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A technical feasibility study of surfactant-free drug suspensions using octenyl succinate-modified starches.

Many new drugs exhibit poor wetting behaviour and low aqueous solubility. This is particularly an issue for preclinical studies like toxicological trials, in which considerably higher doses and volumes are being administered compared to clinical studies. Preclinical vehicles typically contain high levels of surfactants that can exert biological effects. However, the biological inertness of vehicles is pivotal for the application in preclinical studies stressing the need in finding new excipients to solve formulation problems of today's drug discovery. The present study investigated the technical feasibility of surfactant-free suspensions using a new poorly soluble drug as model. It was shown that octenyl succinate-modified starches adequately wetted the drug and homogenous tasteless suspensions were obtained. The polymer xanthan gum was identified as macroscopically compatible gelling agent. Concentration effects of xanthan, drug and different modified starches were studied in a D-optimal design with respect to rheological properties. The suspensions were also tested in an analytical centrifuge using NIR transmission profiles to obtain a measure of sedimentation stability under accelerated conditions. The modified starches exhibited only little influence on the viscosity as well as on the yield point in contrast to the rheological effects of xanthan gum. This gelling agent was the main stabilising excipient as the modified starches hindered to a lesser extent sedimentation. The most stable suspensions displayed convenient flow properties. The viscosity at 100 s(-1) and 25 degrees C was in technically acceptable range of 120-140 mPa s in view of a application via gavage or a syringe in animal studies. The results demonstrated that surfactant-free drug suspensions with excellent technical performance can be obtained using octenyl succinate-modified starches. The vehicles were tasteless and based on the experience of modified starches in the food industry, the vehicles should exhibit good tolerability. The future use of such surfactant-free drug suspensions in toxicological, pharmacokinetic and pharmacodynamic studies will have to determine their advantage in terms of biological inertness.

Chemistry, Pharmaceutical↗

Temperature-induced gelation of concentrated silicon carbide suspensions.

Due to the steric barrier provided by the adsorption of the dispersant hypermer KD1 (a polyester/polyamine condensation polymer), stable and low-viscosity suspensions of SiC, Y(2)O(3), and Al(2)O(3) powder mixtures could be prepared in methyl ethyl ketone (MEK)/ethanol (E) solvent with solids loading as high as 60 vol%. The solvency of the dispersant in MEK/E decreased dramatically on cooling. Steady shear viscosity and oscillatory measurements were performed as a function of temperature for suspensions with different solids loading. The viscosity and elastic modulus of suspension increased with decreasing temperature and became more sensitive with the increase of solids loading. The suspensions with solids loading higher than 40 vol% could be solidified with decreasing temperature, but gelation temperature and gelation stiffness decreased with decreasing solids loading. The 60 vol% solid-loaded suspension was a stable and free-flowing fluid at 20 degrees C and gradually transformed to a very highly viscous and elastic system upon cooling to about 13 degrees C. Complete solidification occurred when the temperature was decreased to 5 degrees C. The gelation mechanism was mainly based on the collapse of the adsorbed layer as the temperature decreases, which induced incipient flocculation and formed a stiff network. The gelled body was further strengthened by separation of the dispersant from the suspension.

Carbon Compounds, Inorganic↗

Preparation of cell suspensions for co-transplantation: methodological considerations.

The purpose of the current study was to determine the optimal strategy for preparing cell suspensions for co-transplantation. In the first experiment, the number of Sertoli cell (SC) aggregates and the number of tyrosine hydroxylase positive neurons were compared over time when cell suspensions of Sertoli or ventral mesencephalic cells were kept as a co-suspension mixed at 0 h. Cells from each suspension were dispensed onto glass slides in a manner similar to transplantation. When dispensed in this manner, the number of SC aggregates and TH-positive neurons decreased over 4 h. In experiment 2, the cell suspensions were mixed just prior to injection at each of four timepoints, the number of aggregates and TH neurons was consistent over time. Clearly this latter strategy resulted consistent recovery of both cell types for transplants up to 3 h after suspension preparation.

Animals↗

Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children.

