- High wbc count and prednisone
Looking for:
- High wbc count and prednisone |
High wbc count and prednisone. Unexplained leukocytosis in a hospitalized patient
- High wbc count and prednisone
Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw uw.
Am J Med. Am J Gastroenterol. J Clin Invest. Skip to main content. Pearl of the Month. Ann Rheum Dis. Glucocorticoid-induced osteoporosis: a review. Clin Rev Bone Miner Metab. Markers of bone metabolism in postmenopausal women with rheumatoid arthritis.
Effects of corticosteroids and hormone replacement therapy. The course of biochemical parameters of bone turnover during treatment with corticosteroids. Correlation between bone markers and bone mineral density in postmenopausal women with osteoporosis. Endocr Pract. Effect of short-term glucocorticoids on serum osteocalcin in healthy young men.
J Bone Miner Res. Changes in calcium and bone metabolism during treatment with low dose prednisone in young, healthy, male volunteers. Clin Rheumatol. Bone density at various sites for prediction of hip fractures. Prevention of early postmenopausal bone loss with cyclical etidronate therapy a double-blind, placebo-controlled study and 1-year follow-up.
Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. Download references. Pfizer personnel were involved in protocol development, conducting the study, data analysis and interpretation, and the decision to submit the manuscript for publication. This study was sponsored by Pfizer Inc. Original data sources supporting the results of this manuscript can be made available on request from the corresponding author.
SD participated in study conduct. All authors contributed to, read, and approved the final manuscript. SD and BGZ have no current financial interests to disclose. The final protocol, any amendments, and informed consent documentation were reviewed and approved by the Institutional Review Board of Jasper Clinic, Inc.
All subjects provided written, informed consent to participate in the study. The study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice guidelines. You can also search for this author in PubMed Google Scholar.
Correspondence to Arnab Mukherjee. Reprints and Permissions. Fleishaker, D. Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study.
BMC Musculoskelet Disord 17 , Download citation. Received : 04 December Accepted : 11 June Published : 16 July Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Research article Open Access Published: 16 July Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study Dona L. Fleishaker 1 , Arnab Mukherjee 1 , Fredrick S.
Abstract Background Glucocorticoids GCs , such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Methods In this randomized, single-blind, placebo-controlled, crossover study A , 37 healthy subjects received placebo or a prednisone dose from 2.
Results Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts.
Conclusions This characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile.
Trial registration number NCT retrospectively registered: 21 April Background Glucocorticoids GCs are commonly used to manage inflammatory and immunologically-mediated conditions [ 1 — 3 ], and continue to have a prominent place in the clinic despite having a profile of serious adverse effects that are dose- and time-dependent [ 4 , 5 ].
Study design This randomized, single-blind, placebo-controlled, crossover study A was designed to characterize the dose—response of prednisone on biomarkers of GC receptor agonism. Table 1 Treatment sequences Full size table. Junqueira LC, Carneiro J. Blood cells. In: Basic Histology.
Junqueira LC, Caneiro J eds. New York, NY. Abramson N, Melton B. Leukocytosis: basic of clinical assessment. Am Fam Physician ; Prednisone-induced leukocytosis. Influenced of dosage, method and duration of administration on the degree of leukocytosis. It can be concluded that even small doses of prednisone, administered over a prolonged period of time, can induce extreme and persistent leukocytosis. This observation is of consequence especially when infection is suspected, particularly in an immunocompromised host.
S Mesens and S Ramael have no conflict of interests to report. The authors want to thank Gary Herman and Alice Reicin for their contributions to the study design and for several helpful discussions, as well as Belma Dogdas for her analysis of the cutaneous allergen challenge results. Dr Brian Schapiro performed the quantitative histological analysis of skin biopsy samples.
We are also very grateful to Dr Paul Atkins for his insights, suggestions and critical reviews of drafts of this manuscript. Mechanisms involved in the side effects of glucocorticoids. Vegiopoulos A , Herzig S. Glucocorticoids, metabolism and metabolic diseases.
Molecular and Cellular Endocrinology 43 — Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? European Journal of Clinical Investigation 39 81 — Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 25 — Glucocorticoid-induced diabetes mellitus: prevalence and risk factors in primary renal diseases.
