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Stability of amiodarone in an oral suspension stored under refrigeration and at room temperature.

OBJECTIVE: Amiodarone is currently available in a tablet dosage form, which cannot be used in young pediatric patients. The objective of our study was to determine the stability of amiodarone in an oral suspension stored at two temperatures. METHODS: Commercially available amiodarone tablets (200 mg each) were dissolved in purified water and a suspension prepared in methylcellulose 1% and syrup to yield a concentration of 5 mg/mL. The dosage form was stored in 10 glass and 10 plastic prescription bottles. One-half of the bottles were stored at 4 degrees C and the others at 25 degrees C. Three samples were taken from each bottle at 0, 7, 14, 28, 42, 56, 70, and 91 days (n = 15). Amiodarone concentrations were measured by a validated and stability-indicating HPLC method; the pH was also determined in each sample. The drug was considered stable if its concentration exceeded 90% of the original concentration. RESULTS: The mean concentration of amiodarone was 90% or more at 4 degrees C for 91 days and at 25 degrees C for 42 days. The concentration was not affected by the type of storage container. Over 91 days, the pH did not change at 4 degrees C; it decreased slightly from 4.4 to 4.3 at 25 degrees C. CONCLUSIONS: Amiodarone was stable in an oral suspension for 3 months under refrigeration and for 6 weeks at room temperature.

Amiodarone↗

Optimizing the crystal size and habit of beta-sitosterol in suspension.

The aim of this work was to survey how processing parameters affect the crystal growth of beta-sitosterol in suspension. The process variables studied were the cooling temperature, stirring time and stirring rate during recrystallization. In addition, we investigated the effect a commonly used surfactant, polysorbate 80, has on crystal size distribution and the polymorphic form. This study describes the optimization of the crystallization process, with the object of preparing crystals as small as possible. Particle size distribution and habit were analyzed using optical microscopy, and the crystal structure was analyzed using X-ray diffractometry. The cooling temperature had a remarkable influence on the crystal size. Crystals with a median crystal length of approximately 23 microm were achieved with a low cooling temperature (<10 degrees C); however, a fairly large number of crystals over 50 microm appeared. Higher cooling temperatures (>30 degrees C) caused notable crystal growth both in length and width. Rapid (250 rpm), continuous stirring until the suspensions had cooled to room temperature created small, less than 50 micro m long (median <20 microm), needle-shaped crystals. The addition of surfactant slightly reduced the size of the initially large crystals. Both hemihydrate and monohydrate crystal forms occurred throughout, regardless of the processing parameters. By using an optimized process, it was possible to obtain a microcrystalline suspension, with a smooth texture.

Chemistry, Pharmaceutical↗

Evaluation of the TSI aerosol impactor 3306/3321 system using a redesigned impactor stage with solution and suspension metered-dose inhalers.

The purpose of this research was to evaluate a redesigned impactor stage for the TSI Model 3306 Impactor Inlet with nozzles adjusted to obtain a target cut-point of 4.7 microm. It has been determined that the previous cut-point used in the Model 3306 was nominally closer to 4.14 microm, thus potentially impacting the characterization of aerosol mass. The reassessment of the Model 3306 was performed on 4 solution and 2 suspension metered-dose inhaler (MDI) formulations. The redesigned impactor stage resulted in a 5% to 6% increase in aerosol mass when compared with the previous impactor stage for the products Ventolin-HFA, Proventil-HFA, and 2 cyclosporin solution formulations with high ethanol concentrations (15% wt/wt). For the formulations with low ethanol concentrations (3% wt/wt), minimal differences were observed between the 2 cut-points. In addition, this study reevaluated the requirement of a vertical inlet extension length when using the TSI 3306/3321 system with the redesigned cut-point. It was shown that the use of a 20-cm extension provides mass and aerosol size distributions that are comparable to the Andersen 8-stage Cascade Impactor, for both solution and suspension MDIs. This work indicates that the TSI 3306/3321 system is suitable for preformulation studies of both suspension and solution MDI systems.

Aerosols↗

Thermal gelation of aqueous curdlan suspension: preparation of curdlan jelly.

