Relationship between compliance with management target values and renal prognosis in multidisciplinary care for outpatients with chronic kidney disease.

BACKGROUND: Although multidisciplinary care (MDC) is necessary for controlling chronic kidney disease (CKD), its impact on compliance with management target values in the CKD guidelines remains unclear. This study was designed to clarify the relationship between compliance with management target values and renal prognosis in CKD outpatients who received MDC. METHODS: There were 255 outpatients with pre-dialysis CKD who received MDC. Achievement rates of systolic, and diastolic blood pressure, hemoglobin, uric acid, low-density lipoprotein cholesterol, and hemoglobin A1c values determined according to CKD guidelines were compared before and 12 months after MDC. In addition, after dividing achievement rates of the target values at 12 months after MDC into four groups (A < 30% ≤ B < 60% ≤ C < 80% ≤ D), dialysis initiation and renal survival rates were compared. RESULTS: There was a significant increase in the overall achievement rate from 62.8 to 69.1% (p < 0.001). The higher the achievement rate after MDC, the lower the dialysis initiation rate (A 72.7%, B 35.3%, C 20.5%, D 8.2%, p < 0.001). There was also a significantly higher renal survival rate (p < 0.001). These findings suggest that MDC for CKD raised awareness of health literacy, and improved the achievement rate of target values. Furthermore, the higher the achievement rate, the later the initiation of dialysis, which led to improvement of renal survival. CONCLUSIONS: MDC can improve compliance with management target values for CKD, suggesting that it may improve renal prognosis.

Effect of multidisciplinary care of dialysis initiation for outpatients with chronic kidney disease.

BACKGROUND: The aim of comprehensive multidisciplinary care (MDC) by the chronic kidney disease (CKD) team is not only to prevent worsening renal function, but also provide education on the selection of renal replacement therapy (RRT) by shared decision making (SDM). The purpose of this study was to examine the effects of MDC for predialysis outpatients on dialysis therapy, especially with regard to peritoneal dialysis (PD). METHODS: This study evaluated 112 CKD patients who underwent dialysis at our hospital starting from 2012, with 53 outpatients receiving MDC from the CKD team and 59 outpatients not receiving MDC. Annual decreases in the estimated glomerular filtration rates (ΔeGFR), the duration from the time of intervention to dialysis initiation, the urgent dialysis rate using a temporary catheter, and the PD selection rate were compared and examined between the two groups. The ΔeGFR, the duration from intervention to PD initiation, and the PD retention rate were compared between 18 PD patients in the MDC group and 10 PD patients in the non-MDC group. RESULTS: The MDC group had a significantly lower ΔeGFR, significantly longer duration, and a significantly lower urgent dialysis initiation rate versus the non-MDC group. Moreover, there was a significantly higher PD selection rate, significantly prolonged duration, and significantly higher PD retention rate. CONCLUSIONS: Multidisciplinary CKD team care for outpatients is effective in delaying the progression of CKD and avoiding the initiation of urgent dialysis; contributing to improved PD selectivity and continuity by SDM.

Neoline, an active ingredient of the processed aconite root in Goshajinkigan formulation, targets Nav1.7 to ameliorate mechanical hyperalgesia in diabetic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Goshajinkigan (GJG), a traditional Japanese Kampo formula, has been shown to exhibit several pharmacological actions, including antinociceptive effects. Processed aconite root (PA), which is considered to be an active ingredient of GJG, has also been demonstrated to have an ameliorative effect on pain, such as diabetic peripheral neuropathic pain. We recently identified neoline as the active ingredient of both GJG and PA that is responsible for its effects against oxaliplatin-induced neuropathic pain in mice. AIM OF THE STUDY: In the present study, we investigated whether GJG, PA, and neoline could inhibit Nav1.7 voltage-gated sodium channel (VGSC) current and whether neoline could ameliorate mechanical hyperalgesia in diabetic mice. MATERIALS AND METHODS: To assess the electrophysiological properties of GJG extract formulation, powdered PA, and neoline on Nav1.7 VGSCs, whole-cell patch clamp recording was performed using human HEK293 cells expressing Nav1.7 VGSCs. In addition, the ameliorative effects of neoline on diabetic peripheral neuropathic pain were evaluated using the von Frey test in streptozotocin (STZ)-induced diabetic model mice. RESULTS: GJG extract formulation significantly inhibited Nav1.7 VGSC peak current. Powdered PA also inhibited Nav1.7 VGSC peak current. Like GJG and PA, neoline could inhibit Nav1.7 VGSC current. When diabetic mice were treated with neoline by intraperitoneal acute administration, the mechanical threshold was increased in diabetic mice, but not in non-diabetic mice, in a behavioral study. CONCLUSION: These results suggest that neoline might be a novel active ingredient of GJG and PA that is one of responsible ingredients for ameliorating mechanical hyperalgesia in diabetes via the inhibition of Nav1.7 VGSC current at least.