Clinical Practice c54 — c Schneiter P , Tappy L. Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans. American Journal of Physiology E — E Saag KG. Glucocorticoid-induced osteoporosis. Endocrinology and Metabolism Clinics of North America 32 — , vii.
De Nijs RN. Glucocorticoid-induced osteoporosis: a review on pathophysiology and treatment options. Minerva Medica 99 23 — Current Opinion in Endocrinology, Diabetes, and Obesity 14 — Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporosis International 18 — Effects of low-dose prednisone on bone metabolism.
Journal of Bone and Mineral Research 20 — Effect of low-dose prednisone with calcium and calcitriol supplementation on calcium and bone metabolism in healthy volunteers. British Journal of Rheumatology 37 27 — Effect of short-term glucocorticoids on serum osteocalcin in healthy young men. Journal of Bone and Mineral Research 3 — Short-term effects of glucocorticoid therapy on biochemical markers of bone metabolism in Japanese patients: a prospective study.
Journal of Bone and Mineral Metabolism 26 — Effects of short-term treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men. Bone 23 — The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporosis International 13 —
❾-50%}- High wbc count and prednisone
Paauw at dpaauw uw. Am J Med. Am J Gastroenterol. J Clin Invest. Skip to main content. Pearl of the Month. Unexplained leukocytosis in a hospitalized patient. By Douglas S. Paauw, MD. What is the most likely cause of his leukocytosis? Due to these known serious adverse effects, a GC such as prednisone is used at the lowest effective dose 5—7. One of the most prevalent adverse effects is that on bone remodeling, specifically, an uncoupling of bone formation and resorption in favor of bone loss via direct effects on osteoblasts [ 8 ].
Indeed, the most common form of iatrogenic osteoporosis is GC induced [ 9 ]. Many other adverse effects, such as electrolyte imbalance, weight gain, and metabolic disturbances, result from GC-induced effects on other tissues including the hypothalamic-pituitary-adrenal HPA axis [ 10 , 11 ]. Similarly, due to a plethora of effects on leukocytes and vascular endothelial cells, such as altered cell distribution patterns, immobilization, and apoptosis, GC therapy can result in dramatic changes in circulating white blood cell profiles that may contribute to an increased risk of GC-associated infection [ 12 — 14 ].
Recent drug discovery and development efforts have focused on approaches to reduce adverse effects, while maintaining efficacy of GC therapy. These approaches include development of a modified-release prednisone formulation and discovery of selective GC receptor ligands that putatively dissociate anti-inflammatory effects mediated by genomic transrepression from adverse effects mediated by genomic transactivation [ 7 , 15 — 18 ].
Despite the present understanding of the known adverse effects of GC therapy, and recent drug development efforts to potentially dissociate efficacy and safety of GCs, the dose—response and time course of the effect of current GCs on various biomarkers of GC receptor agonism anti-inflammatory and adverse effects have not been systematically characterized.
The characterization of the safety and pharmacodynamics PD of multiple doses of a standard GC such as prednisone, over the commonly used clinical dose range 2. The present study was conducted to further characterize the safety and dose—response of 7-day prednisone administration using biomarkers of GC receptor agonism in a healthy adult population.
Subjects with evidence or history of clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease including drug allergies, but excluding untreated, asymptomatic seasonal allergies at time of dosing or any condition possibly affecting drug absorption were excluded from the study. This randomized, single-blind, placebo-controlled, crossover study A was designed to characterize the dose—response of prednisone on biomarkers of GC receptor agonism.
Within 28 days of screening, all eligible subjects were randomly assigned to one of seven treatment sequences, each with three 7-day treatment periods separated by a day washout period Table 1.
The treatments in each sequence included either three of the six prednisone doses evaluated in the study 2. In the first treatment period only, all subjects had baseline assessments on Day 0, the day prior to dosing. Serum samples for morning cortisol were obtained immediately prior to dosing or nominal dosing time on Day 0 baseline, day prior to first dosing and on Days 1 first day of dosing , 2, 4, and 8, in each of the three 7-day treatment periods.
Serum samples for cortisol were obtained at 2, 4, 8, and 12 h following the first sample on Day 0 Period 1 only and following the first prednisone dose on Day 1. A radioimmunoassay Roche Diagnostics, Indianapolis, IN was used initially for measurement of cortisol in serum, but the results indicated the possibility of assay interference from prednisone and its metabolite prednisolone.
