin induced inflammatory reactions based on occurrence of hyperalgesia and allodynia, augmented pain perception, and increased blood flow following capsaicin application compared with the control session. When compared with N-SMT, spontaneous pain was rated significantly lower post-SMT ( P < .014). In addition, areas of both secondary hyperalgesia and allodynia decreased after SMT (hyperalgesia: P < .007; allodynia: P < .003). However, there was no significant treatment effect for local blood flow. Conclusion These results suggest hypoalgesic effects following a single SMT. As local vascular parameter was not affected by the single SMT, the hypoalgesic effects appear to be due to central mechanisms.

Preclinical modeling of improved amifostine (ethyol) use in radiation therapy

Amifostine (Ethyol) has been evaluated clinically as a radioprotective agent for the prevention of xerostomia and mucositis for patients receiving radiotherapy (RT). Currently, amifostine is approved for the prevention of xerostomia in head and neck cancer patients receiving RT when administered intravenously (IV) before RT. For the clinician, there would be several advantages to administering the drug subcutaneously and to being able to show its protective effects on mucositis. The authors have developed a rat RT model to examine the protective effects of amifostine after IV and subcutaneous (SC) administration in a mucositis model. Rats (5 per group) were given 200 mg/kg (human dose equivalent of approximately 1,300 mg/m(2)) of amifostine either IV or SC, and their head and neck regions were exposed to 15.3 Gy of gamma radiation 0.5, 2, 4, and 8 hours after amifostine administration. For 10 days after treatment, the oral cavities of the rats were examined for signs of mucositis. Mucosal erythema and mucosal edema were scored according to 0 through 5 and 0 through 2 scales, respectively, with the scores added to indicate overall mucositis. The average mucositis score for the untreated animals was 3.5. Rats were protected from mucositis up to 4 hours when given amifostine either IV or SC. Rats that received amifostine SC, but not IV, were protected from mucositis 8 hours after administration. Preliminary pharmacokinetic data have revealed slightly higher active metabolite (WR-1065) levels in the parotid gland and small intestine in the rats given amifostine SC compared with IV and equivalent levels in the plasma and kidney. The data showed that SC administration of amifostine gave radioprotection comparable to IV administration up to 4 hours before RT and may be more effective than IV administration at longer pretreatment intervals.

Pain models display differential sensitivity to Ca2+-permeable non-NMDA glutamate receptor antagonists.

Ca2+-permeable non-N-methyl-D-aspartate receptors are found in the spinal dorsal horn and represent a presumptive target for glutamatergic transmission in nociceptive processing. This study characterized the analgesic profile associated with the blockade of these spinal receptors by intrathecally delivered agents known to act at these receptors, the spider venom Joro toxin (JST) and philanthotoxin. Philanthotoxin (0.5, 2.5, or 5 microg) or JST (5 microg) was given spinally before thermal injury to the paw. JST (5 microg) was also given 10 min before subcutaneous formalin injection, after intraplantar administration of carrageenan, and to rats that were allodynic due to tight ligation of spinal nerves. Lower doses of JST (0.25 and 1.0 microg) were given before formalin injection and testing of thermal latencies. Thermal latencies were measured using a Hargreaves box, mechanical thresholds using von Frey hairs, and formalin response by means of counting flinches. Both agents blocked thermal injury-induced mechanical allodynia. JST (5 microg) given 1 h after carrageenan blocked induction of thermal hyperalgesia and mechanical allodynia. JST (5 microg) had no effect in the formalin test, on allodynia after spinal nerve ligation, or when given 3 h after carrageenan. The lowest dose (0.25 microg JST) at pretreatment intervals of 60-120 min resulted in modest hypoalgesia during phase 1 formalin and thermal testing. The behavioral effect of intrathecal Ca2+-permeable non-N-methyl-D-aspartate antagonists indicates an important role for this spinal receptor in regulating hyperalgesic states induced by tissue injury and inflammation and reveals an action that is distinct from those observed with other glutamate receptor antagonists.

