A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy.

BACKGROUND: We performed the first multiple dose study of remimazolam designed to assess both the feasibility of maintaining suitable sedation during colonoscopy and reversing the sedative effects of remimazolam with flumazenil. METHODS: Healthy volunteers received fentanyl followed by remimazolam for sedation during colonoscopy. Three dose groups of 15 volunteers each received remimazolam in increasing initial doses, plus top-up doses to maintain sedation for a 30-minute period. In a separate double-blind crossover part of the trial, 6 volunteers were sedated with a single high dose of remimazolam, followed by flumazenil or placebo to reverse the sedation. RESULTS: Successful sedation that was adequate for colonoscopy was achieved in >70% of subjects. After the procedure, subjects rapidly recovered to fully alert, with a median of <10 minutes overall. Failures were due to the inability to sedate or adverse events, with 1 subject failing due to hypotension (arterial blood pressure 80/40) and low SpO2 (<90%). There were no serious adverse events reported, and no events that were unexpected with the combination of a benzodiazepine and fentanyl. The study also showed that sedation was rapidly reversible (1.0 minutes flumazenil vs 10.5 minutes placebo) without resedation. CONCLUSIONS: Remimazolam has the attributes of a sedative drug, with success rates comparable with recent studies of other drugs. Remimazolam provided adequate sedation in 33 of 44 subjects undergoing colonoscopy, and its sedative effects were easily reversed with flumazenil.

A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics.

BACKGROUND: A new benzodiazepine, remimazolam, metabolized by tissue esterases to an inactive compound, CNS 7054, has been developed to permit a fast onset, a short and more predictable duration of sedative action, and a more rapid recovery profile than with currently available benzodiazepines. We report on the safety and efficacy of the first human study. METHODS: A phase I, single-center, double-blind, placebo- and active-controlled, randomized, single-dose escalation study was conducted. Up to 10 cohorts of healthy subjects were scheduled to receive a single 1-minute IV infusion of remimazolam, midazolam, or placebo. In the 10 possible cohorts, remimazolam doses were from 0.01 to 0.35 mg/kg. In cohorts 1 to 3, 6 subjects received remimazolam and 1 placebo. From cohort 4 onward, an additional 3 subjects in each cohort received midazolam (0.075 mg/kg). Safety, pharmacokinetics, and pharmacodynamics were measured. A stop criterion of loss of consciousness for >5 minutes in >50% of subjects was predefined. RESULTS: The stop criterion was reached in cohort 9 (0.30 mg/kg remimazolam) so that 81 subjects were enrolled. Remimazolam was well tolerated in all dose cohorts, and no serious adverse events (AEs) were reported. Three AEs of mild (Spo(2) 85%-88%) hemoglobin desaturation (2 in the remimazolam groups and 1 in the midazolam group) resolved spontaneously, and 1 AE of moderate hemoglobin desaturation (Spo(2) 75%) resolved with a chin lift in the highest remimazolam dose group. No supplemental oxygen or manual ventilation was required. Vital signs remained stable throughout, although there was an increase in heart rate 2 minutes postdose for both remimazolam and midazolam. There were no reports of hypo- or hypertension. The pharmacokinetic behavior of remimazolam was linear and its systemic clearance approximately 3 times that of midazolam. Clearance was essentially independent of body weight. A rapid onset and dose-dependent sedation was observed after administration of remimazolam at 0.05 mg/kg and higher. Remimazolam (0.075 to 0.20 mg/kg) induced peak sedation levels similar to or higher than those achieved with midazolam (0.075 mg/kg). Median recovery times after approximately equieffective doses of remimazolam (0.10 and 0.15 mg/kg) and midazolam (0.075 mg/kg) were 10 and 40 minutes, respectively. CONCLUSIONS: Remimazolam provided sedation with rapid onset and offset, and was well tolerated. There was no supplemental oxygen or ventilation required. On the basis of these data, further studies on the potential utility of remimazolam for sedation/anesthesia are warranted.

Safety and pharmacokinetics of single intravenous dose of MGAWN1, a novel monoclonal antibody to West Nile virus.

West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (C(max)) of 953 microg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The C(max) of 953 microg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.

Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults.