BACKGROUND: Inhaled glucocorticosteroids (GCS) are the most effective long-term controller medications for the treatment of persistent asthma. Currently, however, available delivery devices limit their use in young children. A nebulized formulation of budesonide has been developed to address the needs of infants and young children. OBJECTIVE: To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS. METHODS: Three hundred fifty-nine children were randomized to receive once-daily budesonide inhalation suspension (0.25 mg, 0.50 mg, or 1.0 mg) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks. Efficacy assessments included nighttime/daytime asthma symptoms, pulmonary function (subset of patients), rescue medication use, and treatment discontinuations. Safety was based on adverse events and assessment of HPA-axis function. RESULTS: Demographics, baseline characteristics, asthma symptoms, and pulmonary function were similar across treatment groups. Mean nighttime/daytime asthma symptom scores were 1.19 +/- 0.63 and 1.34 +/- 0.53, respectively. Mean duration of asthma was 36.3 months and mean FEV1 was 81.3% of predicted with 27.7% reversibility. Following 12 weeks of treatment, all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms (P < or = .049) and significant decreases in rescue medication use (P < or = .038) compared with placebo. Significant improvements (P < or = .044) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups. There were no differences between doses of budesonide inhalation suspension. Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups. CONCLUSION: Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments.

Administration, Inhalation↗

[Effect of homogeneity on cell growth and anthocyanin biosynthesis in suspension cultures of Vitis vinifera].

The instability of secondary metabolite production is a ubiquitous problem in plant cell culture. To understand the instability, the investigation of anthocyanin accumulation in suspension cultures of Vitis vinifera, as a model system, has been initiated in our laboratory. Suspension culture of a relatively homogeneous cell line E of V. vinifera, was established by long-term cell line selection by anthocyanin content differentiation. The aggregate size of E was smaller than that of other cell lines obtained by routine screening method. The variation coefficients of anthocyanin content in suspension cultures of E were 8.7% in long-term subcultures and 5% in repeated flasks, respectively. The effects of elicitor, precursor feeding and light irridiation on biomass and anthocyanin accumulation in suspension cultures of E had been investigated and the results showed that all the variation coefficients were lower than 12% and this indicated the importance of homogeneity on stable production in plant cell culture. With the combination treatment of 30micromol/L phenylalanine and 218micromol/L methyl jasmonate in the dark in suspension cultures of E, the anthocyanin content and production in suspension culture of E was 5.89-fold and 4.30-fold of the controls, respectively, and all the variation coefficients of biomass and anthocyanin accumulation were lower than those of the controls in 5 successive subcultures.

Anthocyanins↗

Preparation and characterization of a cocrystalline suspension of [LysB28,ProB29]-human insulin analogue.

Soluble preparations of [LysB28,ProB29]-human insulin analogue (LysPro) exhibit more rapid absorption than human insulin upon subcutaneous injection. Biphasic mixtures of LysPro and intermediate-acting insulin suspensions could provide advantages over current preparations for the treatment of diabetes. To prepare biphasic mixtures of LysPro, a suspension formulation of the analogue is required. We have devised a method for crystallizing LysPro with the basic peptide protamine yielding neutral protamine LysPro (NPL) suspension. The crystallization conditions are strongly dependent on the precipitation procedure and temperature. Using various techniques, the crystalline and suspension characteristics of NPL are found to be similar to human insulin (neutral protamine Hagedorn, NPH) (8:1 molar ratio insulin:protamine, rod-shaped crystals, particle size of 4.0-6.0 microns, and Point of Zero Charge at 6.0-7.0). Using a dog model with NPL or NPH injected subcutaneously and glucose levels clamped at basal, NPL was found to have kinetic and dynamic responses analogous to human insulin NPH [Cmax (maximal insulin or LysPro concentration, ng/mL) of 2.61 +/- 0.22, NPL; 2.58 +/- 0.36, NPH, attained at Tmax (min) of 93 +/- 22, NPL; 145 +/- 33 NPH, and Rmax (maximal rate of glucose infusion, mg/kg min) of 10.8 +/- 1.2, NPL; 13.2 +/- 1.9, NPH, attained at TRmax (min) of 277 +/- 58, NPL; 265 +/- 38, NPH]. There are no statistically significant differences between the insulin curves or the glucose responses. These results provide insight into the mechanism of action of NPH suspensions and the relationship to duration of action. Furthermore, the formulation of a suspension of LysPro having an intermediate time-action makes possible the preparation of stable biphasic mixtures containing LysPro and NPL.