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model.

OBJECTIVE: Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine. METHOD: Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis. RESULTS: Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus. CONCLUSION: Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

A combination of mirtazapine and milnacipran augments the extracellular levels of monoamines in the rat brain.

Mirtazapine, an antidepressant, antagonizes α(2)-adrenergic autoreceptors and heteroreceptors, which leads to enhanced noradrenergic and serotonergic transmission without inhibiting monoamine transporters. Using a microdialysis technique, we investigated whether co-administration of mirtazapine and a serotonin noradrenaline reuptake inhibitor (SNRI), milnacipran, augments the effects of each drug on the extracellular levels of monoamines by pharmacological synergy. Mirtazapine increased the extracellular levels of noradrenaline and serotonin in the dorsal hippocampus. In contrast, it increased the levels of noradrenaline and dopamine without changing serotonin levels in the prefrontal cortex. Milnacipran increased the levels of all monoamines evaluated in both areas, and the combined treatment with mirtazapine augmented these changes. The combined treatment with idazoxan, an α(2) adrenoceptor antagonist, and milnacipran also increased all monoamine levels in the prefrontal cortex. Ketanserin, a serotonin 5-HT(2A) receptor antagonist, showed no effect in combination with milnacipran, while SB242084, a 5-HT(2C) receptor antagonist, augmented the effects of milnacipran on the levels of serotonin and dopamine in the prefrontal cortex. These results suggest that combined treatment with mirtazapine and milnacipran augments the extracellular levels of noradrenaline, serotonin and dopamine through the blockade of α(2) adrenoceptors without regional specificity, whereas mirtazapine enhances serotonergic transmission in a region-specific manner. 5-HT(2C) receptor antagonism may also partly contribute to the amplification effects of mirtazapine on serotonin and dopamine levels. These neurochemical changes could play a role in reported advantageous clinical effects in patients treated with an SNRI and mirtazapine.

Investigation of the histamine H3 receptor binding site. Design and synthesis of hybrid agonists with a lipophilic side chain.

As a part of our search for novel histamine H3 receptor agonists, we designed and synthesized hybrid compounds in which the lipophilic (4'-alkylphenylthio)ethyl moiety of a novel H3 receptor agonist, 4-(2-(4'-tert-butylphenylthio)ethyl)-1H-imidazole (1), was incorporated into N(alpha)-methylhistamine, immepip, and immethridine derivatives. These hybrid compounds were expected to interact concurrently with the histamine-binding site and a putative hydrophobic region in the H3 receptor. Among them, piperidine- and pyridine-type derivatives displayed partial agonist activity, and (S)-4-(1-(1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenylthio)ethyl)piperidine (36) was identified as a potent H3 agonist. We performed computational docking studies to examine the binding mode of the agonists. The results indicated that immepip interacts with the key residues, Asp114 and Glu206, in a different manner from histamine. The binding mode of 36 to these residues is similar to that of immepip, and the lipophilic tail of 36 has an additional interaction with a hydrophobic region in transmembrane helix 6 of the receptor. These results indicated that 36 served as a useful tool for studies on receptor-agonist interactions and drug design.

Synthesis and structure-activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor.