Stability of cortisol was confirmed in plasma for a time period greater than the duration of storage with up to three freeze-thaw cycles. Serum was also obtained for assaying cortisol levels on Day 8 before and 30 min after low-dose adrenocorticotropic hormone ACTH stimulation. Subjects with an abnormal low-dose ACTH stimulation response on Day 8 were administered the test again after 2 weeks. A radioimmunoassay was used for measurement of serum cortisol from the low-dose ACTH stimulation test.
Assay interference from prednisone and prednisolone was considered unlikely, since complete washout of both moieties was expected at the time these samples were obtained.
Complete blood count with differential data for neutrophils, eosinophils, and lymphocytes are shown was obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8.
Plasma samples for OC, a biomarker of bone formation, were collected serially on Day 0 at nominal dosing time and 2, 4, 8, and 12 h thereafter and serially post-dose on Day 1 2, 4, 8, and 12 h , immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Day 8; plasma samples for procollagen type 1 N-propeptide P1NP , also a bone formation marker, were collected 12 h post-dose on Day 1, immediately prior to dosing on Days 2 and 4, and on Days 0 and 8.
Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen uNTX , a biomarker of bone resorption, were collected from the second pre-noon voiding of the bladder on Days 0, 1, 2, 4, and 8. OC and uNTX were assayed using an enzyme-linked immunosorbent assay method. P1NP was assayed by a validated radioimmunoassay.
A kinetic modification of the Jaffe reaction was used for the quantitative measurement of urinary creatinine uCr. Pacific Biometrics, Inc. Serum samples for fasting glucose and insulin were obtained immediately prior to dosing on Days 0, 1, 2, 4, 6, and 7. For the oral glucose tolerance test OGTT , the subjects were to ingest 75 g of a glucose solution within 5 min of receiving study medication on Day 6; this solution was to be ingested within 10 min, and blood samples for glucose were then collected at 0.
Serum samples for triglycerides were obtained immediately prior to dosing on Days 0, 1 and 4, and on Day 8 and, for adiponectin, immediately prior to dosing on Days 0, 1 and 4, and on Day 8.
Adverse events AEs were monitored throughout, and vital signs sitting blood pressure and pulse rate were performed at screening and prior to dosing on Days 0, 1, 4, and 8; laboratory safety tests hematology, blood chemistry, urinalysis, and hormone and chronic infection tests , were performed at screening and on Day 0; a post-void weight was taken at screening and on Days 1 and 8 of each treatment period.
The change from baseline in primary biomarker endpoints biomarkers of AEs and biomarkers of anti-inflammatory activity for each prednisone dose was compared with the change from baseline for placebo, using a repeated-measures crossover analysis of covariance model containing effects for sequence, period, time, dose, time by dose interaction, and subject within sequence as random effect , as well as baseline as a covariate.
Overall, 37 subjects were screened; all were assigned to study treatment. Five subjects were assigned to each of the seven treatment sequences A-G and received either three active doses of prednisone 2. Ultimately, each of the treatments was received by 15 or 16 subjects. The proportion of subjects completing the study was Two subjects in treatment sequence E prednisone 20 mg, 40 mg, and placebo in Periods 1, 2, and 3, respectively and one subject in treatment sequence G prednisone 60 mg, placebo, and prednisone 5 mg in periods 1, 2, and 3, respectively discontinued from the study.
The subject in treatment sequence G discontinued during Period 2 while receiving placebo due to AEs related to the study treatment. The other two subjects discontinued from the study for reasons not related to study treatment; both subjects withdrew consent. One subject in treatment sequence E was also discontinued during Period 2 while receiving prednisone 40 mg; both subjects that discontinued during Period 2 were replaced following approval by the study statistician.
The other subject in treatment sequence E was in treatment period 1 at discontinuation, and was not replaced. Demographic characteristics were similar among the treatment groups.
Subjects were aged between 18 and 50 years, and the majority were white and male Table 2. Plasma cortisol concentrations decreased rapidly following the first dose of prednisone, and then recovered in a dose-dependent manner Fig. Mean serum cortisol concentrations up to 24 h following the first daily dose of prednisone. Pretreatment cortisol concentrations over 24 h were measured in all subjects the day prior to the first day of dosing in Period 1.