Vitamin E analog modulates UVB-induced signaling pathway activation and enhances cell survival

We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinases 1 and 2 (ERK1/2) and p38 signaling pathways via reactive oxygen species, an effect that can be modulated by antioxidants. Trolox, a water-soluble vitamin E analog, is among the antioxidants that are currently being investigated for their preventive and protective potential against harmful effects of UV radiation to the skin. We found that Trolox inhibits both basal and UVB-induced intracellular H 2O 2 generation in primary keratinocytes in a concentration-dependent manner. Trolox did not significantly affect UVB-induced phosphorylation of EGFR. Stronger inhibition was observed for ERK1/2 activation at lower, and for p38 activation at higher, concentrations of Trolox added to cells before exposure to UVB. Similarly different effects were found with regard to length of pretreatment with Trolox before UVB exposure—increasing inhibition for ERK1/2 activation at shorter, and for p38 activation at longer, pretreatment intervals. UVB-induced c-jun-N-terminal kinase activation was potently suppressed by Trolox. Also, increasing the pretreatment time of Trolox decreased the rate of cell death following UVB. In conclusion, UVB-induced signaling pathway activation is differentially modulated by Trolox. Further investigation into the time-dependent biologic activation of Trolox and its metabolic products, and modulation of signal transduction with cell outcome should facilitate development of rational strategies for pharmacologic applications.

Cardiovascular effects of intravaginal misoprostol in the mid trimester of pregnancy

Objective: Our aim was to evaluate the cardiovascular effects of high-dose intravaginal misoprostol administration by means of transthoracic electrical bioimpedance monitoring. Study Design: Healthy women undergoing mid trimester pregnancy interruption with intravaginal misoprostol were eligible for this prospective observational study. Baseline blood pressure was obtained for 1 hour and transthoracic electrical bioimpedance monitoring was performed before misoprostol administration, 600 μg vaginally. Posttreatment assessments were made every 15 minutes for a total of 4 hours, with patients in a left lateral recumbent position. Heart rate, mean arterial pressure, cardiac index, stroke index, systemic vascular resistance index, and end-diastolic volume index were determined. Measurements were averaged for 30-minute intervals and reported as mean ± SD. Statistical analyses included the paired t test and repeated-measures analysis of variance. Results: Nine women consented to have transthoracic electrical bioimpedance monitoring, and no statistically significant changes in any of the measured cardiac parameters for the 4-hour monitoring interval were noted. Direct comparisons between the pretreatment and 2-hour posttreatment intervals (reported time peak of blood misoprostol levels) also revealed no significant differences in the cardiovascular index values. Conclusion: High-dose intravaginal misoprostol in the mid trimester does not alter maternal cardiac function as measured by transthoracic electrical bioimpedance. (Am J Obstet Gynecol 2000;183:1100-2.)

Characterization of the discriminative stimulus effects of GABA(A) receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions.

The current study was designed to extend our knowledge of the GABA(A) receptor system in mediating discriminative stimulus effects of ethanol in non-human primates. To characterize the discriminative stimulus effects of ethanol, pentobarbital, midazolam, muscimol and morphine in male and female monkeys under different ethanol training conditions. Adult male (n=8) and female (n=10) Macaca fascicularis monkeys were divided into four groups and trained to discriminate 1.0 g/kg ethanol (n=8) versus water or 2.0 g/kg ethanol (n=10) versus water in a 2x2 design with training dose and sex as main group factors. Solutions were administered intragastrically (20% ethanol w/v) and responding was maintained under a fixed-ratio schedule of food reinforcement. Dose-response determinations of ethanol, pentobarbital, midazolam, muscimol and morphine were made under the training condition of 30 min pretreatment interval. The ethanol pretreatment interval in training sessions was then increased to 60 min and the effects of ethanol, pentobarbital and midazolam were redetermined. Training dose influenced the ED50 of ethanol to produce substitution under both pretreatment intervals and pentobarbital to produce substitution under the 30-min pretreatment training interval. There were no group differences in sensitivity to midazolam. The potency of the ligands to produce ethanol substitution was consistent across groups with midazolam>pentobarbital>ethanol. There were no sex differences in substitution of the ligands for ethanol. Blood ethanol concentrations at the onset of ethanol training sessions were higher in the 2.0 g/kg groups and under longer pretreatment times, but were not different on the basis of sex. Pentobarbital and midazolam produce ethanol-like discriminative stimulus effects in male and female cynomolgus monkeys suggesting a significant GABA(A) component mediating the behavioral effects of ethanol. There was limited evidence that training dose of ethanol influenced substitution pattern of the GABA(A) ligands in cynomolgus monkeys, unlike previous findings in rats. Finally, there appear to be no sex differences in the profile of GABA(A) mechanisms involved in the discriminative stimulus effects of ethanol.