Effects of dietary protein concentration on performance and nutrient digestibility in Pekin ducks during aflatoxicosis.

A 14-d study was conducted to determine the impact of dietary crude protein concentration on performance, serum biochemistry, and nutrient digestive functions in Pekin ducklings during aflatoxicosis. A total of 144 male Pekin ducklings were randomly allotted to 4 dietary treatments arranged in a 2×2 factorial with 2 crude protein (CP) (20 and 24% on an analyzed basis) with or without 0.2 mg/kg aflatoxin B1 (AFB1) (0.21 mg/kg analyzed). The AFB1 reduced BW gain, feed intake, and breast muscle weight by 33 to 43% (P<0.0001). Serum concentration of protein, glucose, and Ca were also decreased by AFB1 (P≤0.0015), while pancreatic activities of amylase and lipase were increased by AFB1 (P<0.005). Apparent N digestibility was not affected by dietary treatment, whereas apparent ileal digestible energy was reduced 7.6% by AFB1 (P=0.0003). Higher dietary CP improved BW gain, gain:feed ratio, and breast muscle weight (P≤0.021), and tended to improve feed intake (P=0.094), but did not improve serum measures, digestive enzyme activity, or nutrient digestibility. No statistical interaction of AFB1 by CP was observed for any measures. Results from the current study suggest that AFB1 at low concentration can significantly impair performance of Pekin ducklings primarily through inhibited feed intake, as well as influence nutrient digestion processes (jejunum morphology, digestive enzyme activity, and apparent energy digestibility). Higher dietary CP can improve growth performance of ducklings regardless of AF exposure, but did not interact with dietary AFB1 on performance, serum biochemistry, or nutrient digestion in Pekin ducklings from hatch to 14 d.

Effect of dietary methionine content on growth performance, carcass traits, and feather growth of Pekin duck from 15 to 35 days of age.

A study was conducted to establish the response of Pekin ducks to dietary Met from 15 to 35 d age. Experimental diets were formulated to contain 0.35, 0.45, 0.55, 0.65, and 0.75% Met (0.30, 0.39, 0.45, 0.56, and 0.68% on an analyzed basis, respectively) and 0.3% cysteine (0.25, 0.27, 0.26, 0.26, and 0.28% on an analyzed basis, respectively). Each diet was fed to 10 pens of 55 ducks/pen. Carcass yields and feather growth were determined at 28 and 35 d. Results showed that feeding 0.30% Met (0.55% Met+Cys) significantly impaired ADG, feed-to-gain (F:G) ratio, breast meat yield, and feather growth in comparison to the other dietary treatments (P < 0.05). BW, ADG, F: G, carcass and breast meat weight and yield, breast skin and subcutaneous fat weight and yield, the fourth primary wing feather length, and feather coverage showed significant quadratic broken-line or quadratic polynomial response to increasing dietary Met (P < 0.05). From 15 to 28 d age, the optimal Met requirement for the BW, breast meat yield, and the fourth primary wing feather length were 0.510, 0.445, and 0.404%, respectively, based on quadratic broken-line model, and correspondingly were 0.606, 0.576, and 0.559% by quadratic regression. For ducks from 15 to 35 d age, the optimal Met requirement for BW, breast meat yield, and feather coverage were 0.468, 0.408, and 0.484%, respectively, by quadratic broken-line model, and 0.605, 0.564, and 0.612%, by quadratic regression, respectively.

The improved efficacy of a fixed-dose combination of fluticasone furoate and levocabastine relative to the individual components in the treatment of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a common chronic disease, which has significant detrimental effect on well-being and quality of life as well as substantial socio-economic impact. Combination pharmacotherapy is utilized by 40-50% of patients to treat their symptoms. OBJECTIVE: To compare the effects of intranasal fluticasone furoate (FF)/levocabastine (LEVO) fixed-dose combination (FDC) with each component alone on allergen-induced nasal and ocular symptoms. METHODS: A randomized, double-blind, placebo-controlled, three-way, incomplete block, cross-over, proof-of-concept study in 71 patients with AR, evaluated FF 100 µg, LEVO 200 µg and FDC (FF 100/LEVO 200 µg), once daily via intranasal spray for 8 days. On days 1 and 8, total nasal symptom score (TNSS) and total ocular symptom score (TOSS) were assessed every 15 min during a 4-h allergen exposure in the Vienna Challenge Chamber. The primary endpoint was Day 8 weighted mean TNSS. RESULTS: After 8 days, FDC resulted in both statistically and clinically significant reductions in mean TNSS compared with FF and LEVO alone [adjusted mean differences (95% CI): FDC vs. FF: -2.26 (-2.90, -1.62); FDC vs. LEVO: -2.57 (-3.21, -1.93)]. All active treatments were significantly superior to placebo [adjusted mean difference (95% CI) from placebo: FDC: -4.1 (-4.86, -3.34); FF: -1.84 (-2.66, -1.03); LEVO: -1.53 (-2.34, -0.72)]. Onset of action was rapid following FDC and LEVO treatment with an approximate two unit reduction in mean TNSS from pre-dose levels by 30 min and 1 h. Mean TOSS was also reduced following all active treatments relative to placebo (range 0.6-0.8 unit reduction). All treatments were equally well tolerated. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that once daily FF/LEVO FDC could provide a clinical therapeutic advantage to existing standard monotherapies in the treatment of moderate-to-severe AR, and support progression to evaluation in larger phase III clinical studies.