Two subjects required a third test and one subject required a fourth test before their responses returned to normal. The two subjects who did not achieve a normal response within 2 weeks received prednisone doses of either 40 mg or 60 mg in the last treatment period.
Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent effects on white blood cell counts. Eosinophil counts relative to placebo demonstrated acute dose-dependent reductions on Day 1. A significant reduction versus placebo was observed as early as 2 h post-dose with prednisone 60 mg Fig.
At 4 h reductions were significant at all doses, and from 4—12 h counts relative to placebo were relatively stable Fig. Reductions in eosinophil counts relative to placebo were seen at most doses on Day 8 Fig. Mean change from baseline difference from placebo in white blood cell counts.
Eosinophil, neutrophil, and lymphocyte counts for Day 1 by hour a , c , e and for Days 1 through 8 b , d , f for each daily prednisone dose. Differences in neutrophil counts relative to placebo were variable over the next 7 days: significant increases were observed with higher doses on Days 2 and 8, whereas decreases, which were significant with the lower doses, were seen on Day 4 Fig.
As was observed with neutrophil counts, lymphocyte counts demonstrated acute dose-dependent reductions versus placebo on Day 1, with significant reductions observed with all doses as early as 2 h post-dose Fig. Reductions in lymphocyte counts relative to placebo were greatest with most doses at 4 h post-dose, and were similar to placebo with the lower doses at 12 h post-dose Fig.
Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent effects on biomarkers of bone metabolism. OC and P1NP are biomarkers of bone formation. On Day 1, plasma OC significantly decreased relative to placebo as early as 2 h post-dose, and continued to decrease in a dose-dependent manner until 12 h post-dose Fig.
Therefore, it is important for the clinician to put all of these factors in context when assessing, monitoring and treating the patient's medical condition. About Us Disclaimer Contact Us. Toggle navigation. Please enter text to search. Search by Outlines. Set Search Limits. Summary : Glucocorticoids e. The biologic effects that contribute to the increase in PMNs in the circulation are multifactorial with demargination of neutrophils contributing the most, as well as delayed migration of PMNs into tissue, delayed rate of apoptosis and the release of immature bands neutrophils from the bone marrow into the circulation.
Editor-in-Chief: Anthony J. Junqueira LC, Carneiro J. Blood cells. In: Basic Histology. Junqueira LC, Caneiro J eds. The long-term pattern of prednisone-induced leukocytosis was examined in 80 patients.
Although the degree of leukocytosis was related to the dosage administered, it did appear sooner with higher doses.
A year-old man is evaluated for a persistent leukocytosis. He was hospitalized 10 days ago for a severe exacerbation of chronic obstructive pulmonary disease. He was intubated for 3 days, was diagnosed with a left lower lobe pneumonia, and was treated with antibiotics.
His white blood cell count on admission was 20, per mcL. He is on oral prednisone 15 mg once daily. Chest x-ray shows no infiltrate. Urinalysis without WBCs. The most likely diagnosis in otherwise unexplained leukocytosis in a hospitalized patient is C. Anna Wanahita, MDof the St. John Clinic in Tulsa, Okla. For study purposes, leukocytosis was defined as a WBC greater than 15, per mcL.
Any patient for whom C. More than half of the patients with a positive C. In another study, Mamatha Bulusu, and colleagues did a retrospective study of 70 hospitalized patients who had diarrhea and underwent testing for C. The mean WBC for C.
They described three patterns: one in which leukocytosis occurred at the onset of diarrhea; a pattern in which unexplained leukocytosis occurred days prior to diarrhea; and a pattern in which patients treated for infection with leukocytosis had a worsening of their leukocytosis at the onset of diarrheal symptoms. Treatment with metronidazole led to a resolution of leukocytosis in all the C. Prednisone can increase WBC as early as the first day of therapy.
The important pearl is that steroid-induced leukocytosis involves an increase of polymorphonuclear white blood cells with a rise in monocytes and a decrease in eosinophils and lymphocytes. Douglas S. Pearl: Think of underlying C. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington.
Contact Dr. Paauw at dpaauw uw. Am J Med. Am J Gastroenterol. J Clin Invest. Skip to main content. Pearl of the Month. Unexplained leukocytosis in a hospitalized patient. By Douglas S. Paauw, MD. What is the most likely cause of his leukocytosis?
