Eosinophilic bronchitis in asthma: A model for establishing dose-response and relative potency of inhaled corticosteroids

2006 ◽  
Vol 117 (5) ◽  
pp. 989-994 ◽  
Author(s):  
Margaret M. Kelly ◽  
Richard Leigh ◽  
Lata Jayaram ◽  
Charlie H. Goldsmith ◽  
Krishnan Parameswaran ◽  
...  
Keyword(s):  
Dose Response ◽  
Inhaled Corticosteroids ◽  
Relative Potency ◽  
Eosinophilic Bronchitis

scholarly journals Clinical Models to Compare the Safety and Efficacy of Inhaled Corticosteroids in Patients with Asthma

2003 ◽  
Vol 10 (1) ◽  
pp. 27-34 ◽  
Author(s):  
Krishnan Parameswaran ◽  
Richard Leigh ◽  
Paul M O'Byrne ◽  
Margaret M Kelly ◽  
Charlie H Goldsmith ◽  
...  
Keyword(s):  
Dose Response ◽  
Inhaled Corticosteroids ◽  
Adenosine Monophosphate ◽  
Relative Potency ◽  
Pharmaceutical Equivalence ◽  
Inhaled Steroids ◽  
Advantages And Disadvantages ◽  
Flat Dose ◽  
Clinical Models ◽  
Airway Responses

There is no consensus on the methods to compare the clinical efficacy of different inhaled corticosteroids. A comparison needs to be made in terms of relative potency, and studies should include two-, or preferably, three-dose comparisons. A number of clinical models and outcomes are available; they have their relative advantages and disadvantages. While measurements of symptoms and spirometry are easy and readily available, they show a flat dose-response relationship. Measurements of bronchial hyper-responsiveness to exercise and adenosine monophosphate, allergen-induced airway responses, and measurements of inflammation in sputum and exhaled air show steep dose-response relationships, particularly to low doses of inhaled steroids. An uncontrolled asthma model followed by stabilization with a short course of additional steroid, with measurements of airway responsiveness and airway inflammation, in a crossover study seems more promising than the other models. Drug deposition studies and mathematical modelling of drug pharmacokinetics in the airway may provide complementary information to clinical drug relative potency studies. Fine particle dose and emitted doses, rather than the nominal dose, should be considered in the estimation of clinical and systemic effects, respectively. When a second entry (generic) drug is being evaluated in comparison with the innovator drug (same compound and same device), it may be appropriate to consider accepting a generic as bioequivalent if it satisfies pharmaceutical equivalence.

ANTI-OVULATORY ACTIVITY OF STEROIDS ADMINISTERED BY GAVAGE IN THE ADULT OESTRUS RABBIT

1963 ◽  
Vol 42 (2_Suppl) ◽  
pp. S17-S30
Author(s):  
Fred A. Kind ◽  
Ralph I. Dorfman
Keyword(s):  
Dose Response ◽  
Active Compound ◽  
Subcutaneous Injection ◽  
Response Curve ◽  
Parent Compound ◽  
Dose Response Curve ◽  
Relative Potency ◽  
Reference Standard ◽  
Highly Active ◽  
Dose Levels