Effect of dietary energy and protein content on growth and carcass traits of Pekin ducks.

A study was conducted to determine the influence of dietary energy and protein concentrations on growth performance and carcass traits of Pekin ducks from 15 to 35 d of age. In experiment 1, 14-d-old ducks were randomly assigned to 3 dietary metabolizable energy (11.8, 12.8, and 13.8 MJ/kg) and 3 crude protein concentrations (15, 17, and 19%) in a 3×3 factorial arrangement (6 replicate pens; 66 ducks/pen). Carcass characteristics were evaluated on d 28, 32, and 35. In Experiment 2, 15-d-old ducks (6 replicate cages; 6 ducks/cage) were randomly allotted to the 9 diets that were remixed with 0.5% chromic oxide. Excreta were collected from d 17 to 19, and ileal digesta was collected on d 19 to determine AMEn and amino acid digestibility. In Experiment 1, there were interactions (P<0.05) between dietary metabolizable energy and crude protein (CP) on body weight (BW) gain and feed intake, wherein BW gain increased more to increasing dietary CP as dietary metabolizable energy increased. However, feed intake was only influenced by dietary crude protein at 11.8 MJ ME/kg and not 12.8 or 13.8 MJ/kg. As dietary CP increased from 15 to 19%, breast meat yield increased by 10.8% on d 35 (P<0.01). Conversely, increasing metabolizable energy from 11.8 to 13.8 MJ/kg increased dressing percentage, breast skin, and subcutaneous fat, but decreased breast meat yield (% but not weight) on d 35 (P<0.01). In Experiment 2, the determined AMEn for diets formulated to contain 11.8, 12.8, or 13.8 MJ ME/kg were 11.66, 12.68, and 13.75 MJ/kg, respectively; determined standardized ileal digestible Lys was 0.95, 1.00, and 1.21% for diets formulated to contain 15, 17, or 19% crude protein, respectively. The best body weight gain and feed conversion ratio was obtained when ducks were fed a high dietary AMEn (13.75 MJ/kg) and high CP (19%, 1.21% SID Lys). These results provide a framework for subsequent modeling of amino acid and energy inputs and the corresponding outputs of growth performance and carcass components.

Dietary threonine requirement of Pekin ducks from 15 to 35 days of age based on performance, yield, serum natural antibodies, and intestinal mucin secretion.

A study was conducted to establish the dietary Thr requirement of Pekin ducks from 15 to 35 d of age. Experimental diets were formulated to contain 0.55, 0.60, 0.65, 0.75, and 0.85% Thr (0.57, 0.60, 0.64, 0.72, and 0.80% on an analyzed basis) and were studied in 2 experiments. In experiment 1, each diet was fed to 10 pens of 52 drakes per pen. Samples were collected at d 35 for determinations of carcass yields, serum immune parameters, and intestinal characteristics. Experiment 2 was a digestibility study, wherein 0.5% chromic oxide was mixed into the experimental diets and fed from 15 to 19 d. Ileal digesta were collected at d 19 to analyze mucin secretions and apparent ileal Thr digestibility. The results showed that feeding 0.72% versus 0.64% Thr improved 15 to 35 d BW gain by 55 g (P < 0.05), reduced feed-to-gain by 0.04 (P < 0.05), as well as increased carcass and breast meat yields by 22 and 24 g, respectively. Also, 0.72% Thr had the highest crude mucin secretion on a DM intake (DMI) basis (P < 0.05), although Thr had no effect on villus height, crypt depth, goblet cells, and MUC2 gene expression in the jejunum and ileum. In addition, serum natural IgY linearly increased (P < 0.0001) with dietary Thr increase. Using nonlinear regressions, Thr requirement was estimated to range from a low of 0.70% to maximize dry crude mucin secretion on a DMI basis to a high of 0.80% to maximize carcass weight and serum IgY production by the linear or quadratic regression. Equivalently, Thr requirement varied between a low of 0.62% to minimize mortality and a high of 0.73% to maximize dry crude mucin secretion expressed as DMI using the quadratic broken-line model. Correspondingly, the apparent ileal digestible Thr requirements were estimated to be 0.52 to 0.66% (0.70 to 0.80% dietary Thr) by quadratic and 0.47 to 0.56% (0.62 to 0.73% dietary Thr) by quadratic broken-line model.

