Pharmacokinetic interaction between efavirenz and ketoconazole in rats

1. It is well known that efavirenz and ketoconazole act as an inducer and inhibitor of CYP3A4, respectively. As a result of these actions, co-administration of these drugs may result in changes in the pharmacokinetic parameters of one or both of them.

2. Duodenum-cannulated rats have been used to compare the effect of intraduodenal (KC_i.d.) and intravenous administration of ketoconazole (KC_i.v.) on the pharmacokinetics of efavirenz after intraduodenal administration, as well as the potential effect of efavirenz as a CYP450 inducer on ketoconazole pharmacokinetic profile.

3. While KC_i.v. did not show any significant effect on efavirenz pharmacokinetic profile, KC_i.d. increased significantly (p < 0.05) the peak concentration (C_max) and the area under the plasma concentration–time curve (AUC) of efavirenz by 25.5% and 44.5%, respectively. In addition, the time necessary to reach peak concentration (T_max) increased markedly by 71%. However, the mean total clearance (CL/F) of efavirenz was significantly decreased by 45%. Efavirenz did not produce any alteration in ketoconazole pharmacokinetics.

4. These findings suggest that when the treatment starts with enteral administration of ketoconazole, the inhibitor effect on CYP450 prevails over the inducer effect of efavirenz.

     

Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study

AIMS

To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control.

METHODS

A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers ({"type":"clinical-trial","attrs":{"text":"NCT00903747","term_id":"NCT00903747"}}NCT00903747). Volunteers were randomized to receive prucalopride 2–10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally.

RESULTS

Estimated mean difference in study specific corrected QT interval (QT_cSS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl −0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT_cSS were all <10 ms. There were no outlying QT_cSS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT_cSS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min^–1), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment.

CONCLUSION

Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.     

The effects of ketoconazole on ziprasidone pharmacokinetics —a placebo‐controlled crossover study in healthy volunteers

Aims   To assess the effects of multiple oral doses of ketoconazole on the single‐dose pharmacokinetics of oral ziprasidone HCl.
Methods   This was a 14‐day, open‐label, randomized, crossover study in 14 healthy subjects aged 18–31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash‐out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods.
Results   Co‐administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,∞) increased by 33%, from 899 ng ml^{− 1} h with placebo to 1199 ng ml^{− 1} h with ketoconazole. Mean C _max increased by 34%, from 89 ng ml^{− 1} to 119 ng ml^{− 1}, respectively. The treatment effect on both of these parameters was statistically significant ( P < 0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study.
Conclusions   The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.     

Pharmacokinetic interaction between fluoxetine and metoclopramide in healthy volunteers

The pharmacokinetic interaction of fluoxetine with metoclopramide in healthy volunteers was evaluated. A dose of 20 mg metoclopramide in combination with 60 mg fluoxetine was administered to 24 healthy male volunteers in a two treatment study design, separated by 8 days in which the fluoxetine alone was administered as a single p.o. dose daily. Plasma concentrations of metoclopramide were determined during a 24 h period following drug administration. Metoclopramide plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of metoclopramide were calculated using non-compartmental analysis. In the two periods of treatment, the mean peak plasma concentrations (Cmax) were 44.02 ng/ml (metoclopramide alone) and 62.72 ng/ml (metoclopramide after pre-treatment with fluoxetine). The times taken to reach Cmax and tmax, were 1.15 h and 1.06 h, respectively. The total areas under the curve (AUC(0-infinity)) were 312.61 ng.h/ml and 590.62 ng.h/ml, respectively. The half-life values (t1/2) were 5.52 h and 8.47 h. Statistically significant differences were observed for both AUC(0-infinity) and t1/2 of metoclopramide when administered alone or after 8 days treatment with fluoxetine. The experimental data demonstrate the pharmacokinetic interaction between fluoxetine and metoclopramide and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.     