Curdlan jelly was prepared by heating an aqueous curdlan suspension at 70 degrees C for 5 min. Theophylline, as a model drug, was entrapped in the jelly network. Curdlan jelly had a hardness comparable with that of commercially available jelly for confectionary. Syneresis was observed for 8 days after the preparation and was not detected during the experimental term from the gel prepared from 10% w/v curdlan suspension. Release of theophylline from the jellies was sustained, and was increasingly delayed with an increase in the curdlan concentration. An aqueous curdlan suspension was studied by means of differential scanning calorimetry (DSC) up to 80 degrees C and down to -25 degrees C, and subsequent re-heating to 30 degrees C. Enthalpy increased with the concentration of curdlan, while the temperature at the onset of the endothermic peak decreased with the concentration of curdlan. The enthalpy due to thermal gelation of 1 mg curdlan was 12.2 mJ. An increase in curdlan concentration decreased the enthalpy and lowered the onset temperature of the endothermic peak during the DSC re-heating scan. The results are due to an increase in the amount of non-freezing water and freezing bound water and a decrease in free water. The number of water molecules entrapped in the curdlan jelly as non-freezing water was 8.1 per glucopyranose residue.

Calorimetry↗

Preoperative rofecoxib oral suspension as an analgesic adjunct after lower abdominal surgery: the effects on effort-dependent pain and pulmonary function.

UNLABELLED: Rofecoxib is a selective cyclooxygenase-2 inhibitor that reduces pain and inflammation without inhibiting platelet function. We examined its effects on effort-dependent pain, postoperative morphine requirements, and pulmonary function in 48 patients recovering from open abdominal surgery. Spirometric measurement of forced expiratory volume(1) and vital capacity (FVC) were assessed preoperatively. One hour before the induction of a standardized general anesthetic, patients were given either placebo oral suspension (Group A), or rofecoxib oral suspension (25 mg [Group B] or 50 mg [Group C]) in a double-blinded manner. Postoperative pain control was provided with IV morphine in the postanesthesia care unit and IV-patient-controlled analgesia morphine on the patient care unit. Morphine dose, pain intensity at rest, and pain after respiratory effort (postoperative spirometry) were assessed at 12 and 24 h after study drug administration. The patient-controlled analgesia morphine dose at 24 h was reduced 44% in Group B (30.3 +/- 17.5 mg) and 59% in Group C (22.1 +/- 16.5 mg) versus Group A (53.7 +/- 31.1 mg); P < 0.01 (A versus B). At 12 h, pain scores at rest and after spirometry were lower in Groups B and C than in A (P < 0.05). At 24 h, resting pain scores were lowest in Group C (P < 0.05). Twelve-hour FVC was best preserved in Group C (P < 0.03). There were no inter-group differences in adverse effects or perioperative blood loss. Rofecoxib oral suspension provided a morphine-sparing effect, as well as improvements in pain control and 12-h FVC in patients recovering from open abdominal surgery. IMPLICATIONS: Rofecoxib belongs to class of analgesics known as cyclooxygenase-2 inhibitors that reduce pain and inflammation with less risk of bleeding than standard nonsteroidal antiinflammatory drugs. We found that patients treated with rofecoxib 25 or 50 mg before open abdominal surgery required less IV morphine during the first day of recovery. Despite reductions in morphine requirements, rofecoxib-treated patients reported lower pain intensity scores at rest and after a vigorous cough. In the 50-mg group, improvements in pain control correlated with greater preservation of baseline cough effectiveness (vital capacity) at 12 h. These findings may offer clinical advantages in patients with preexisting pulmonary disease.

Abdomen↗

Morphologic examination of rabbit nasal mucosa after the nasal administration of insulin peanut oil suspension and a powder dosage form with soybean-derived sterylglucoside.

Soybean-derived sterylglucoside mixture (SG) is a potentially effective absorption enhancer for the nasal absorption of insulin. Insulin is a peanut oil suspension dosage form and in a powder dosage form with SG were administered into the rabbit nasal cavity. After 0.5 or 1 h, nasal mucosa was taken from the nasal cavity and side effects were examined by an optiphoto light microscope. The insulin in the peanut oil suspension produced a histological change in the nasal epithelium mucosae, as well as mucodermal phlogistic cellular infiltration. The peanut oil suspension with SG showed side effects slightly stronger than without SG. SG alone and the insulin powder dosage form with SG produced no signs of inflammation, erosion or squamous metaplasia. The results from this study indicate that SG can be considered safe.