Maribavir, an oral antiviral drug with activity against cytomegalovirus, is currently undergoing studies to assess its efficacy and safety as cytomegalovirus prophylaxis following stem cell or solid organ transplantation. The main objective of this study was to assess the effects of oral ketoconazole, a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) isoenzyme, on the pharmacokinetics of maribavir. This was an open-label crossover study with 20 healthy adults. Subjects were administered a single dose of maribavir at 400 mg. After a washout period, subjects received a single dose of ketoconazole at 400 mg followed by a single dose of maribavir. Blood samples were collected for each drug sequence, and pharmacokinetic parameters for maribavir and its principal metabolite, VP 44469, were determined. Safety was evaluated by physical examination, clinical laboratory testing, 12-lead electrocardiogram, and monitoring for adverse events. Ketoconazole moderately reduced the clearance of both maribavir and VP 44469; oral clearance values were 35% and 13% lower, respectively, for maribavir-plus-ketoconazole treatment than for maribavir alone. Based on the assumption of complete inhibition of CYP3A4 activity, CYP3A4 is responsible for 35% of the overall clearance of maribavir. Treatment was generally well tolerated. The most-common adverse event was dysgeusia (taste disturbance), reported by nine (47%) and seven (35%) subjects in the maribavir alone and maribavir-plus-ketoconazole groups, respectively. The pharmacokinetic findings, in combination with the acceptable tolerability within the maribavir and maribavir-plus-ketoconazole treatment groups, suggest that no dose adjustment of maribavir is necessary when coadministered with CYP3A4 inhibitors or substrates.

The effect on heart rate of combining single-dose fingolimod with steady-state atenolol or diltiazem in healthy subjects.

OBJECTIVE: The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) is known to elicit a negative chronotropic effect at treatment initiation that attenuates over time with continued dosing. The authors determined the effect of combining a single dose of fingolimod with steady-state atenolol or diltiazem on heart rate and mean arterial pressure. METHODS: In a partially randomized, single-blind, placebo-controlled, three-period, crossover study, 25 healthy subjects received (1) a single oral 5-mg dose of fingolimod, (2) either 50 mg atenolol or 240 mg diltiazem once daily for 5 days, and (3) the antihypertensive for 5 days and a single dose of fingolimod on day 5. Telemetry and pharmacokinetic data were collected. RESULTS: The daytime mean heart rate nadir was 15% lower when fingolimod was combined with atenolol (42 +/- 7 bpm) compared with fingolimod alone (51 +/- 9 bpm) yielding a combination/monotherapy ratio of 0.85 (90%CI, 0.79-0.92). The daytime mean heart rate nadir from fingolimod alone (55 +/- 5 bpm) was not altered when combined with diltiazem (56 +/- 8 bpm) yielding a ratio of 0.99 (0.94-1.05). There was no clinically relevant change in mean arterial pressure when fingolimod was administered with atenolol or diltiazem compared with administration of the drugs alone in normotensive subjects. The pharmacokinetics of the drugs were not altered during coadministration. CONCLUSION: Adding fingolimod to a beta-blocker such as atenolol resulted in a moderately lower mean heart rate nadir compared with fingolimod alone. However, subjects who had a stronger negative chronotropic response to fingolimod alone (nadir < 50 bpm) had minimal or no further reduction in heart rate with the drug combination. Adding fingolimod to a calcium channel blocker such as diltiazem did not further lower the heart rate compared to fingolimod alone.

Analysis and reversal of the inhibition of cytophilic antibody receptors produced by antibody.

Administration of hyperimmune antibody to leukemia L1210 to allogeneic mice inhibited the development of macrophage-mediated immunity to L1210 in those hosts. In contrast to immunized mice, animals pretreated with antibody showed rapid activation of their peritoneal macrophages, followed by their disappearance and the inability of the residual peritoneal monocytic cells to attach L1210 cells even in the presence of proved cytophilic antibody to L1210. The inhibitory activity of the antibody, which resided entirely in its IgG2 fraction, was manifested only when the specific antigen (L1210 cells) was also injected within 2 days. Pretreatment with antibody to a different leukemia, EL4, failed to inhibit the monocytic uptake of L1210, but it did inhibit uptake of EL4 by monocytes if injected with its homologous antigen. Restoration of the functional capacity of macrophages was accomplished by injecting 1 X 10-7 bone marrow cells i.v. into "suppressed" mice, but 1.5 X 10-7 thymocytes failed to correct the defect. Significantly, thymocytes antagonized the restorative capability of bone marrow cells when they were injected concomitantly. These results indicate that specific inhibition of cytophilic antibody receptors on monocytes could be accomplished through a direct mechanism involving activation and exhaustion of macrophages and an indirect mechanism, perhaps mediated through "suppressor" thymus-derived cells. Although enhancement of the growth of leukemia cells did not occur, several parallels exist in mice with enhanced growth of different tumors. This inhibiotry phenomenon may thus represent another instance of "blocking" in tumor immunity, where the target of suppressive antibody-antigen is the macrophage as well as the lymphocyte.