Analysis of Variance↗

Development of a topical suspension containing three active ingredients.

The objective of this study was to develop a topical suspension that contains sarafloxacin hydrochloride (1 mg/mL), triamcinolone acetonide (1 mg/mL), and clotrimazole (10 mg/mL), and is stable at room temperature (15-28 degrees C) for clinical usage. Due to the difference in the physicochemical properties and chemical stability profiles of these three active ingredients, it is a challenge to develop a stable suspension formulation containing these three drugs. In this study, the stability of these drugs in different buffer solutions was determined under different accelerated isothermal conditions. The Arrhenius equation was subsequently utilized to predict the room-temperature stability of these three drugs in these buffer solutions. By knowing the room-temperature solubility of the drugs in the buffer solution, the stability of the drugs in suspension was predicted. As a result, a 0.02 M phosphate buffer (pH 7.0) containing 0.02% (w/v)polysorbate 20, 1% (w/v) NaCl, and 0.1% (w/v) EDTA was determined to be an acceptable medium. In addition, 0.35% (w/v) high-viscosity carboxymethylcellulose (HV-CMC) was first selected as the suspending agent to enhance the redispersibility of the suspension. Stability data further supported that all three drugs were stable in the suspension containing HV-CMC with less than 5% potency loss for at least 6 months at 40 degrees C and 12 months at 25 degrees C. However, the viscosity drop of this HV-CMC formulation at 25 degrees C and 40 degrees C became a product stability concern. To improve the viscosity stability of the suspension, the medium-viscosity carboxymethylcellulose (MV-CMC) was selected to replace the HV-CMC as the suspending agent. The optimal combination of MV-CMC and sodium chloride in achieving the most desirable dispersion properties for the formulation was determined through the use of a 32 factorial design. The optimal formulation containing 1% MV-CMC and 1% sodium chloride has shown improved viscosity stability during storage and has been used for clinical studies.

Administration, Topical↗

THE STIMULATION OF DNA SYNTHESIS IN CULTURES OF RABBIT LYMPH NODE AND SPLEEN CELL SUSPENSIONS BY HOMOLOGOUS CELLS.

An early proliferative response follows the mixing of homologous spleen or lymph node suspensions obtained from two unrelated rabbits. The rate of incorporation of radioactive thymidine has been used as a quantitative measure of this response. Thymus cells do not respond to homologous cell suspensions but may on occasion serve to stimulate the response in homologous spleen or lymph node cells. Homologous erythrocytes or autologous tissues do not stimulate a response. No response occurs if the two cell populations are separated by a Millipore membrane. Autoradiographic studies have established that 1 to 2 per cent of the intial cell population is involved in the response and they are large undifferentiated cells by the time they can first be identified as responders. There was no morphological evidence of any cellular interaction and the viability of mixed suspensions was not measurably different from that observed in separate suspension. Simultaneous additive responses could be obtained to homologous cells and to antigen when cell suspensions from immunized rabbits were used. The interaction of the cell populations from the two rabbits did not appear to suppress the response of each to antigen. The speed and magnitude of the response were in everyway comparable with the secondary response of cell suspensions from immunized rabbits exposed to the immunizing antigen. No evidence was obtained of any enhancement of the response to homologous cells by prior immunization with homologous tissues, but the possibility that it had occurred was not rigidly excluded.

Animals↗

Stability of nevirapine suspension in prefilled oral syringes used for reduction of mother-to-child HIV transmission.