Administration, Intranasal↗

Observations on the behaviour of barium sulphate suspensions in gastric secretion.

A number of barium sulphate suspensions showed varying patterns of stability when provoked with gastric secretion. The stability of the suspensions was affected by the pH, the mucin content and the volume of secretion used. These studies indicate that flocculation of the suspension in the presence of gastric residue decreases as the amount of undiluted barium sulphate in the mixture is increased.

Adsorption↗

Disorganization of honey-comb immunoreactive pattern of desmin and plectin in rat atrophic soleus muscle fiber induced by hindlimb suspension.

Immunoreactivity for desmin, plectin and alpha-actinin was investigated in rat atrophic soleus muscle fibers induced by hindlimb suspension between 1 and 4 weeks (hindlimb suspension group, HSG), and compared with that of the control group (CG). Some of the HSG for 4 weeks were allowed unrestricted cage activity for 2 weeks as the recovery group (RG). In the cross-sectioned muscle fibers of the CG, desmin and plectin showed honey-comb immunoreactive patterns extending throughout the sarcoplasm. Superimposed images by double immunofluorescence labeling showed overlapping of both immunoreactivities. In the longitudinally sectioned profiles, superimposed images of alpha-actinin and desmin were overlapped at the level of Z-discs. The focal disorganization of the above honeycomb immunoreactive patterns, followed by the reduction of the cross-sectional area (CSA) of atrophic soleus muscle fibers and the appearance of Z-streaming, uniquely arose in the HSG from the first week and extended throughout the sarcoplasm in proportion to the suspension period. Such honey-comb patterns of both desmin and plectin were already restored in the RG at 2 weeks, followed by the disappearance of Z-streaming, prior to the recovery of the CSA. These findings indicate that the disorganization of topological and structural relationships of desmin and plectin with Z-discs surrounding individual myofibrils is primarily evoked, which leads to Z-streaming of atrophic soleus muscle fibers, and that the restoration of the muscle activity results in an early arrangement recovery of desmin and plectin around myofibrils.

Animals↗

Single-dose and steady-state pharmacokinetics of a new oral suspension of ciprofloxacin in children.

OBJECTIVE: Quinolones are used ever increasingly in pediatrics, although officially they are still contraindicated. Lack of evidence of arthropathic effects in human offspring favors their use, but little is known about the pharmacokinetics of oral or parenteral ciprofloxacin in children, especially those without cystic fibrosis. DESIGN: We studied 16 non-cystic fibrosis patients ranging in age from 0.3 to 7.1 years to whom the new suspension formulation of ciprofloxacin (10 mg/kg body weight) was given orally three times daily. Single-dose and steady-state pharmacokinetic parameters were elucidated. RESULTS: Ciprofloxacin was rapidly absorbed. The maximum plasma concentrations, with the means varying from 1.7 to 3.6 mg/L, were reached within 1 hour, almost regardless of whether single-dose administration or steady state. The mean oral clearance was lower in children <6 years of age than in those >/=6 years. Terminal half-life values, with the means varying only between 4.2 and 5.1, suggest that dosing recommendations based on body weight are pertinent, although caution should be exercised in small infants. No arthropathic or other adverse events attributable to ciprofloxacin suspension were observed. CONCLUSION: A dose of the suspension form of ciprofloxacin of 10 mg/kg body weight given orally three times daily seems appropriate in children, provided the drug is clearly indicated.

Administration, Oral↗

Nebulized budesonide inhalation suspension compared with cromolyn sodium nebulizer solution for asthma in young children: results of a randomized outcomes trial.