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers.

RATIONALE: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. OBJECTIVES: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. METHODS: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. RESULTS: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r (2) = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. CONCLUSIONS: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

Influence of prolonged recumbency on drug disposition.

The disposition of lidocaine and penicillin was studied in normal subjects before and after 7 days of total recumbency. Penicillin (1,000,000 U) and lidocaine (100 mg) were administered intravenously. Lidocaine protein binding was also followed. Total body clearance, elimination half-life, and volume of distribution were calculated. There were no statistically significant differences in these disposition parameters before and after 7 days of recumbency. The binding of lidocaine also was not changed after bed rest. We conclude that the physiologic changes that occur during prolonged bed rest do not affect distribution or elimination of lidocaine or penicillin.

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated. METHODS: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen. RESULTS: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P <.010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P <.010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P <.010). CONCLUSIONS: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.

Mechanisms for decreased exercise capacity after bed rest in normal middle-aged men.

The mechanisms responsible for the decrease in exercise capacity after bed rest were assessed in 12 apparently healthy men aged 50 +/- 4 years who underwent equilibrium gated blood pool scintigraphy during supine and upright multistage bicycle ergometry before and after 10 days of bed rest. After bed rest, echocardiographically measured supine resting left ventricular end-diastolic volume decreased by 16% (p less than 0.05). Peak oxygen uptake during supine effort after bed rest was diminished by 6% (p = not significant [NS]), whereas peak oxygen uptake during upright effort declined by 15% (p less than 0.05). After bed rest, increases in heart rate were also greater during exercise in the upright than in the supine position (p less than 0.05). Values of left ventricular ejection fraction increased normally during both supine and upright effort after bed rest and were higher than corresponding values before bed rest (p less than 0.05). After bed rest, increased left ventricular ejection fraction and heart rate largely compensated for the reduced cardiac volume during supine effort, but these mechanisms were insufficient to maintain oxygen transport capacity at levels during upright effort before bed rest. These results indicate that orthostatically induced cardiac underfilling, not physical deconditioning or left ventricular dysfunction, is the major cause of reduced effort tolerance after 10 days of bed rest in normal middle-aged men.

Beta blockade in the compensation for bed-rest cardiovascular deconditioning: physiologic and pharmacologic observations.

Beta-adrenergic blockade using intravenous propranolol was evaluated as a countermeasure for bedrest-induced cardiovascular deconditioning. After propranolol administration, tolerance to a maximal lower body negative pressure (LBNP) test after bed rest improved to at least the -70 mm Hg level; following this, there was a sharp decrease in tolerance time. Propranolol decreased mean tolerance time by 36% (17.7 +/- 2.4 to 11.5 +/- 2.3 minutes) before bed rest, and by only half as much (16.6%) after bed rest (14.4 +/- 2.2 to 12.0 +/- 2.3 minutes). Systemic vascular resistance was maintained and even slightly increased after propranolol despite a decrease in cardiac output, indicating beta 2-adrenergic blockade. Heart rates at all levels of LBNP were lower during beta blockade, yet increases occurred with successive LBNP steps, both before and after bed rest, indicating withdrawal of parasympathetic nervous system influences. Results support the use of propranolol in small dosages as a countermeasure after bed rest, and the findings may also be extrapolated to space-flight deconditioning.

Lack of a pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline.