ABSTRACT Thirty-seven steroids have been studied as orally effective inhibitors of ovulation in the mated oestrus rabbit. Norethisterone served as the reference standard and a dose response curve was established between the 0.31 and 1.25 mg dose levels. Nine highly active anti-ovulatory compounds are described listed in a decreasing order of potency with norethisterone having the arbitrary value of one: 6-chloro-Δ6-dehydro-17α-acetoxyprogesterone (35), 6α-methyl-Δ1-dehydro-17α-acetoxyprogesterone (≥ 10), 6-fluoro-Δ6-dehydro-17α-acetoxyprogesterone(9), 6-methyl-Δ6-dehydro-17α-acetoxyprogesterone (5), Δ6-dehydro-17α-acetoxyprogesterone (≥ 3), 6α-methyl-17α-acetoxyprogesterone (2.6), 6-chloro-Δ1,6-bisdehydro-17α-acetoxyprogesterone (≥ 2), 2-hydroxymethyl-17α-methyl-17β-hydroxyandrostan-3-one (≥ 2), and 6α-fluoro-16α-methyl-17α-acetoxyprogesterone (≥ 1.25). The anti-ovulatory activity of a compound was not related necessarily to the progestational activity of a compound nor to the anti-gonadotrophic activity as measured in parabiotic rats. 6-Chloro-Δ60dehydro-17-acetoxyprogesterone was as effective by gavage as previously shown by subcutaneous injection. 2-Hydroxymethyl-17α-methyl-17β-hydroxyandrostan-3-one was at least 2.5 times more active by gavage than by injection. While 17α-acetoxyprogesterone was a very weak anti-ovulatory steroid, modifications of the structure by addition of methyl or halogen at the 6α position with or without unsaturation greatly increased the activity. 6-Chloro-Δ6-dehydro-27α-acetoxyprogesterone was the most active compound in this series showing a relative potency of 3500 times that of the parent compound 17α-acetoxyprogesterone.

A Random-allocation Graded Dose–Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery

2017 ◽  
Vol 127 (6) ◽  
pp. 934-941 ◽  
Author(s):  
Warwick D. Ngan Kee
Keyword(s):  
Blood Pressure ◽  
Spinal Anesthesia ◽  
Cesarean Delivery ◽  
Dose Response ◽  
Relative Potency ◽  
First Episode ◽  
Response Analysis ◽  
Random Allocation ◽  
Dose Response Study ◽  
Different Doses

Abstract Background Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context. Methods In a random-allocation, graded dose–response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenylephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose–response analysis was performed using nonlinear regression to derive four-parameter logistic dose–response curves, which were compared to determine relative potency. Results Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). The estimated relative potency ratio for the two drugs was 13.1 µg (95% CI, 10.4 to 15.8 µg). Conclusions Comparative dose–response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 µg was norepinephrine 8 µg (95% CI, 6 to 10 µg). These results may be useful to inform the design of future comparative studies.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth

2014 ◽  
Author(s):  
Aniela I Pruteanu ◽  
Bhupendrasinh F Chauhan ◽  
Linjie Zhang ◽  
Sílvio OM Prietsch ◽  
Francine M Ducharme
Keyword(s):  
Dose Response ◽  
Inhaled Corticosteroids ◽  
Persistent Asthma

scholarly journals Oral steroid-sparing effect of high-dose inhaled corticosteroids in asthma

2019 ◽  
Vol 55 (1) ◽  
pp. 1901147 ◽  
Author(s):  
Ingrid Maijers ◽  
Nethmi Kearns ◽  
James Harper ◽  
Mark Weatherall ◽  
Richard Beasley
Keyword(s):  
Dose Response ◽  
Oral Corticosteroid ◽  
Inhaled Corticosteroids ◽  
Adrenal Suppression ◽  
Oral Steroid ◽  
Systemic Effects ◽  
High Dose ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Sparing Effect

BackgroundThe proportion of the efficacy of high-dose inhaled corticosteroids (ICS) in oral corticosteroid-dependent asthma that is due to systemic effects is uncertain. This study aimed to estimate the ICS dose–response relationship for oral corticosteroid-sparing effects in oral corticosteroid-dependent asthma, and to determine the proportion of oral corticosteroid-sparing effects due to their systemic effects, based on the comparative dose–response relationship of ICS versus oral corticosteroids on adrenal suppression.MethodsSystematic review and meta-analysis of randomised controlled trials reporting oral corticosteroid-sparing effects of high-dose ICS in oral corticosteroid-dependent asthma. In addition, reports of oral corticosteroid to ICS dose-equivalence in terms of adrenal suppression were retrieved. The primary outcome was the proportion of the oral corticosteroid-sparing effect of ICS that could be attributed to systemic absorption, per 1000 µg increase of ICS, expressed as a ratio. This ratio estimates the oral corticosteroid sparing effect of ICS due to systemic effects.Results11 studies including 1283 participants reporting oral corticosteroid-sparing effects of ICS were identified. The prednisone dose decrease per 1000 µg increase in ICS varied from 2.1 mg to 4.9 mg, depending on the type of ICS. The ratio of the prednisone-sparing effect due to the systemic effects per 1000 µg of fluticasone propionate was 1.02 (95% CI 0.68–2.08) and for budesonide was 0.93 (95% CI 0.63–1.89).ConclusionIn patients with oral corticosteroid-dependent asthma, the limited available evidence suggests that the majority of the oral corticosteroid-sparing effect of high-dose ICS is likely to be due to systemic effects.