OBJECTIVE: To reduce mother-to-child transmission (MTCT) of HIV, we assessed the stability of nevirapine suspension in an oral dosing syringe over a range of storage conditions. DESIGN: A mother-to-child transmission dosing kit, containing a maternal nevirapine tablet and infant nevirapine suspension in an oral syringe that can be dispensed to the pregnant woman to use at delivery. However, the manufacturer only packages nevirapine in 240 mL, multidose containers and there are no published stability data for nevirapine suspension repackaged in an oral syringe. METHODS: Nevirapine suspension 6 mg/0.6 mL in 3 mL amber BAXA Exacta-Med Oral Dispensers (Baxa Corporation, Englewood, CO) were stored under the following conditions: 26 degrees C/high relative humidity (RH), 40 degrees C/low RH, 40 degrees C/high RH, refrigerated and frozen -30 degrees C for 6 months. The samples were assayed monthly for nevirapine by HPLC-UV. At 3, 4, and 6 months the samples were cultured for pathogens. RESULTS: : There were no significant decreases in nevirapine concentrations in the prefilled syringes compared with baseline. Nevirapine became more concentrated in syringes incubated at 40 degrees C/low RH due to evaporation resulting in the suspension becoming more viscous. No pathogens were cultured. CONCLUSIONS: Nevirapine suspension is stable and pathogen free at varying conditions for 6 months in Baxa Exacta-Med Oral Dispensers.

Administration, Oral↗

Gastric retention of sucralfate gel and suspension in upper gastrointestinal diseases.

This study was designed to compare by scintigraphy the gastric retention of a new dosage form of sucralfate as gel (Gastrogel) with that of sucralfate suspension in 25 patients with upper gastrointestinal symptoms referred for routine endoscopy. After endoscopy 4 subgroups were defined: macroscopically normal mucosa (n = 7), antral gastritis and/or erosions (n = 6), gastric ulcer (n = 6) and duodenal ulcer (n = 6). Each patient received either sucralfate gel or sucralfate suspension in equivalent doses (5 ml containing 1 g sucralfate). Both formulations were labelled with 111 MBq 99mTc-DTPA before administration. The mean value of t1/2 in the total group was significantly longer when patients were taking sucralfate gel (61.6 min) compared to sucralfate suspension (33.8 min) (P < 0.001). The mean values of t1/2 were significantly longer for sucralfate gel compared to sucralfate suspension also among the subgroups (macroscopically normal P < 0.02, antral gastritis P < 0.05, gastric ulcer P < 0.02 and duodenal ulcer P < 0.05). After 2 and 3 hours, the percentage residual activity in the gastric area was significantly higher following administration of sucralfate gel compared to sucralfate suspension. This study has shown that, compared to sucralfate suspension, sucralfate gel persists longer in the stomach of patients with gastritis and peptic ulcer.

Adolescent↗

Relative bioavailability of rectally administered carbamazepine suspension in humans.

The relative bioavailability of an investigational carbamazepine suspension was studied following rectal administration in human volunteers. Carbamazepine, in doses of approximately 6 mg/kg, was given to nine men. The routes of administration were oral tablet, oral suspension, and rectal suspension. There was no significant difference (p greater than 0.05) in total absorption, maximum serum concentration, and time to achieve maximum serum concentration between the orally-administered tablet and the rectally administered suspension. Orally administered suspension was absorbed more quickly and completely. All volunteers complained of a strong defecatory urge after the suspension was given rectally. The slow absorption after rectal administration precludes the use of this route in status epilepticus; however, it may be a satisfactory alternative for maintenance therapy when administration by the oral route is not possible.

Adult↗

Phosphorus-31 and carbon-13 nuclear magnetic resonance studies of glucose and xylose metabolism in cell suspensions and agarose-immobilized cultures of Pichia stipitis and Saccharomyces cerevisiae.

The metabolism of glucose and xylose as a function of oxygenation in Pichia stipitis and Saccharomyces cerevisiae cell suspensions was studied by 31P and 13C nuclear magnetic resonance spectroscopy. The rate of both glucose and xylose metabolism was slightly higher and the production of ethanol was slightly lower in aerobic than in anoxic cell suspensions of P. stipitis. As well, the cytoplasmic pH of oxygenated cells was more alkaline than that of nonoxygenated cells. In contrast, in S. cerevisiae, the intracellular pH and the rate of glucose metabolism and ethanol production were the same under aerobic and anoxic conditions. Agarose-immobilized Pichia stipitis was able to metabolize xylose or glucose for 24 to 60 h at rates and with theoretical yields of ethanol similar to those obtained with anoxic cell suspensions. Cell growth within the beads, however, was severely compromised. The intracellular pH [pH(int)] of the entrapped cells fell to more acidic pH values in the course of the perfusions relative to corresponding cell suspensions. Of importance was the observation that no enhancement in the rate of carbohydrate metabolism occurred in response to changes in the pH(int) value. In contrast to P. stipitis, agarose-immobilized Saccharomyces cerevisiae showed a dramatic twofold increase in its ability to metabolize glucose in the immobilized state relative to cell suspensions. This strain was also able to grow within the beads, although the doubling time for the entrapped cells was longer, by a factor of 2, than the value obtained for log-phase batch cultures. Initially, the pH(int) of the immobilized cells was more alkaline than was observed with the corresponding S. cerevisiae cell suspensions; however, over time, the intracellular pH became increasingly acidic. As with immobilized P. stipitis, however, the pH(int) did not play a key role in controlling the rate of glucose metabolism.