AIM: To study the potential pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline at steady state. METHODS: Theophylline 200 mg extended-release formulation was administered twice daily on days 1-11 to 30 healthy, non-smoking males. On days 5-11, 15 subjects received concomitant lansoprazole 30 mg once daily (o.d.) and 15 subjects received concomitant pantoprazole 40 mg o.d. RESULTS: No significant changes in the steady-state theophylline maximum plasma concentration (Cmax), time to Cmax (Tmax), minimum plasma concentration (Cmin), area under the plasma concentration-time curve over the 12-h dosing interval (AUC0-12), or apparent total oral clearance (CL/F) were observed within the two treatment groups when theophylline was administered alone or in combination with lansoprazole or pantoprazole. In addition, no significant differences in the changes of steady-state theophylline pharmacokinetics from day 4 to day 11 were noted between the two treatment groups. Treatment with theophylline in combination with either lansoprazole or pantoprazole was well tolerated. All adverse events were transient and rated mild to moderate in severity. CONCLUSION: Co-administration of either lansoprazole or pantoprazole in healthy subjects does not significantly affect the steady-state pharmacokinetics of theophylline at the therapeutic doses tested.

Acid suppression in healthy subjects following lansoprazole or pantoprazole.

AIM: To compare the effect of lansoprazole, 30 mg once daily, with that of pantoprazole, 40 mg once daily, for the inhibition of gastric acid secretion. METHODS: Two randomized, single-blind, two-way, crossover studies were conducted in 74 healthy male volunteers. Lansoprazole, 30 mg, or pantoprazole, 40 mg, was administered once daily for five consecutive days with at least a 2-week washout period between regimens. Ambulatory 24-h intragastric pH was recorded at baseline and on days 1 and 5 of each crossover treatment period. RESULTS: On day 1 in both studies, lansoprazole, 30 mg, produced significantly higher mean 24-h intragastric pH values when compared to pantoprazole, 40 mg (3.78 vs. 3.08, P < 0.001, and 3.97 vs. 3.20, P < 0.001, in the first and second studies, respectively). In both studies, lansoprazole, 30 mg, produced significantly greater proportions of time that the intragastric pH was above 3, 4 and 5 when compared with pantoprazole, 40 mg (P < 0.005 in all comparisons). By treatment day 5 in the first study, lansoprazole, 30 mg, continued to produce a higher mean 24-h intragastric pH (4.15 vs. 3.91, P=0.014) and a significantly greater percentage of time that the intragastric pH was above 4 (63% vs. 56%, P=0.017) and 5 (41% vs. 30%, P < 0.001) when compared with pantoprazole, 40 mg. In the second study, the effects on intragastric pH were comparable between the two treatment groups. Headache was the most commonly reported adverse experience (nine lansoprazole-treated subjects, seven in the first study and two in the second study; six pantoprazole-treated subjects, five in the first study and one in the second study). CONCLUSIONS: Lansoprazole, 30 mg once daily, produces a faster onset and greater degree of acid inhibition than pantoprazole, 40 mg once daily. The implications for these differences on symptom relief and healing of erosive oesophagitis should be explored.

Atropine unmasks bed-rest effect: a spectral analysis of cardiac interbeat intervals.

Bed-rest deconditioning is suspected to reduce cardiac reserve, possibly by impairing autonomic function. Heart rate response in normal subjects reveals considerable variability, reflected by a relatively broadband interbeat interval power spectrum. A reduction in this autonomically modulated variability would be predicted to cause a narrowing of the spectrum. We retrospectively analyzed data from 10 aerobically conditioned men (age range 35-49 yr) who had undergone orthostatic tolerance testing with lower body negative pressure pre-bed rest and after 7-10 days of bed rest, while on placebo and after intravenous atropine. Spectra were derived by Fourier analysis of 128 interbeat interval data sets. Spectral power was estimated by computing the root-mean-square (rms) values (mean +/- SD) for the band encompassing the 2nd to 64th harmonics from subjects with a sufficient number of beats: placebo rms is 93 +/- 33 ms for pre-bed rest and 84 +/- 38 ms for bed rest (NS, n = 6); atropine rms is 63 +/- 24 ms for pre-bed rest and 40 +/- 23 ms for bed rest (P less than 0.01; n = 7). These data suggest that atropine "unmasks" a deconditioning effect of bed rest in athletic men, evidenced by a reduction in interbeat interval spectral power not apparent with placebo. Spectral analysis offers a useful means of quantitating the effects of bed-rest deconditioning and autonomic perturbations on cardiac dynamics.