Delayed ultraviolet erythema not suppressed by oral prednisolone: a randomized crossover study.

BACKGROUND: The anti-inflammatory potency of topical dermatological corticosteroids in suppressing ultraviolet (UV) erythema is routinely measured. No such model exists to assess the potency of systemically administered steroids. OBJECTIVE: To determine whether or not suppression of delayed UV erythema by a systemic corticosteroid could provide a useful model for assessing the anti-inflammatory potency of systemic corticosteroids. METHODS: We conducted a randomized, placebo-controlled, patient and assessor blinded, crossover study of oral prednisolone effects on the delayed UV-induced erythemal response in normal subjects. Six healthy volunteers were phototested with a xenon arc monochromator and then dosed with 30 mg of oral prednisolone or matching placebo daily for 4 days. Repeat phototesting was performed on the 4th day of dosing. The minimal erythema dose (MED) was assessed immediately after test UV doses were administered and 24 h later. After a 2-week washout period, the dosing and testing were repeated in a crossover fashion. RESULTS: A suppression index (SI) [1/(baseline MED value divided by on prednisolone/placebo value)] allowed comparison of the degree of suppression on and off prednisolone. Oral prednisolone did not significantly suppress the threshold UV erythema response (MED). We may have missed small effects in this study and possibly a larger dose or a longer duration of corticosteroid would have had an effect. Possibly, assessment of corticosteroid potency in suppressing established UV erythema rather than on the development of threshold erythema would have yielded different results. CONCLUSION: The threshold UV erythema suppression model assessed in this study could not distinguish between oral prednisolone and placebo. This UV-erythema suppression test system is not promising as a model to test the anti-inflammatory potency of systemic steroids.

A combination of cetirizine and pseudoephedrine has therapeutic benefits when compared to single drug treatment in allergic rhinitis.

UNLABELLED: Antihistamines and nasal decongestants are well-established therapeutics in allergic rhinitis. However, no data are available which directly compare the effect size of the single substances with their combination in a single study including placebo (PLA) treatment. OBJECTIVE: The aim of this study was to evaluate the effect of a combination of cetirizine (CET) and pseudoephedrine (PSE) and to compare it to treatment with CET or PSE alone and to PLA during grass pollen allergen challenge in an environmental challenge chamber (ECC). MATERIAL AND METHODS: In a randomized, double-blind, placebo-controlled, four-way crossover study the effect of a combination of 10 mg CET with 120 mg PSE (CET + PSE) versus CET or PSE alone or PLA on symptoms, nasal flow, and nasal secretions was investigated in 49 patients with intermittent allergic rhinitis. Subjects underwent four 6-h pollen exposures in an ECC with administration of the drugs after 2 h. RESULTS: The induction of nasal symptoms, nasal secretion and nasal obstruction (measured as nasal flow) during the first 2 h of pollen exposure was highly reproducible at the 4 consecutive exposures. The symptom of nasal obstruction was significantly reduced after treatment with CET + PSE compared to the treatment with CET or PSE alone or PLA (p < 0.0001). Furthermore, the combination treatment significantly reduced the total nasal symptom score (TNSS) and visual analogue scale score (VAS) compared to the single treatments or PLA. Nasal flow was significantly increased after treatment with CET + PSE and PSE and nasal secretions were significantly reduced by CET + PSE and CET without significant additional improvement of the combination therapy. CONCLUSION: The combination treatment with CET and PSE is more effective than treatment with single substances in subjects with allergic rhinitis.

Digital image referral for suspected skin malignancy--a pilot study of 300 patients.