4-((1H-imidazol-4-yl)methyl)-1-aryl-piperazine and piperidine derivatives were designed and synthesized as candidate human histamine type 3 agonists. The piperazine derivatives were found to have low (or no) affinity for human histamine H3 receptor, whereas the piperidine derivatives showed moderate to high affinity, and their agonistic activity was greatly influenced by substituents on the aromatic ring. Among the piperidine-containing compounds, 17d and 17h were potent human histamine H3 receptor agonists with high selectivity over the closely related human H4 receptor. Our results indicate that appropriate conformational restriction, that is, by the piperidine spacer moiety, favors specific binding to the human histamine H3 receptor.

Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice.

The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an alkylated benzene rings maintained or increased the H3R binding affinity. The most potent compound, 4-(2-(4-tert-butylphenylthio)ethyl)-1H-imidazole, possessed in vivo agonistic activity, decreasing brain N(tau)-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the mouse resident-intruder test.

Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic.

RATIONALE: Histamine H3 receptor functions as a presynaptic auto- and hetero-receptor on histaminergic and non-histaminergic neurons in the brain regulating the synaptic release of numerous neurotransmitters. Therefore, the ligands for this receptor have been proposed to be of therapeutic interest for the treatment of various neuropsychiatric disorders. At present, however, the psychopharmacological profiles of H3 ligands, particularly H3 agonists, have not been extensively studied. OBJECTIVE: The present study investigated the anxiolytic-like profiles of H3-selective agonists in a variety of classical (benzodiazepine-sensitive) and atypical (antidepressant-effective) animal models of anxiety. Comparator drugs used were diazepam and both fluvoxamine and desipramine in the former and latter models, respectively. RESULTS: H3 agonist R-alpha-methylhistamine and immepip were inactive in rat elevated plus maze test and Vogel type conflict test where diazepam (5 mg/kg) produced significant anxiolytic-like effects. Meanwhile, these H3 agonists (10-30 mg/kg) significantly reduced isolation-induced vocalizations in guinea pig pups and isolation-induced aggressive behavior in mouse resident-intruder test. Moreover, in rat conditioned fear stress test, R-alpha-methylhistamine (30 mg/kg) and immepip (10 mg/kg) significantly decreased freezing time, which were completely reversed by concomitant treatment with H3 antagonist, thioperamide (10 mg/kg). In contrast to the limited efficacy obtained with desipramine (30 mg/kg), fluvoxamine (20-60 mg/kg) exhibited anxiolytic-like effects in all the latter three atypical models. CONCLUSIONS: These data suggest that the H3 agonists may have anxiolytic-like effects similar to those of selective serotonin reuptake inhibitors but not benzodiazepine anxiolytics and represent a novel strategy for the treatment of some anxiety disorders in which selective serotonin reuptake inhibitors are prescribed.

Anxiolytic-like profile of mirtazapine in rat conditioned fear stress model: Functional significance of 5-hydroxytryptamine 1A receptor and alpha1-adrenergic receptor.

Mirtazapine is an antidepressant with a unique mechanism of action and has been categorized as a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA). Although numerous clinical trials suggested the usefulness of mirtazapine for not only major depressive disorders but also a variety of anxiety disorders, efficacy studies in animal anxiety models have been rarely reported. The present study investigated a potential anxiolytic-like profile of mirtazapine in rat conditioned fear stress model. A 5-hydroxytryptamine (5-HT) 1A receptor partial agonist, buspirone (1-5 mg/kg) exhibited a significant reduction in freezing time, and its maximal effect was reversed by a selective 5-HT(1A) antagonist, WAY-100635 (1 mg/kg). Mirtazapine (1-10 mg/kg) also reduced the freezing time in a dose-related fashion, a substantial proportion (approx. 50%) of which was likewise antagonized by WAY-100635 (1 mg/kg). Mianserin (1-30 mg/kg), a structural analogue for mirtazapine, was ineffective. Furthermore, co-administration of alpha1 adrenoceptor antagonist, prazosin (0.03 mg/kg) completely reversed mirtazapine (10 mg/kg)-induced reduction of freezing time. These findings represent the first demonstration that the anxiolytic-like action of mirtazapine involves activation of 5-HT(1A) receptor and alpha1 adrenoceptor to different extents, and are compatible with one aspect of mirtazapine's pharmacological profile as NaSSA.

Temporal strength changes from resistance exercise and albuterol on unloaded muscle.