Pharmacokinetic interaction between ketoconazole and SPP301 in healthy volunteers

BACKGROUND: SPP301 is a potent and highly selective ETA receptor blocker. The primary aim of the present study was to investigate the effect of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of SPP301. METHODS: In a randomized, open-label 2-period oral crossover study, 12 healthy male subjects received treatments A and B. Treatment A consisted of 200 mg ketoconazole once daily on Days 1 - 4 and concomitantly 5 mg SPP301 on Day 3. Treatment B consisted of 5 mg SPP301 administered alone. Plasma concentrations of SPP301 and its hydroxymethyl metabolite were measured by LC-MS/MS. RESULTS: Ketoconazole coadministration increased the systemic availability of SPP301 and its hydroxymethyl metabolite 3-fold and prolonged their half-lives by a factor of 2. The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of ketoconazole for SPP301 and its metabolite were C(max) (maximum plasma concentration) 1.22 (1.13, 1.32) and 1.2 (1.05, 1.37), AUC(0-infinity) (area under the plasma concentration-time curve from time zero to infinity) 3.16 (2.84, 3.51) and 3.14 (2.49, 3.70) and t1/2 (apparent terminal half-life) 2.21 (1.55, 2.87) and 2.00 (1.17, 2.84), i.e. an increase of systemic exposure by a factor of 3.2, with individual exposures increasing up to 5.9-fold. Single oral doses of SPP301 were well tolerated when administered alone or together with multiple doses of ketoconazole. CONCLUSION: In the presence of potent CYP3A4 inhibitors exposure of SPP301 may be increased up to 6-fold.     

Troleandomycin-triazolam interaction in healthy volunteers: Pharmacokinetic and psychometric evaluation

Summary Seven healthy volunteers received a single oral dose of triazolam 0.25 mg after 7 days on troleandomycin 2 g/day p.o. or placebo in a double-blind cross-over study. Plasma triazolam and psychometric and memory tests (including Critical Flicker Fusion threshold, Choice Reaction Time, Digit Symbol Substitution and Self-Rating Scales) were assessed at regular intervals after the final treatment.Troleandomycin was found to prolong the psychomotor impairment and amnesia produced by triazolam.There was a significant enhancement of the AUC, the peak concentration and the delay to t_max of triazolam after 7 days treatment with troleandomycin compared to placebo.Thus, there is a pharmacokinetic interaction, and the combination of triazolam and troleandomycin should be avoided or the dose of triazolam should be adjusted. The most likely mechanism is a diminished hepatic first-pass effect, and a decrease in the apparent oral clearance of triazolam.     

Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects

Pharmacokinetic interaction between benazepril (ACE inhibitor) and amlodipine (calcium channel blocker) was studied in 12 healthy subjects. Single doses of benazepril hydrochloride (10-mg tablet) and amlodipine besylate (tablet equivalent to 5 mg amlodipine) were administered alone or in combination according to a three-way, Latin-Square, randomized crossover design. Serial blood samples were collected following each administration for the determination of benazepril and its active metabolite benazeprilat and amlodipine. The mean values of AUC (0–4 h), C_max andT _max for benazepril given as combination versus given alone were 161 vs 140 ng·h·ml⁻¹, 168 vs 149 ng·ml⁻¹, and 0.5 vs 0.6 h. The mean values of AUC (0–24 h), C_max andT _max for benazeprilat after benazepril given as combination versus given alone were 1470 vs 1410 ng·h·ml⁻¹, 292 vs 257 ng·ml⁻¹, and 1.7 vs 1.5 h. The mean values of AUC (0–144 h), C_max andT _max for amlodipine given as combination versus given alone were 118 vs 114 ng·h·ml⁻¹, 2.5 vs 2.3 ng·ml⁻¹, and 8.3 vs 9.0 h. The differences in these pharmacokinetic parameters between the combination and monotherapy treatments were not statistically significant based on ANOVA. The results of this study indicate that no pharmacokinetic interaction existed between the two drugs.     