OBJECTIVE: The availability of antiinflammatory asthma medications for infants and young children has been limited. The objective of this study was to compare effects of nebulized budesonide inhalation suspension and cromolyn sodium nebulizer solution on asthma-related health outcomes in young children with asthma. METHODS: We conducted a randomized, parallel-group, 52-week, open-label study in 36 US clinical sites. Patients included 335 children who were 2 to 6 years of age and had persistent asthma that had been treated with at least 1 long-term control medication; 287 children (86%) completed the study. Patients received budesonide inhalation suspension, 0.5 mg daily (n = 168), or cromolyn sodium nebulizer solution, 20 mg 4 times daily (n = 167), for 8 weeks, followed by dose titration at the investigator's discretion. The main outcome measure was the rate of asthma exacerbations over 52 weeks. Secondary measures included times to first asthma exacerbation and first use of additional asthma therapy, asthma symptom scores, rescue medication use, and health care resource use. RESULTS: The budesonide group had a mean (median) asthma exacerbation rate of 1.23 (0.99) per year compared with 2.41 (1.85) for the cromolyn group, significantly longer times to first exacerbation and first use of additional long-term asthma medication, greater improvements in asthma symptom scores, reduced use of rescue medication, and fewer urgent care visits. Both treatments were well tolerated. CONCLUSIONS: Budesonide inhalation suspension was more effective than nebulized cromolyn sodium in young children with persistent asthma. Both treatments were well tolerated with similar adverse event profiles.

Administration, Inhalation↗

Eslicarbazepine acetate (BIA 2-093) : relative bioavailability and bioequivalence of 50 mg/mL oral suspension and 200mg and 800mg tablet formulations.

PURPOSE: To investigate the bioavailability and bioequivalence of three different formulations of eslicarbazepine acetate (BIA 2-093): 50 mg/mL oral suspension (test 1), 200mg tablets (test 2) and 800mg tablets (reference). DESIGN, SUBJECTS AND METHODS: Single-centre, open-label, randomised, three-way crossover study in 18 healthy subjects. The study consisted of three consecutive periods separated by a washout period of 7 days or more. Each subject received a single dose of eslicarbazepine acetate 800mg on three different occasions: 16mL of oral 50 mg/mL suspension, four 200mg tablets or one 800mg tablet. RESULTS: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUCinfinity) were, respectively (arithmetic mean +/- SD), 18.0 +/- 4.6 microg/mL and 325.7 +/- 64.9 microg x h/mL for test 1, 16.0 +/- 4.0 microg/mL and 304.2 +/- 66.0 microg x h/mL for test 2, and 17.0 +/- 4.1 microg/mL and 301.1 +/- 60.0 microg x h/mL for the reference formulation. Point estimate (PE) and 90% confidence intervals (CIs) for AUCinfinity test 1/reference geometric mean ratio were 1.09 and 1.01, 1.15; for Cmax ratio, PE and 90% CI were 1.07 and 0.97, 1.15. When test 2 and the reference formulations were compared, the PE and 90% CI were 0.99 and 0.94, 1.07 for the AUCinfinity ratio, and 0.94 and 0.86, 1.02 for the Cmax ratio. Bioequivalence of test versus reference formulations is thus accepted for both AUCinfinity and Cmax because the 90% CIs lie within the acceptance range of 0.80-1.25. CONCLUSION: The pharmacokinetic profiles of eslicarbazepine acetate oral 50 mg/mL suspension, 200mg tablet and 800mg tablet formulations were essentially similar, and the formulations can be considered bioequivalent.

Administration, Oral↗

Flavor and taste of lansoprazole strawberry-flavored delayed-release oral suspension preferred over ranitidine peppermint-flavored oral syrup: in children aged between 5-11 years.

OBJECTIVE: To compare the flavor and taste preference of two acid-inhibitory therapies in healthy children aged between 5-11 years. METHODS: A single-site, single-blind, taste test trial was conducted in which 111 children participated after parental consent. One teaspoonful (5 mL) of lansoprazole delayed-release oral suspension (strawberry-flavored) and ranitidine oral syrup (peppermint-flavored) were provided to each child with a 10-minute break between samples. Children tasted the sample, swished it in their mouth for 10 seconds, and then expectorated the sample. Spring water and crackers were used to clear the palate between samples. After each sampling, children were observed for facial expressions and asked to rate their degree of liking of each sample based on a 5-point facial hedonic scale (5=like it very much, 1=dislike it very much). Likes, dislikes, and product preference were recorded. RESULTS: Of the 56 female and 54 male children who tasted both samples, 95% (105/110) preferred lansoprazole. Taste and flavor were the most often cited reasons for preferring lansoprazole (61 and 17 children, respectively) while three children preferred the flavor of ranitidine oral syrup. Lansoprazole received a higher mean liking rating compared with ranitidine (mean liking scores of 4.1 and 2.2, respectively). There was no significant difference in the preference for lansoprazole between age groups and gender with the degree of liking scores ranging between 3.5-4.4. Forty-two children disliked the texture of the lansoprazole oral suspension, citing the granules (31/110), thickness (7/110), or consistency/texture (4/110), specifically. CONCLUSION: After sampling both products, 95% of children preferred the flavor and taste of the strawberry-flavored lansoprazole delayed-release oral suspension compared with the peppermint-flavored ranitidine oral syrup.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Cimetidine tablets or suspension for the prevention of gastrointestinal mucosal lesions caused by non-steroidal, anti-inflammatory drugs.