Echocardiographic evaluation of space shuttle crewmembers.

Echocardiographic measurements were obtained before and after space flight from 17 members of four shuttle crews. Measurements obtained 1 h after landing (L+0) compared with preflight values (n = 7) demonstrated an increase in heart rate (HR) (16 beats/min, 30.5%, P less than 0.05), mean arterial pressure (12%, P less than 0.05), and systemic vascular resistance (34%, P less than 0.05). End-diastolic volume index (EDVI) fell 17 ml/m2 (-23%, P less than 0.005) and stroke volume index (SVI) fell 15 ml/m2 (-28%, P less than 0.05). Repeat measurements taken 1-2 wk later (n = 17) demonstrated that HR had returned to normal (4 beats/min, P less than 0.05); however, EDVI remained significantly below preflight levels (-11%, P less than 0.005). End-systolic volume index (ESVI) was also still significantly lower (-23%, P less than 0.01). This delayed recovery occurred despite ability of the subjects to fully ambulate and exercise during the postflight period. These results indicate that spaceflight induces significant changes in heart volume affecting left ventricular function. The exact reasons for these specific changes remain unknown and will require additional measurements before, during, and after flight. The prolonged recovery period for the present subject group probably relates to their high level of aerobic conditioning.

Influence of suspension on the oxidative burst by rat neutrophils.

The influence of spaceflight on the oxidative burst of neutrophils is not known. The present study was designed to evaluate the influence of antiorthostatic suspension, a ground-based modeling system designed to simulate certain aspects of weightlessness that occur after spaceflight, on the capacity of rat neutrophils to express the oxidative burst, an important host defense mechanism against microbial pathogens. Rats were suspended in whole body harnesses in the antiorthostatic orientation for a 3- or 7-day period. Control rats were suspended orthostatically or allowed to remain in vivarium cages without the attachment of any suspension materials. After suspension, peripheral blood was harvested and neutrophils were isolated by density gradient centrifugation. The enriched neutrophil preparations were stimulated with N-formyl-methionyl-leucine-phenylalanine and phorbol myristic acid to induce the oxidative burst. It was found that neutrophils isolated from suspended animals released the same levels of superoxide anion as did vivarium control animals that were not suspended, indicating that whole body suspension did not alter this aspect of rat neutrophil function.

A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl-6-chloromelatonin.

Clinical investigation of melatonin agonists has been hampered by side effects such as hypothermia, hypotension and bradycardia. The availability of a melatonin agonist devoid of these side effects would improve our understanding of the mechanisms by which melatonin agonists affect sleep. This study investigated the pharmacokinetics, pharmacodynamics and safety of the melatonin agonist beta-methyl-6-chloromelatonin at doses up to 100 mg in healthy volunteers. The design was a single blind, across subjects, placebo controlled, group wise dose escalation using doses of 20, 35, 50 and 100 mg beta-methyl-6-chloromelatonin. Eight subjects received one dose of study drug or placebo. Pharmacokinetic analysis showed a consistent Tmax across all doses with a mean of 1.12 +/- 0.11 hr for all groups (mean +/- SD). The half-life was also consistent across dose, with a mean of 1.04 +/- 0.04 hr. Maximum plasma concentrations increased with increasing dose with values of 44.83 +/- 29.79, 100.3 +/- 41.08, 79.84 +/- 26.36 and 410.3 +/- 129.4 ng/ml at doses of 20, 35, 50 and 100 mg, respectively. Area under the curve showed similar increases. No consistent changes in vital signs occurred as a function of dose or time after study drug. The incidence of all adverse events, the severity of the event or the event's relationship to treatment did not increase with higher doses of beta-methyl-6-chloromelatonin. Sleepiness was reported after all doses of beta-methyl-6-chloromelatonin. beta-methyl-6-chloromelatonin appears safe and well tolerated at doses up to 100 mg. These doses are not associated with hypothermia, bradycardia or hypotension. A melatonin agonist lacking these side effects should allow investigation of the direct soporific effects of melatonin agonists.

Aerobic fitness does not contribute to prediction of orthostatic intolerance.