A Pulmonary embolus. B Lung abscess. C Perinephric abscess. D Prednisone. E Clostridium difficile infection. Next Article: Short, simple antibiotic courses effective in latent TB. Infectious Diseases Pulmonology.
Menu Menu Presented by. Menu Close.
Glucocorticoids (e.g., dexamethasone, methylprednisolone, prednisone) are known to increase the white blood cell (WBC) count upon their initiation. The increase. Leukocytosis reached maximal values within two weeks in most cases, after which the white blood cell count decreased, albeit not to pretreatment levels. The. Differential peripheral WBC counts changed significantly within hours of prednisone administration. Ex vivo, LPS-stimulated TNF-α was significantly reduced. Prednisone can increase WBC as early as the first day of therapy. The elevation and rapidity of increase are dose related. The important pearl. Glucocorticoids (e.g., dexamethasone, methylprednisolone, prednisone) are known to increase the white blood cell (WBC) count upon their initiation. The increase. New York, NY. There was no discernible effect of prednisone on either day 1 or 7 data not shown. Accordingly, the OGTT was conducted during the mid-late afternoon. Vegiopoulos A Herzig S. Short-term treatment 7—14 days with oral prednisone is used for many acute inflammatory and allergic conditions. Two subjects in treatment sequence E prednisone 20 mg, 40 mg, and placebo in Periods 1, 2, and 3, respectively and one subject in treatment sequence G prednisone 60 mg, placebo, and prednisone 5 mg in periods 1, 2, and 3, respectively discontinued from the study. Ultimately, each of the treatments was received by 15 or 16 subjects.Metrics details. Glucocorticoids GCs , such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent.
Short-term treatment 7—14 days with oral prednisone is used for many acute inflammatory and allergic conditions.
This study was conducted to characterize the safety and pharmacodynamic PD dose—response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.
In this randomized, single-blind, placebo-controlled, crossover study A , 37 healthy subjects received placebo or a prednisone dose from 2.
White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide P1NP were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8.
Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen uNTX were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8. Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts.
Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin.
The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects. This characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile.
NCT retrospectively registered: 21 April Peer Review reports. Glucocorticoids GCs are commonly used to manage inflammatory and immunologically-mediated conditions [ 1 — 3 ], and continue to have a prominent place in the clinic despite having a profile of serious adverse effects that are dose- and time-dependent [ 4 , 5 ].
Due to these known serious adverse effects, a GC such as prednisone is used at the lowest effective dose 5—7. One of the most prevalent adverse effects is that on bone remodeling, specifically, an uncoupling of bone formation and resorption in favor of bone loss via direct effects on osteoblasts [ 8 ]. Indeed, the most common form of iatrogenic osteoporosis is GC induced [ 9 ]. Many other adverse effects, such as electrolyte imbalance, weight gain, and metabolic disturbances, result from GC-induced effects on other tissues including the hypothalamic-pituitary-adrenal HPA axis [ 10 , 11 ].
Similarly, due to a plethora of effects on leukocytes and vascular endothelial cells, such as altered cell distribution patterns, immobilization, and apoptosis, GC therapy can result in dramatic changes in circulating white blood cell profiles that may contribute to an increased risk of GC-associated infection [ 12 — 14 ].
Recent drug discovery and development efforts have focused on approaches to reduce adverse effects, while maintaining efficacy of GC therapy. These approaches include development of a modified-release prednisone formulation and discovery of selective GC receptor ligands that putatively dissociate anti-inflammatory effects mediated by genomic transrepression from adverse effects mediated by genomic transactivation [ 7 , 15 — 18 ]. Despite the present understanding of the known adverse effects of GC therapy, and recent drug development efforts to potentially dissociate efficacy and safety of GCs, the dose—response and time course of the effect of current GCs on various biomarkers of GC receptor agonism anti-inflammatory and adverse effects have not been systematically characterized.
The characterization of the safety and pharmacodynamics PD of multiple doses of a standard GC such as prednisone, over the commonly used clinical dose range 2. The present study was conducted to further characterize the safety and dose—response of 7-day prednisone administration using biomarkers of GC receptor agonism in a healthy adult population. Subjects with evidence or history of clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease including drug allergies, but excluding untreated, asymptomatic seasonal allergies at time of dosing or any condition possibly affecting drug absorption were excluded from the study.