We compared the protection offered by cimetidine 400 mg b.i.d. as tablets or suspension vs. placebo, in Naproxen-induced gastrointestinal damage in 17 healthy males. Upper endoscopy was performed before and after each drug period, with separate evaluation of duodenal mucosa distal to the duodenal bulb. 51Cr-EDTA absorption tests were done to assess distal mucosal integrity, and symptoms were registered. All regimens caused a significant increase in mucosal damage (p less than 0.01). Cimetidine tablets gave a significantly lower damage score than placebo for gastritis/duodenitis and hemorrhagic lesions in the stomach/duodenal bulb, and for the sum of scores in both scoring regions (p = 0.02). Cimetidine suspension was not significantly different from placebo for any of the endoscopic parameters. The 51Cr-EDTA absorption was significantly increased after all drug periods. However, there was no difference between the three drug combinations. Symptoms reported were mild and equal in the three groups. Cimetidine tablets offered protection against Naproxen-induced mucosal damage, primarily in the stomach and duodenal bulb, but lacked any effect on permeability changes. Cimetidine suspension was not significantly different from placebo in any respect.

Absorption↗

Effects of hindlimb suspension and elevated ambient CO2 on rat growth and renal function.

BACKGROUND: Previous studies show that an ambient CO2 concentration of 2.0% may complicate interpretation of animal experiments conducted in spaceflight, while 0.7% CO2 exposure produces minimal effects. HYPOTHESIS: With additional spaceflight factors, such as microgravity, effects from the 0.7% CO2 exposure may be amplified. METHODS: To investigate the combined effects from microgravity and elevated CO2 on growth and renal function, two groups of rats were hindlimb suspended for 37 d, and a third group served as an ambulatory vivarium control (AMB). One suspension group was exposed to 0.7% CO2 for 30 d (HLS + 0.7% CO2), while the other group (HLS) served as a suspended control. Both the AMB and HLS groups breathed room air at 0.03% CO2. RESULTS: The HLS group showed responses consistent with past hindlimb suspension studies when compared with AMB, indicating similar reductions in organ and tissue weights and body weight gain. When comparing HLS + 0.7% CO2 animals to HLS controls, exposure to CO2 revealed lowered food consumption and increased urine volume, NH3 and CO2 excretion, with no differences in any of the other measured parameters, such as body weight gain, pH values, or electrolyte handling. CONCLUSION: This study shows that chronic exposure to both 0.7% ambient CO2 and hindlimb suspension together have little additional effect on rat growth and renal function.

Air Pollution, Indoor↗

[Studies on kinetics of somatic embryo suspension culture in Picea meyeri Rehd. et Wils].

Embryogenic calli were produced from mature zygotic embryos of Picea meyeri Rehd. et Wils. which were cultured on modified LP medium containing 30 g/L sucrose, 2 mg/L 2,4-D and 1 mg/L 6-BA. The growth rate of embryogenic calli could be improved by way of suspension culture in medium MS containing 20 g/L sucrose, 1 mg/L 2,4-D and 1 mg/L KT. The optimum values of initial cell density and shake rate of flask in suspension culture were 3.0% (fresh weight) and 150 r/min respectively. Several parameters which might be correlated with growth were determined over a 10 day period. Maximum growth in terms of fresh weight, dry weight and number of ESM occurred during 6-10 day. pH and conductivity attained the lowest point during 6-8 day. A lot of somatic embryos were obtained following transfer of the suspension cultures to medium MS containing 5 mg/L ABA. Mature somatic embryos grew into plantlets with well developed cotyledons after being cultured on 1/2 MS medium supplemented with 0.5% activated charcoal but without hormone.