Several investigations have suggested that orthostatic tolerance may be inversely related to aerobic fitness (VO2max). To test this hypothesis, 18 males (age 29 to 51 yr) underwent both treadmill VO2max determination and graded lower body negative pressures (LBNP) exposure to tolerance. VO2max was measured during the last minute of a Bruce treadmill protocol. LBNP was terminated based on pre-syncopal symptoms, and LBNP tolerance (peak LBNP) was expressed as the cumulative product of LBNP and time (torr-min). Changes in heart rate, stroke volume, cardiac output, blood pressure, and impedance rheographic indices of mid-thigh-leg fluid accumulation were measured at rest and during the final minute of LBNP. For all 18 subjects, mean (+/- SE) fluid accumulation index and leg venous compliance index at peak LBNP were 139 +/- 22 ml and 3.9 +/- 0.4 ml . 100 ml . torr-min-2 x 10(3), respectively. Pearson product-moment correlations and step-wise linear regression were used to investigate relationships with peak LBNP. Variables associated with endurance training, such as VO2max and percent body fat, were not found to correlate significantly (P less than 0.05) with peak LBNP and did not add sufficiently to the prediction of peak LBNP to be included in the step-wise regression model. The step-wise regression model included only fluid accumulation index, leg venous compliance index, and blood volume, and resulted in a squared multiple correlation coefficient of 0.978. These data do not support the hypothesis that orthostatic tolerance as measured by LBNP is lower in individuals with high aerobic fitness.

Anabolic steroids support postoperative gut/liver amino acid metabolism.

The effects of an anabolic steroid (nandrolone decanoate, 5 mg/kg) on postoperative splanchnic fuel metabolism were studied in order to gain further understanding of the regulation of the altered gut/liver amino acid metabolism that occurs following catabolic illness. In addition to studying glutamine and alanine, which together transport 60% of whole blood amino acid nitrogen, we determined the fluxes of glutamate and glucose across the gastrointestinal tract and liver in 12 postoperative dogs. Substrate exchange (flux) was calculated by multiplying bloodflow by the arterial-venous concentration difference for each substrate. Arterial glutamine, glutamate, and alanine were significantly increased in dogs receiving the anabolic steroid (AS) compared to control animals (p less than 0.05). Intestinal bloodflow was unchanged, but gut glutamine uptake doubled in dogs receiving steroids (1.4 +/- 0.3 mumol/kg/min in controls vs 2.8 +/- 0.7 in AS, p less than 0.05). Simultaneously, gut alanine release was augmented by 100% in dogs receiving steroids (p less than 0.05). Control dogs demonstrated net glutamate release by the gut, while dogs treated with the anabolic steroid demonstrated glutamate balance (p less than 0.05). Liver bloodflow remained unchanged in AS dogs, but hepatic alanine uptake nearly tripled (p less than 0.01) and hepatic glucose production increased by 60% (p less than 0.05). Anabolic steroids appear to support postoperative splanchnic fuel metabolism by increasing blood amino acid levels, enhancing gut/liver amino acid uptake and processing, and augmenting hepatic gluconeogenesis.

Effects of enterectomy on postoperative visceral organ glucose exchange.

The effects of a 60% small-bowel resection on postoperative visceral organ glucose exchange was studied in order to gain further understanding of the role of the intestinal tract as a supplier of gluconeogenic substrate to the liver following operative stress. We determined the flux of glucose across the gastrointestinal tract, liver, and kidneys in 20 postoperative dogs. With enterectomy portal bloodflow and total hepatic bloodflow were diminished by 33% and 25%, respectively. Arterial glucose was slightly lower in the enterectomized group 6 hr following the operation. Intestinal glucose uptake was diminished by more than 50% in the enterectomized dogs (p less than 0.01). Net hepatic glucose release fell from 22 mumole/kg/min to 8 mumole/kg/min (p less than 0.01). In control animals the kidney was an organ of slight glucose uptake while in the enterectomized group, the kidney released glucose at the rate of 4.1 mumole/kg/min (p less than 0.05). The data suggest that the gut is an important supplier of gluconeogenic precursors to the liver which are used to support gluconeogenesis in the postoperative period. The ability of the kidney to accelerate glucose production in this setting suggests that metabolic adaptation and cooperation between organs occurs during organ absence or dysfunction which helps preserve glucose homeostasis.