Pharmacokinetic interactions between ciprofloxacin and itraconazole in healthy male volunteers

Objective. To investigate the pharmacokinetic interaction between ciprofloxacin and itraconazole in healthy male volunteers. Methods. Ten healthy male volunteers were assigned into a 2‐sequence, 3‐period pharmacokinetic interaction study. In phase 1, all subjects were randomly assigned to receive 500 mg of ciprofloxacin alone and 200 mg of itraconazole alone twice daily for 7 days with a 14 day wash‐out period in a crossover design. Phase 2 was performed 14 days after finishing phase 1, all subjects received 500 mg of ciprofloxacin in combination with 200 mg of itraconazole twice daily for 7 days. Ciprofloxacin and itraconazole pharmacokinetics were studied and adverse effects noted. Results. Ciprofloxacin significantly increased the C_max and AUC_{0 ? ∞} of itraconazole by 53.13% and 82.46%, respectively. The half‐life and CL of itraconazole were not changed significantly. The combination of itraconazole and ciprofloxacin could therefore result in an increase in adverse drug reactions. Conversely, itraconazole had no significant effect on the pharmacokinetics of ciprofloxacin. Conclusion. Ciprofloxacin decreases the metabolism of itraconazole, most likely through inhibition of CYP3A4. The dosage of itraconazole should be reduced and its therapeutic outcome should be monitored closely when these two agents are concomitantly administered. Copyright © 2011 John Wiley & Sons, Ltd.     

Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers

AIMS: To evaluate the pharmacokinetic interaction between ritonavir and mefloquine. METHODS: Healthy volunteers participated in two separate, nonfasted, three-treatment, three-period, longitudinal pharmacokinetic studies. Study 1 (12 completed): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloquine 250 mg once daily for 3 days then once weekly for 4 weeks, ritonavir restarted for 7 days simultaneously with the last mefloquine dose. Study 2 (11 completed): ritonavir 200 mg single dose, mefloquine 250 mg once daily for 3 days then once weekly for 2 weeks, ritonavir single dose repeated 2 days after the last mefloquine dose. Erythromycin breath test (ERMBT) was administered with and without drug treatments in study 2. RESULTS: Study 1: Ritonavir caused less than 7% changes with high precision (90% CIs: -12% to 11%) in overall plasma exposure (AUC(0,168 h)) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios. Mefloquine significantly decreased steady-state ritonavir plasma AUC(0,12 h) by 31%, Cmax by 36%, and predose levels by 43%, and did not affect ritonavir binding to plasma proteins. Study 2: Mefloquine did not alter single-dose ritonavir pharmacokinetics. Less than 8% changes in AUC and Cmax were observed with high variability (90%CIs: -26% to 45%). Mefloquine had no effect on the ERMBT whereas ritonavir decreased activity by 98%. CONCLUSIONS: Ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose. Mefloquine had variable effects on ritonavir pharmacokinetics that were not explained by hepatic CYP3A4 activity or ritonavir protein binding.     

Pharmacokinetic interaction between verapamil and everolimus in healthy subjects

AIMS: We sought to define the influence of verapamil, an inhibitor of CYP3A and P-glycoprotein, on the pharmacokinetics of everolimus, a substrate of this enzyme and transporter. METHODS: This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1 subjects received a single 2 mg oral dose of everolimus. In period 2 they received verapamil 80 mg three times daily for a total of 6 days and a single 2 mg dose of everolimus co-administered on the second day of verapamil therapy. RESULTS: During verapamil co-administration, everolimus C(max) increased 2.3-fold (90% CI, 1.9, 2.7) from 21 +/- 8 to 47 +/- 18 ng ml(-1) and AUC increased 3.5-fold (90% CI, 3.1, 3.9) from 115 +/- 45 to 392 +/- 142 ng ml(-1) h. Everolimus half-life was only prolonged to a minor extent (32 +/- 6 vs. 37 +/- 6 h). Verapamil predose concentrations doubled from 32 +/- 16 to 74 +/- 42 ng ml(-1) after single dose administration of everolimus. CONCLUSIONS: Multiple dosing with verapamil increased blood concentrations of everolimus after a single dose by an average 3.5-fold. During verapamil treatment, dose reduction for everolimus should be made guided by blood monitoring and for verapamil by blood pressure monitoring.     