To assess unloaded knee extensor temporal strength changes, healthy subjects without asthma performed 40 continuous days of unilateral limb suspension, whereby their left leg refrained from normal weight-bearing and ambulatory activity. During the 40-day period, subjects performed resistance exercise (REX) with their unloaded leg on an inertial resistance ergometer and, as part of a double-blind design, consumed the maximal oral therapeutic dosage of albuterol (i.e., 16 mg.d) or a placebo (i.e., lactose) with no crossover. Workout data were partitioned into 4 10-day periods that ran consecutively. Dependent strength variables included concentric total work, eccentric total work, concentric average power (CAP), and eccentric average power (EAP). Dependent variables were analyzed with 5 (time) x 2 (group) x 2 (gender) mixed factorial analyses of variance and the Tukey honestly significant difference test. Concentric total work, CAP, and EAP each demonstrated a time-group-gender (p < 0.05) interaction. Female REX-placebo subjects had the greatest percentage of unloaded knee extensor strength loss. However, female REX-albuterol subjects fared best throughout the 40-day period and incurred significant unloaded knee extensor strength gains. Differences in strength changes between male and female REX-albuterol subjects was likely due to the higher relative dosage administered to the latter, as body mass showed a gender (i.e., men > women) effect. Future research may elucidate the ideal dose-response relationship for REX-albuterol treatment for use aboard manned space flights and in other disuse models. Coaches and practitioners should carefully examine their sport-governing bodies' rules on albuterol administration and give the drug only if an athlete's health warrants such treatment.

Albuterol and exercise effects on ankle extensor strength during 40 days of unloading.

INTRODUCTION: In-flight ankle extensor (AEXT) strength losses are an impediment to long-term space travel. The current study examines if albuterol helps resistance exercise (RE) abate AEXT strength loss incurred over a 40-d unloading period. METHODS: All subjects (21 men, M; 15 women, W) performed unilateral limb suspension (ULLS) and exercised on a flywheel ergometer (FERG) with their otherwise unloaded AEXT. With a double-blind randomization assignment, subjects either received placebo (PLA, lactose) or albuterol (ALB, 16 mg x d(-1)) via four daily capsule doses with no crossover. FERG calf press workouts done 3 d x wk(-1) provided concentric and eccentric total work (CTW, ETW) and average power (CAP, EAP) measures. Workout data from the 40-d period were averaged and partitioned into four consecutive 10-d periods. Data were compared with a 2 (gender) x 2 (treatment) x 4 (time) MANCOVA, with day 0 AEXT strength measurements and a drug/body mass ratio as covariates. RESULTS: CTW and ETW days 11-20, 21-30, and 31-40, as well as CAP and EAP days 11-20 and 21-30 showed the following significant results: ALB-W > ALB-M, PLA-M > PLA-W. CAP and EAP days 31-40 showed the following significant results: ALB-W, ALB-M, PLA-M > PLA-W. DISCUSSION: The combined RE-albuterol treatment most likely evoked unloaded AEXT strength gains in women due to heightened myofibril sensitivity for Ca+2. Despite a drug/body mass covariate, gender-related differences should be interpreted with caution. Future work should compare absolute and relative beta2 agonist dosages on gender-related muscle mass and strength changes.

Desensitization of 5-HT2A receptor function by chronic administration of selective serotonin reuptake inhibitors.

We have previously shown that chronic treatment with selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and paroxetine, attenuated m-chlorophenylpiperazine (mCPP)-induced hypolocomotion in rats. The effect of these SSRIs on the response to mCPP is thought to be caused by the desensitization of 5-HT2C receptor function. In the present study, we investigated whether chronic administration of SSRI could reduce another pharmacological response to mCPP in rats, i.e., the induction of the secretion of corticosterone. The mCPP-induced increase in the serum concentration of corticosterone was not blocked by the 5-HT2C antagonist SB242084, but was blocked by the 5-HT2A antagonist ketanserin. Chronic treatment with fluvoxamine and paroxetine attenuated the response to mCPP, while these SSRIs had no effects in control rats. These results suggest that the desensitization of 5-HT2A receptor function occurs in the same way as that of 5-HT2C receptor function through chronic treatment with either fluvoxamine or paroxetine as a consequence of prolonged exposure to elevated levels of serotonin. The hypersensitivity of 5-HT2A receptors is observed in depressed patients, and chronic treatment with many antidepressants such as tricyclic antidepressants have been reported to reduce 5-HT2A receptor density and/or efficacy. The desensitization of 5-HT2A receptor function might contribute to the therapeutic mechanism of action of these SSRIs, as seen with other classes of antidepressants.