This randomized, single-blind, placebo-controlled, crossover study A was designed to characterize the dose—response of prednisone on biomarkers of GC receptor agonism. Within 28 days of screening, all eligible subjects were randomly assigned to one of seven treatment sequences, each with three 7-day treatment periods separated by a day washout period Table 1. The treatments in each sequence included either three of the six prednisone doses evaluated in the study 2. In the first treatment period only, all subjects had baseline assessments on Day 0, the day prior to dosing.
Serum samples for morning cortisol were obtained immediately prior to dosing or nominal dosing time on Day 0 baseline, day prior to first dosing and on Days 1 first day of dosing , 2, 4, and 8, in each of the three 7-day treatment periods.
Serum samples for cortisol were obtained at 2, 4, 8, and 12 h following the first sample on Day 0 Period 1 only and following the first prednisone dose on Day 1. A radioimmunoassay Roche Diagnostics, Indianapolis, IN was used initially for measurement of cortisol in serum, but the results indicated the possibility of assay interference from prednisone and its metabolite prednisolone. Stability of cortisol was confirmed in plasma for a time period greater than the duration of storage with up to three freeze-thaw cycles.
Serum was also obtained for assaying cortisol levels on Day 8 before and 30 min after low-dose adrenocorticotropic hormone ACTH stimulation. Subjects with an abnormal low-dose ACTH stimulation response on Day 8 were administered the test again after 2 weeks. A radioimmunoassay was used for measurement of serum cortisol from the low-dose ACTH stimulation test. Assay interference from prednisone and prednisolone was considered unlikely, since complete washout of both moieties was expected at the time these samples were obtained.
Complete blood count with differential data for neutrophils, eosinophils, and lymphocytes are shown was obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8.
Plasma samples for OC, a biomarker of bone formation, were collected serially on Day 0 at nominal dosing time and 2, 4, 8, and 12 h thereafter and serially post-dose on Day 1 2, 4, 8, and 12 h , immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Day 8; plasma samples for procollagen type 1 N-propeptide P1NP , also a bone formation marker, were collected 12 h post-dose on Day 1, immediately prior to dosing on Days 2 and 4, and on Days 0 and 8.
Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen uNTX , a biomarker of bone resorption, were collected from the second pre-noon voiding of the bladder on Days 0, 1, 2, 4, and 8. OC and uNTX were assayed using an enzyme-linked immunosorbent assay method. P1NP was assayed by a validated radioimmunoassay. A kinetic modification of the Jaffe reaction was used for the quantitative measurement of urinary creatinine uCr.
Pacific Biometrics, Inc. Serum samples for fasting glucose and insulin were obtained immediately prior to dosing on Days 0, 1, 2, 4, 6, and 7.
For the oral glucose tolerance test OGTT , the subjects were to ingest 75 g of a glucose solution within 5 min of receiving study medication on Day 6; this solution was to be ingested within 10 min, and blood samples for glucose were then collected at 0. Serum samples for triglycerides were obtained immediately prior to dosing on Days 0, 1 and 4, and on Day 8 and, for adiponectin, immediately prior to dosing on Days 0, 1 and 4, and on Day 8.
Adverse events AEs were monitored throughout, and vital signs sitting blood pressure and pulse rate were performed at screening and prior to dosing on Days 0, 1, 4, and 8; laboratory safety tests hematology, blood chemistry, urinalysis, and hormone and chronic infection tests , were performed at screening and on Day 0; a post-void weight was taken at screening and on Days 1 and 8 of each treatment period. The change from baseline in primary biomarker endpoints biomarkers of AEs and biomarkers of anti-inflammatory activity for each prednisone dose was compared with the change from baseline for placebo, using a repeated-measures crossover analysis of covariance model containing effects for sequence, period, time, dose, time by dose interaction, and subject within sequence as random effect , as well as baseline as a covariate.
Overall, 37 subjects were screened; all were assigned to study treatment. Five subjects were assigned to each of the seven treatment sequences A-G and received either three active doses of prednisone 2. Ultimately, each of the treatments was received by 15 or 16 subjects. The proportion of subjects completing the study was Two subjects in treatment sequence E prednisone 20 mg, 40 mg, and placebo in Periods 1, 2, and 3, respectively and one subject in treatment sequence G prednisone 60 mg, placebo, and prednisone 5 mg in periods 1, 2, and 3, respectively discontinued from the study.