A drug interaction study between cicletanine and tolbutamide in healthy volunteers

Objective: To determine the possible interaction between the antihypertensive agent cicletanine and the hypoglycaemic drug tolbutamide. Methods: Time-courses of glycaemia and serum immunoreactive insulin (IRI) were followed in 10 healthy subjects after two tolbutamide infusions in each volunteer: initially alone and 9 days later concomitantly with repeated oral cicletanine. Any drug interaction was quantified on the basis of a decrease or increase in the AUC with time of glycaemia and IRI by subtraction of baseline concentration (AUC₀ ²⁴⁰-GLY and AUC₀ ⁶⁰-IRI). Peak glycaemia and peak IRI, and the corresponding time to peaks, were also assessed. Results: Following tolbutamide, mean AUC₀ ²⁴⁰-GLY values were 97.7 and 98.8 mmol⋅l⁻¹⋅min, without or with cicletanine, respectively; the corresponding AUC₀ ⁶⁰-IRI were 485 and 321 mU⋅l⁻¹⋅min. Mean peak glycaemia values were 0.996 and 1.071 mmol⋅l⁻¹. Regarding the peak IRI, a decrease was observed after tolbutamide and cicletanine: median values were 29.2 and 17.4 mU⋅l⁻¹. The corresponding median time to peak of glycaemia and IRI values were 30 and 30 min, and 5 (all subjects) and 5 min. Conclusion: No clinically relevant interaction was shown after the concomitant administration of repeated oral doses of cicletanine and acute intravenous tolbutamide to healthy volunteers. Received: 28 June 1995/Accepted in revised form: 7 November 1995     

Effect of ketoconazole and terbinafine on the pharmacokinetics of caffeine in healthy volunteers

The effects of single oral doses of ketoconazole 400 mg and terbinafine 500 mg on the hepatic microsomal system have been investigated in 8 healthy male volunteers. Microsomal activity caffeine was assessed by following the metabolism of 3 mg/kg bodyweight i.v. administered 1 h after the drug. The inhibitory effect of terbinafine was more pronounced than that of ketoconazole: clearance was decreased from 1.34 ml.kg-1.min-1 in controls to 1.06 and 1.21 ml.kg-1.min-1, respectively, and the corresponding half-life was increased from 5.8 h in controls to 7.6 and 6.7 h, respectively. The apparent volume of distribution remained unchanged. The serum levels of the antimycotics were within the therapeutic range in each subject. Although all three substances are metabolised by microsomes, the kinetic parameters (Cmax, half-life, elimination constant) of the antimycotics were poorly if at all correlated with the elimination of caffeine.     

Triterpenoids and polysaccharide peptides-enriched Ganoderma lucidum: a randomized,double-blind placebo-controlled crossover study of its antioxidation and hepatoprotective efficacy in healthy volunteers

Context: Ganoderma lucidum (Leyss: Fr) Karst. (Polyporaceae) is an oriental medicinal fungus, commonly used in traditional Chinese medicine (TCM) for treating various condition or diseases such as hypertension, hyperglycaemia, hepatitis and cancer.

Objective: The current study examines whether triterpenoids and polysaccharide-enriched G. lucidum (GL) influence antioxidation and hepatoprotective efficacy by suppressing oxidative stress.

Materials and methods: Forty-two healthy subjects (22 male and 20 female) were recruited and segregated into two groups as experimental or placebo and requested to intake GL (n?=?21) or placebo (n?=?21) capsule (225?mg; after lunch or dinner) for six consecutive months and vice versa with one month washout period in between. The anthropometric analysis and biochemical assays, as well as abdominal ultrasonic examination were performed.