[Role of the serotonergic nervous system in anxiety disorders and the anxiolytic mechanism of selective serotonin reuptake inhibitors].

Some selective serotonin reuptake inhibitors (SSRIs) have recently been approved for the treatment of anxiety disorders such as obsessive-compulsive disorder, panic disorder and social anxiety disorder, and they are considered first-line treatment for anxiety disorders in Japan as well as in other countries. Previous clinical studies have suggested that the 5-HT2C receptors in subjects with anxiety disorders are hypersensitive. We recently reported that chronic treatment with fluvoxamine or paroxetine desensitized 5-HT2C receptor function. The desensitization of 5-H T2C receptor function has also been reported with other SSRIs and is considered to be a common mechanism of action of SSRIs in the treatment of anxiety disorders. In addition, some studies have suggested that 5-HT2A receptors and 5-HTIA receptors participate in anxiety disorders and the therapeutic mechanism. Both clinical studies and animal studies have indicated that the amygdala plays an essential role in anxiety and fear response. Thus, it may be important to elucidate functional changes in these 5-HT receptor subtypes in brain regions including the amygdala under the chronic administration of SSRIs to understand the anxiolytic mechanism of SSRIs.

A comparison of isoload and isoinertial leg press training on bone and muscle outcomes.

The subjects of this study (n = 20; 16 women, 4 men) performed 10 weeks of leg press training using one of two exercise modes (isoload or isotonic) with no crossover. Their workouts, which were performed 3 times per week, involved 4 sets of 8 repetitions with maximal voluntary effort. Testing was performed pre- and posttraining to examine bone and muscle changes. Posttraining, both groups incurred significant concentric knee extensor strength and leg muscle mass gains, while the percentage of body fat and total body fat mass each decreased. Leg and total body bone mineral densities showed group-by-time interactions, as isoload exercise caused posttraining gains, while isoinertial values were unchanged. Bone resorption assays showed insignificant changes. Isoload training likely involved greater strain magnitudes and rates to evoke higher peak forces and osteogenesis. Transduction of the training stimulus may have involved (a) formation in response to microdamage, and (b) piezoelectric-induced potentials that stimulated site-specific osteoblast activity and osteogenesis.

Albuterol aids resistance exercise in reducing unloading-induced ankle extensor strength losses.

While resistance exercise (REX) reduces ankle extensor (AE) mass and strength deficits during short-term unloading; additional treatments, concurrently administered with REX, are required to attenuate the greater losses seen with longer unloading periods. Subjects performed left leg REX, which otherwise refrained from ambulatory and weight-bearing activity for 40 days, while randomized to a capsule (placebo, albuterol) dosing regimen with no crossover to note whether albuterol helps REX mitigate unloading-induced AE losses. A third group of subjects served as unloaded controls. On days 0, 20, and 40, the following data were collected from the left leg: calf cross-sectional area and AE strength measures. Cross-sectional area was estimated using anthropometric methodology, whereas AE strength data were obtained from eight unilateral calf-press repetitions on an inertial-based REX device. Repeated-measures mixed-factorial 3 x 3 analyses of covariance, with day 0 values as a covariate, revealed group x time interactions for the strength variables eccentric total work (ETW) and average power (EAP). Tukey's honestly significant difference shows REX-placebo subjects incurred significant ETW and EAP losses by day 40, whereas the REX-albuterol treatment evoked strength gains to those same variables without concurrent muscle accretion. Corresponding concentric variables did not display similar changes. Day 40 control data significantly declined for many variables; relative to the REX-albuterol treatment, some losses were significant after 20 days. ETW and EAP gains to unloaded AE may be due to one or more mechanisms. Continued research identifying mechanisms responsible for such changes, as well as the safety of REX-albuterol administration in other models, is warranted.