BIOLOGICALLY ACTIVE LUTEINIZING HORMONE (LH) IN PLASMA

1976 ◽  
Vol 83 (3) ◽  
pp. 454-465 ◽  
Author(s):  
P. Romaní ◽  
D. M. Robertson ◽  
E. Diczfalusy
Keyword(s):  
Menstrual Cycle ◽  
Dose Response ◽  
Gel Filtration ◽  
Biologically Active ◽  
Relative Potency ◽  
Response Curves ◽  
Plasma Pool ◽  
Dose Response Curves ◽  
Post Menopausal

ABSTRACT A recently described in vitro bioassay method for the measurement of biologically active LH (Van Damme et al. 1974) has been applied to the plasma of normally menstruating and post-menopausal women. The specificity of the procedure was established according to the following evidence: 1. Parallelism was observed between dose response curves obtained with serial dilutions of a standard LH preparation (HMG 2nd IRP) and plasma pools collected during the follicular phase, at the LH-peak, during the luteal phase and after menopause. 2. There was no evidence for the presence of any synergistic or antagonistic factor in the various plasma specimens. The assay design used to establish this consisted of assaying the standard and plasma pool separately and then together as a mixture followed by an asssessment of the difference (if any) in the potencies obtained. Strict additivity should yield a relative potency of 1.0. Plasma pools which were obtained every 2–3 days throughout the menstrual cycle were assayed using this design against the standard (HMG 2nd IRP) and against a mid-cycle plasma pool obtained at the time of the LH-peak. The latter was also assayed against partially purified plasma fractions obtained from a post-menopausal plasma pool after gel filtration and isoelectric focusing. With the exception of 3 assays, in which the estimates of relative potency were 0.91, 0.94 and 0.95, respectively, in 19 assays of additivity, the fiducial limits always included unity. 3. Non-detectable LH levels were found in the plasma or serum of either hypophysectomized or hypopituitary hypogonadal men or women treated with oestrogen/progestogen combined pills. 4. The presence of calf or human serum in the assay medium is an essential requirement for a valid comparison of standard and unknown preparations. In their absence, non-parallel dose response curves between plasma and standard were obtained. The other established criteria of reliability (sensitivity and precision) were also examined. The method is sufficiently sensitive (3.5–8.0 mIU/ml plasma; HMG (2nd IRP) as standard) for the measurement of LH throughout the cycle. The mean index of precision (λ) in 230 multiple assays was 0.040. It is concluded that the modified bioassay yields valid and reliable estimates of LH when applied to human plasma obtained throughout the menstrual cycle and after menopause.

scholarly journals Parameterizing Dose-Response Models to Estimate Relative Potency Functions Directly

2012 ◽  
Vol 129 (2) ◽  
pp. 447-455 ◽  
Author(s):  
Gregg E. Dinse ◽  
David M. Umbach
Keyword(s):  
Dose Response ◽  
Relative Potency ◽  
Response Models

scholarly journals Dose-response effects of inhaled corticosteroids in asthma: What endpoint should we measure?

2007 ◽  
Vol 101 (1) ◽  
pp. 191
Author(s):  
Graeme P. Currie ◽  
Chris Skinner ◽  
Kris McLaughlin
Keyword(s):  
Dose Response ◽  
Inhaled Corticosteroids
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