Results: Consumption of GL substantially improved (p?p?Discussion and Conclusion: The outcome of the present intervention demonstrated the antioxidation, anti-aging and hepatoprotective nature of GL by effectively curbing oxidative stress.     

Delay of ovulation by meloxicam in healthy cycling volunteers: A placebo-controlled, double-blind, crossover study

This study aimed to assess the effect of meloxicam on female ovulation. Twenty consented fertile females were monitored for 4 menstrual cycles: a baseline cycle, 2 treatment cycles, and a washout cycle between treatment cycles. In the first cycle visit, transvaginal ultrasound was performed, a blood sample for progesterone and meloxicam analysis was withdrawn, and volunteers were given a luteinizing hormone (LH) urine test kit and meloxicam or placebo. Volunteers started the treatment on the following day and asked to return the day the LH kit was positive to detect the dominant follicle. At subsequent visits, transvaginal ultrasound and progesterone and meloxicam levels were investigated. Compared to placebo, a 5-day delay in follicle rupture, a 55.7% increase in the mean maximum follicle diameter, and 33.5% decrease of plasma progesterone level were observed in the meloxicam-treated group. Such demonstrated meloxicam effects were reversed in participants who were randomized to meloxicam first and then placebo. Only minor side effects were reported by volunteers during the course of treatment. It is concluded that meloxicam resulted in a reversible delay of ovulation, an increase in follicular diameter, and a decrease in plasma progesterone level.     

Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized,single-blind,crossover study

Aim:

To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers.

Methods:

This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin.

Results:

The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects.

Conclusion:

Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.     

NXY-059 does not affect bleeding time in healthy volunteers: a randomized, double-blind, placebo-controlled, 3-period crossover phase I study

NXY-059 is a novel free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. It is the first neuroprotectant to demonstrate a reduction in global disability in a phase III clinical trial, as measured by the modified Rankin Scale. Any effect of NXY-059 on hemostasis may be important when treating stroke patients. This phase I randomized, double-blind, placebo-controlled, 3-period crossover study compared the effect of NXY-059, desmopressin, and placebo on bleeding time, platelet aggregation, and adhesion in 30 healthy volunteers. NXY-059 did not prolong bleeding time compared with placebo: mean (SD) time for NXY-059, 369.5 seconds (125.0 seconds) versus placebo, 369.1 seconds (136.0 seconds). There were no significant effects on platelet aggregation or adhesion. At a mean unbound plasma concentration (Cu(ss)) of 335 micromol/L, NXY-059 was well tolerated, with no major safety concerns identified. In conclusion, NXY-059 does not appear to affect primary hemostasis.     

Metamizole-furosemide interaction study in healthy volunteers

Summary The pharmacokinetic and pharmacodynamic interactions between metamizole (dipyrone) and furosemide were investigated in 9 of 12 healthy female subjects able to complete the study. They received oral metamizole 3×1 g for 3 days or placebo (cross-over) and on the last day of both study periods furosemide 20 mg IV. On the last two days a balanced sodium diet (120 mEq) and on Day 3 an oral water load (600 ml) were given. Metamizole significantly inhibited basal urine flow, whereas the fractional excretion of sodium and chloride and the 12 h-GFR remained unchanged. Metamizole significantly reduced furosemide clearance (175 vs 141 ml · min^–1), furosemide-stimulated plasma renin activity (1.42 vs 0.79 ng AI · ml^–1 · h^–1) and the urinary excretion of prostacyclin metabolites and of prostaglandin F₂ (by 70–81%). The renal clearance and terminal half-life of furosemide, peak renal chloride and volume excretion were unchanged. Thus, metamizole did not interact with the renal excretion and the diuretic effect of furosemide, although prostaglandin synthesis was significantly reduced.Parts of the results have been presented at the Ninty-first Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21–23, 1990, San Francisco     