The subject in treatment sequence G discontinued during Period 2 while receiving placebo due to AEs related to the study treatment. The other two subjects discontinued from the study for reasons not related to study treatment; both subjects withdrew consent. One subject in treatment sequence E was also discontinued during Period 2 while receiving prednisone 40 mg; both subjects that discontinued during Period 2 were replaced following approval by the study statistician.
The other subject in treatment sequence E was in treatment period 1 at discontinuation, and was not replaced. Demographic characteristics were similar among the treatment groups.
Subjects were aged between 18 and 50 years, and the majority were white and male Table 2. Plasma cortisol concentrations decreased rapidly following the first dose of prednisone, and then recovered in a dose-dependent manner Fig. Mean serum cortisol concentrations up to 24 h following the first daily dose of prednisone. Pretreatment cortisol concentrations over 24 h were measured in all subjects the day prior to the first day of dosing in Period 1.
Two subjects required a third test and one subject required a fourth test before their responses returned to normal. The two subjects who did not achieve a normal response within 2 weeks received prednisone doses of either 40 mg or 60 mg in the last treatment period. Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent effects on white blood cell counts.
Eosinophil counts relative to placebo demonstrated acute dose-dependent reductions on Day 1. A significant reduction versus placebo was observed as early as 2 h post-dose with prednisone 60 mg Fig. At 4 h reductions were significant at all doses, and from 4—12 h counts relative to placebo were relatively stable Fig. Reductions in eosinophil counts relative to placebo were seen at most doses on Day 8 Fig. Mean change from baseline difference from placebo in white blood cell counts.
Eosinophil, neutrophil, and lymphocyte counts for Day 1 by hour a , c , e and for Days 1 through 8 b , d , f for each daily prednisone dose. Differences in neutrophil counts relative to placebo were variable over the next 7 days: significant increases were observed with higher doses on Days 2 and 8, whereas decreases, which were significant with the lower doses, were seen on Day 4 Fig.
As was observed with neutrophil counts, lymphocyte counts demonstrated acute dose-dependent reductions versus placebo on Day 1, with significant reductions observed with all doses as early as 2 h post-dose Fig. Reductions in lymphocyte counts relative to placebo were greatest with most doses at 4 h post-dose, and were similar to placebo with the lower doses at 12 h post-dose Fig. Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent effects on biomarkers of bone metabolism.
OC and P1NP are biomarkers of bone formation. On Day 1, plasma OC significantly decreased relative to placebo as early as 2 h post-dose, and continued to decrease in a dose-dependent manner until 12 h post-dose Fig. P1NP levels increased slightly relative to placebo on Day 2, and then decreased in a dose- and time-dependent manner until Day 8 Fig. Mean change from baseline difference from placebo in biomarkers of bone metabolism. Urinary NTX is a biomarker of bone loss.
The results for fasting glucose and insulin on Days 1 and 8 are shown in Table 4. Increases from baseline in both glucose and insulin concentrations at 0. After 6 days of prednisone treatment, the changes from baseline in both glucose and insulin concentrations relative to placebo were not significant at most time points data not shown.
The effect of prednisone relative to placebo on serum triglyceride levels was variable. On Day 1, prednisone 20 mg and 40 mg significantly raised triglyceride levels. On Day 8, prednisone raised triglyceride levels, but the relationship to dose was inconsistent, and the impact generally was not significant Table 4.
Dose- and time-dependent effects of prednisone on adiponectin were also observed relative to placebo. On Day 8, adiponectin was significantly increased with higher prednisone doses Table 4.
However, no clear pattern for the treatment arms appeared in either assessment. There were no serious adverse events SAEs or deaths reported. There were no clinically significant changes in vital signs or body weight at any time point. The incidence of AEs with prednisone was not dose related. Three subjects reported severe AEs; all were headaches experienced while on prednisone 2.
This study was designed to characterize the dose—response and time course of prednisone effects on biomarkers of GC receptor agonism in a healthy adult population over 7 days.
Daily doses of prednisone up to 60 mg were generally well-tolerated and resulted in dose- and time-dependent effects on a number of biomarkers. As would be expected, a decrease relative to placebo was noted in biomarkers of bone formation OC and P1NP , whereas there was an increase in a biomarker of bone turnover uNTX.
Comments
Post a Comment