Fermentation↗

Hemolysis evaluation of centrifugal pumps using microcapsule suspension.

OBJECTIVES: Bovine and human blood has been widely used for in vitro hemolysis testing to evaluate centrifugal cardiac assist pumps. However, results from such tests are complicated by variations in the susceptibility of individual red blood cells to shear. The objective of this study was to evaluate the use of microcapsule suspension as an alternative to bovine or human blood for hemolysis testing. METHODS: Microcapsule suspensions of 100 micro m maximal diameter (average 79.1 micro m) with a polyurethane membrane were used. Each microcapsule contained a leuco dye, which was used to measure "hemolysis" in the suspension after exposure to mechanical stress. Six centrifugal pumps were used to measure and compare the hemolysis values of microcapsule suspensions, bovine blood and human blood. RESULTS: Correlations were significant between the hemolysis values measured using microcapsule suspensions and those using bovine blood (R = 0.965, p = 0.002) and human blood (R = 0.940, p = 0.005). CONCLUSIONS: Microcapsule suspension can be successfully used instead of blood to compare the relative hemolytic performance of centrifugal blood pumps.

Animals↗

Low itraconazole serum concentrations following administration of itraconazole suspension to critically ill allogeneic bone marrow transplant recipients.

OBJECTIVE: To report itraconazole serum concentrations following administration of itraconazole suspension via orogastric feeding tubes to 2 critically ill allogeneic bone marrow transplant recipients. CASE SUMMARIES: A 38-year-old man and a 29-year-old man, each allogeneic bone marrow transplant recipients, were treated with oral itraconazole for documented fungal infections. Intubation and mechanical ventilation impeded ingestion of itraconazole capsules. Itraconazole was prepared initially as a suspension in intravenous lipid emulsion 20% and later as a suspension in citric acid 1.5% in D5W USP. Itraconazole serum concentrations were assayed using HPLC. Predose itraconazole serum concentrations were undetectable to 72 ng/mL. Postdose itraconazole serum concentrations were 5-97 ng/mL. Itraconazole concentrations measured in these patients were markedly lower than serum concentrations reported in the literature for similar doses administered to fed subjects. DISCUSSION: Efficacy of this antifungal agent is limited currently by the patient's ability to ingest and absorb the itraconazole capsules. Pathophysiologic factors and suspension formulation issues that likely contributed to decreased itraconazole absorption are discussed. CONCLUSIONS: Preparation and administration of itraconazole as a suspension did not enhance drug absorption in these patients. Furthermore, efficacy of itraconazole suspension may be affected by physical compatibility and chemical stability of the extemporaneous preparations.

Adult↗

Physical changes of beta-sitosterol crystals in oily suspensions during heating.

The aim of this research was to describe the thermal behavior of beta-sitosterol crystals in oil-suspensions with a focus on the role of water during heating. The suspensions were prepared by recrystallization in order to achieve a microcrystalline particle size. The structural changes together with the mechanical properties of the suspensions during heating were studied by using variable temperature X-ray powder diffractometry (VT-XRPD), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). Hydrated beta-sitosterol crystals in an oil-suspension dehydrated, despite the composition of the suspensions, at low temperatures. At high beta-sitosterol concentration, the monohydrate crystal form changed partially to a hemihydrated form, and when only a small amount of water was initially incorporated, the hemihydrate crystal form dehydrated to a mostly anhydrate crystal form. The released water, which was immiscible in the surrounding oil, caused the recrystallization of hydrated beta-sitosterol during cooling. This procedure indicated a reversible dehydration process. Structural and thermal analysis of beta-sitosterol crystals in suspensions, together with mechanical analysis made it possible to understand various physical changes during heating.