Cell Differentiation↗

[Can a tail-suspension model be applied to simulate the reproduction system under weightlessness?].

A tail-suspension model to simulate weightlessness is widely used for studies on physiological changes not only of the musculoskeletal system but also of the cardiovascular system. In the present study, we applied this model to investigate whether or not it is possible for male spermatogenesis to occur, and for female rats to maintain pregnancy in this model. Two male rats were suspended with the right inguinal canal ligated loosely for 14 days, and female rats were suspended after copulation (the day when spermatozoa were identified on a smear from the female rat, was referred to as Day 0 for her in this paper). The duration of suspension was chosen dependent upon events to be confirmed during the course of pregnancy. To demonstrate the effects of suspension on implantation, the first and second groups consisted respectively of non-suspended rats penetrated at the base of the tail in the same way as suspended rats, and rats suspended during the former half of pregnancy (Days 0-12, and 0-14). The third group consisted of rats suspended during the latter half (Days 10-20, 10-21, 10-26, and 10-28), and in the final group a rat suspended throughout pregnancy (Days 0-22) was placed. Histological analysis of the male rat testes showed that the testes on the ligated side were scarcely impaired, while the others became degenerated presenting similar appearances of cryptorchidism. The levels of serum testosterone were lower than the control values. As for the female rats, one animal in the final group was successful in parturition, and implantation appeared to be delayed in the second group. A tail-suspended rat, if it is acclimatized to its environment, could succeed in parturition. By employing this model, we can certainly elucidate some new aspects of mammalian reproduction in space.

Animals↗

The venous tone is not altered after three-week tail suspension in rats.

Cardiovascular deconditioning observed in humans during spaceflight has been suggested to be related in part to changes in venous compliance, mechanisms including skeletal muscle deconditioning. However, increased venous compliance was observed during very short term simulations (24 to 48 hours), and during an over 28-day simulation the hyperdistensibility tended to decrease whereas the muscular changes were still present (2). In the first case, muscular changes can not explain the venous alterations because of the short delay. In the second case, the relationship between muscular and venous alterations disappeared. Finally, it is suggested that factors other than muscular ones could explain the changes in venous compliance observed during spaceflights. The fact that orthostatic hypotension has never been observed after hindlimb suspension in the rat raises issue with the use of tail-suspended rats as a valid model for the study of the mechanisms involved in cardiovascular deconditioning induced by spaceflight in humans. However, in vitro altered responsiveness of the vena cava to norepinephrine were observed in rat after spaceflight and tail suspension. The purpose of the experiments was to verify if any change occurs in venous tone measured in vivo in rats after three-week tail suspension.

Animals↗

[The dynamic changes of NOSmRNA in endothelial cells of aortae and pulmonary arteries in rats under tail suspension].

Objective. Through the observations of dynamic changes of eNOSmRNA and iNOSmRNA in arterial endothelial cells of systematic circulation and pulmonary circulation under simulated weightlessness, to collect some data for studies of the adaptive mechanisms of local regulation in arterial systems. Method. Wistar rats were -30 degrees tail suspended to simulate the effects of weightlessness. The rats were randomly divided into three groups: control group (CON), 7-day tail suspension group (TS7) and 14-day tail suspension group (TS14). Changes of NOSmRNA expresses in endothelial cells of the thoracic aortae and pulmonary arteries were observed with in situ hybridization technique. Result. The eNOSmRNA and iNOSmRNA of thoracic aortic and pulmonary arterial endothelial cells in TS7 rats increased very significantly. The eNOSmRNA of thoracic aortic endothelial cells from TS14 rats returned to control level, but remained very significantly increased in pulmonary arteries. The iNOSmRNA in pulmonary arterial endothelial cells from TS14 rats decreased very significantly, but that in thoracic aortae returned to the control level. Conclusion. The responses of eNOSmRNA and iNOSmRNA in arterial endothelial cells of systematic circulation to tail suspension were similar, but they were different in pulmonary arterial endothelial cells, which might be due to the difference in the peak course of the shift of fluid from lower body entering the pulmonary or systematic circulation during initial period of simulated weightlessness. It could be a kind of important sign of depressed local regulative function under simulated weightlessness and might contribute to orthostatic intolerance after simulated weightlessness.

Animals↗