The effect of metoclopramide on QT dynamicity: double-blind,placebo-controlled,cross-over study in healthy male volunteers

BACKGROUND: Metoclopramide, a central and peripheral dopamine type 2 receptor antagonist, has been used as an attractive and safer alternative to cisapride. However, cardiac side-effects have also been reported with this drug. AIM: To evaluate the effects of intravenous metoclopramide administration on cardiac repolarization using QT dynamicity, a reliable indicator of arrhythmic side-effects. METHODS: The effect of metoclopramide on cardiac repolarization was evaluated in 10 healthy male volunteers in the supine position. Metoclopramide (10 mg) or placebo was administered intravenously at random in a double-blind, cross-over manner to the participants during continuous electrocardiographic recording in the supine position. The 30-min stationary segments of the recordings before and after drug administration were used to investigate QT dynamicity. RESULTS: Metoclopramide administration, but not placebo, resulted in steeper QT/RR slopes compared with the pre-drug values (metoclopramide: 0.037 +/- 0.004 vs. 0.064 +/- 0.012; P = 0.041; placebo: 0.045 +/- 0.006 vs. 0.050 +/- 0.004; P = 0.563). In a two-way analysis of variance model, metoclopramide administration also increased the QT variance independently (F = 6.225, P = 0.023). CONCLUSIONS: Metoclopramide administration increases the QT/RR slope and QT variance. These findings may partly explain the underlying mechanism of ventricular arrhythmias associated with metoclopramide.     

Estradiol in premenstrual asthma: a double-blind,randomized, placebo-controlled,crossover study

STUDY OBJECTIVES: To characterize asthma symptoms and pulmonary function throughout two menstrual cycles, with and without exogenous estradiol administration, in women with premenstrual asthma, and to determine the effect of estradiol administration on asthma symptoms, pulmonary function, quality of life, and biomarkers of airway inflammation. DESIGN: Double-blind, randomized, placebo-controlled, crossover study. SETTING: Respiratory clinic and clinical research center. SUBJECTS: Twelve women with documented premenstrual asthma (> or = 20% premenstrual worsening of asthma symptoms and/or of peak expiratory flow [PEF] during a 1-month screening phase). INTERVENTION: Each woman received either estradiol 2 mg or placebo orally between cycle days 23 and 28 (i.e., premenstrually, or before the onset of menses) in the first cycle and then crossed over to the other arm in the second cycle. Throughout both cycles, the women recorded daily morning and evening PEF readings and asthma symptoms. MEASUREMENTS AND MAIN RESULTS: Spirometry testing and measurement of serum estradiol and biomarkers of airway inflammation were performed on days 8 (follicular phase), 22 (luteal phase), and 28 (premenstrually) of both the estradiol and placebo cycles. During the two premenstrual visits, the Asthma Quality of Life Questionnaire was administered. No notable differences were observed between the estradiol and placebo cycles in daily PEF recordings or composite asthma symptoms scores. The area under the curve (AUC) for the composite asthma symptoms versus time profile was numerically, but not statistically, lower (denoting less severe symptoms) during the estradiol cycle than during the placebo cycle. Likewise, no significant difference in AUC values for morning PEF or evening PEF was found between the estradiol cycle and the placebo cycle. Despite differences (p<0.05) in day-28 estradiol concentrations for estradiol and placebo cycles, no significant differences were found in forced expiratory volume in 1 second, serum endothelin-1, serum and urine eosinophil protein X, urine leukotriene E4, or quality-of-life scores. CONCLUSION: Exogenously administered estradiol did not have a significant effect in women with premenstrual asthma whose asthma was classified predominantly as mild and under excellent control. As in the case of premenstrual syndrome, the placebo effect may be prominent in premenstrual asthma. Further trials, involving women with more severe asthma under poorer control, are warranted to discern underlying mechanisms for the worsening of asthma in relation to menstruation.