Can albuterol help resistance exercise attenuate unloading-induced bone loss?

Hind-limb-suspended rats incur attenuated bone loss with beta(2)-agonists, and humans note similar changes with concurrent resistance exercise. To examine if the beta(2)-agonist albuterol helps resistance exercise reduce unloading-induced bone loss, human subjects performed 40 days of unilateral limb suspension with their left legs, otherwise refraining from normal ambulatory activity. While performing left leg strength training 3 days.week(-1), subjects received a concurrent placebo or albuterol (16 mg.day(-1)) treatment. Left leg muscle and bone changes were analyzed with 2 x 2 analyses of covariance (ANCOVAs). Mechanical loading values were calculated from workouts and compared using a 2 x 5 analysis of variance (ANOVA) and a Tukey post hoc test. The resistance exercise-albuterol assignment evoked significant (p < 0.05) left leg bone mineral content (BMC) gains (+2.24%) after 40 days. During the final unloading days, the resistance exercise-placebo group's mechanical loading data declined (-13.91%) significantly (p < 0.05) versus initial values. A resistance exercise-albuterol assignment likely increased BMC by maintaining the mechanical loading stimulus.

Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats.

The effectiveness of fluvoxamine, a selective serotonin re-uptake inhibitor (SSRI), in the treatment of anxiety disorders, such as obsessive-compulsive, panic and social anxiety disorders, has been confirmed in clinical studies. The hypersensitivity of 5-HT2C receptors has been reported in subjects with these disorders, and SSRIs have been suggested to have therapeutic effects in such cases through the desensitization of the 5-HT2C receptor function. In the present study, we investigated whether chronic administration of fluvoxamine desensitizes 5-HT2C receptors using a putative in vivo rat model of 5-HT2C receptor function. Acute treatment with fluvoxamine or another SSRI, paroxetine, reduced spontaneous locomotion, as observed with the administration of m-chlorophenylpiperazine (mCPP). This effect of fluvoxamine was reversed by treatment with a selective 5-HT2C receptor antagonist, SB 242084. On the other hand, chronic treatment with fluvoxamine or paroxetine inhibited mCPP-induced hypolocomotion, while they had no effects in control rats. In addition, chronic treatment with these drugs had no effects on the mCPP concentration in the rat brain. These results suggest that 5-HT2C receptors are desensitized by chronic treatment with fluvoxamine, as well as paroxetine. Thus, the clinical efficacy of fluvoxamine on anxiety disorders might involve the normalization of the 5-HT2C receptor function.

Albuterol helps resistance exercise attenuate unloading-induced knee extensor losses.

INTRODUCTION: While resistance exercise (REX) attenuates knee extensor (KE) mass and strength deficits during short-term unloading, additional treatments concurrently administered with REX are required to reduce the greater losses seen with longer periods of unloading. METHODS: To determine whether albuterol helps REX attenuate unloading-induced KE losses, two groups of subjects strength trained their left thigh three times per week, and otherwise refrained from ambulatory and weight-bearing activity for 40 d while receiving a capsule dosing treatment (albuterol, placebo) with no crossover. A third group served as unloaded controls (CTRL). On days 0, 20, and 40, the following data were collected from the nonweight-bearing (left) thigh: cross-sectional area (CSA); integrated electromyography (IEMG); and concentric and eccentric KE strength measures. Thigh CSA was estimated using anthropometric methodology. IEMG was used to provide root mean square (RMS) values from submaximal (100 nm) and maximal isometric contractions. Concentric and eccentric strength were measured from eight-repetition unilateral leg press sets. RESULTS: Repeated-measures mixed-factorial 3 x 3 ANCOVAs with day 0 values as a covariate showed group by time interactions for concentric and eccentric total work (CTW, ETW). Tukey's post hoc test showed REX-albuterol evoked significant (p < 0.05) day 40 CTW and ETW gains vs. within-group day 0 and within-time REX-placebo and CTRL values. By days 20 and 40, CTRL subjects incurred significant decrements. CONCLUSIONS: Albuterol augmented the effects of REX to increase CTW and ETW. Research identifying possible mechanisms responsible for such changes, as well as the safety of REX-albuterol administration in other models, is warranted.