Chemical Phenomena↗

Stability of mycophenolate mofetil as an extemporaneous suspension.

OBJECTIVE: To evaluate the physical and chemical stability of a suspension of mycophenolate mofetil (MMF) prepared in the hospital from commercially available MMF capsules. METHODS: Suspensions of MMF were prepared at room temperature and stored at 5, 25, 37, and 45 degrees C over a period of 50 to 210 days. The contents of MMF and its degradation product, mycophenolic acid, in the suspension were measured at various time points by HPLC. RESULTS: MMF suspensions were stable (as determined by the presence of > or = 90% of the labeled amount) at 45 degrees C for at least 11 days, at 37 degrees C for at least 28 days, at 25 degrees C for at least 28 days, and at 5 degrees C for at least 210 days. The suspension was also physically stable at 5 degrees C during the entire test period. CONCLUSIONS: The compounded MMF suspension was stable for at least 11 days at all the temperatures studied and for as long as 210 days at 5 degrees C. This formulation appears to be clinically acceptable and provides a convenient dosage form for pediatric patients and for adults during the early postoperative period.

Chromatography, High Pressure Liquid↗

Effect of sorbitol on the phosphate adsorptive capacity of ferrihydrite suspensions.

The purpose of this study was to stabilize the phosphate adsorptive capacity of aqueous suspensions of ferrihydrite, a potential phosphate binder. Ferrihydrite was precipitated by the addition of 1 N NaOH to 1 M FeCl3 until pH 8.0 was reached. The ferrihydrite suspension was divided into three portions and an amount of sorbitol was added to produce sorbitol concentrations of 0, 1, or 5% w/v, respectively. The phosphate adsorptive capacity and X-ray diffraction pattern were periodically determined during aging at room temperature. The phosphate adsorptive capacity of the ferrihydrite suspension containing 0% sorbitol decreased steadily from 0.012 mgP/mg to 0.007 mgP/mg during the 1-year aging period. In contrast, suspensions containing 1 or 5% sorbitol exhibited constant phosphate adsorptive capacities during this period. X-ray diffraction patterns revealed that ferrihydrite transformed to hematite and goethite during aging of the control suspension. The presence of 1 or 5% sorbitol prevented the transformation of ferrihydrite to more crystalline iron oxides. This study suggests that the phosphate adsorptive capacity of ferrihydrite suspensions can be stabilized by the incorporation of small amounts of sorbitol into the formulation.

Adsorption↗

Adrenocortical response to tail-suspension in young and old rats.

We recently showed that increased glucocorticoid secretion aggravates disuse atrophy when induced by skeletal unloading. Disuse atrophy in the elderly is becoming a serious problem in many developed countries. In this study we attempted to examine how aging affects the glucocorticoid response to skeletal unloading. Three groups of rats (aged 5 weeks, 12 months and 18 months) were subjected to 7 days of hind limb unloading by tail-suspension. Urinary excretion of corticosterone over a 24-hr period were monitored every other day. Corticosterone excretion in the control group of 5-week-old rats was initially 87.4 +/- 12.8 ng/day and did not change throughout the experiment. Tail-suspension experiments yielded a significant increase (more than 3 fold) in excretion on days 1 and 3 of the suspension before returning to control levels. In the 12-month-old rats, a marked increase in the basal corticosterone level was observed in the control rats throughout the experiment, while the increase by tail-suspension was attenuated with a transient, significant increase on day 5. In 18-month-old rats, a further increase in the basal level was observed in the control group, although excretions tended to increase steadily from day 1 to day 3 and remained high until day 7. Urinary excretion of corticosterone among the 18-month-old suspension group was similar to those observed in the control group. These results indicate that the younger (5-week-old) rats adapted the stress load caused either by tail-suspension or manipulation alone faster than the older rats did (12 or 18 months old). The observation that basal corticosterone excretion increases with age suggests, alterations in the hypothalamic-pituitary-adrenal axis among the aged rats which might aggravates disuse atrophy induced by skeletal unloading.

Adaptation, Physiological↗