Referral of suspect skin cancers as well as non malignant symptomatic skin lesions using high quality digital images transferred via a secure electronic referral system (ERS) potentially offers significant advantages regarding speed of referral, diagnosis and subsequent treatment over conventional pathways. However concerns over safety of the diagnostic process have been raised. This prospective study looks at 300 patients referred by ERS. A comparison of the diagnoses made from digital images with the diagnoses confirmed on pathology reports for lesions excised is described using a random selection of patients' images and referrals. Intra observer analysis of was also assessed. A sample group of patients with lesions deemed as benign, not requiring surgery or other treatment and therefore not seen in secondary care were revisited at a special clinic to determine the safety of the referral system. In this series of 300 patients the study concludes that digital image referral for skin malignancy and other cutaneous lesions reduced the interval between referral and diagnosis by 81% and referral to commencement of treatment in suspect lesions by 30%. Diagnostic accuracy in a random sample of 30 patients was comparable to that reported for patients seen in face to face consultations. High levels of GP and patient satisfaction were recorded. In conclusion digital image referral for skin malignancy and other cutaneous lesions is a safe and cost effective referral pathway, significantly reducing the interval between referral diagnosis and onset of treatment for skin malignancy.

Elevated expression of adenosine A1 receptor in bronchial biopsy specimens from asthmatic subjects.

Asthmatics, unlike healthy subjects, experience bronchoconstriction in response to inhaled adenosine, and extracellular adenosine concentrations are elevated in the bronchoalveolar lavage fluid and exhaled breath condensate of asthmatic subjects. However, little is known about the location and expression of adenosine receptors in asthmatic airways. The aim of the present study was to investigate the distribution of adenosine A(1) receptors in bronchial biopsy specimens from mildly asthmatic steroid-naïve subjects and then compare the degree of expression with that of healthy subjects. Biopsy sections were immunostained using an adenosine A(1) receptor antibody, the selectivity of which was validated in specific experiments. Image analysis was then performed in order to determine differences in immunostaining intensity. Immunostaining of biopsy sections from the asthmatic subjects revealed strong expression of the A(1) receptor, located predominantly in the bronchial epithelium and bronchial smooth muscle. In comparison, very weak immunostaining was observed in biopsy specimens obtained from healthy subjects. Image analysis revealed that the intensity of positive staining of the asthmatic bronchial epithelium and smooth muscle regions was significantly greater than that observed for the healthy epithelium and smooth muscle. In conclusion, the sensitivity of asthmatics to inhaled adenosine coupled with increased adenosine A(1) receptor expression implies that these receptors play a role in the pathophysiology of this disease.

Topical corticosteroid inhibits interleukin-4, -5 and -13 in nasal secretions following allergen challenge.

BACKGROUND: Cytokines and chemokines produced by allergen-reactive T-helper type 2 (Th2) cells may be pivotal to the pathophysiology of allergic disorders. OBJECTIVE: This study was performed to assess the effect of 7 days of topical corticosteroid on nasal allergen challenge (NAC) in terms of eosinophils, cytokines and chemokines obtained by nasal lavage and filter paper methods. METHODS: Patients with grass pollen seasonal-allergic rhinitis (n = 13) out of season received nasal challenge following matched placebo (twice daily into each nostril for 7 days) and fluticasone propionate (100 microg twice daily into each nostril for 7 days). Chemokine and cytokine levels were analysed using a sensitive automated bead immunoassay system at intervals up to 8 h after NAC. RESULTS: Levels of cytokines and chemokines from filter paper were generally higher than from nasal lavage. Fluticasone propionate caused a reduction in symptoms, total leukocyte counts and eosinophils, and abrogation of IL-4, IL-5, IL-6 and IL-13 responses in the filter paper taken in the late phase (P < 0.05 for IL-4 and IL-13, P < 0.01 for IL-5 and IL-6). Levels of chemokines (eotaxin, RANTES, MCP-1, MIP-1alpha, IL-8 and IP-10) were also reduced in the late phase (P < 0.01 at 8 h). However, levels of IL-2, IL-3, IL-7, IL-12 (p40 and p70), -15, TNF-alpha, IFN-gamma and GM-CSF were not affected. CONCLUSION: Fluticasone propionate has selective inhibitory effects on Th2 cytokine synthesis following nasal challenge, while also decreasing release of chemokines, but not affecting levels of Th1 cytokines.

Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?

Maintenance treatment with PDE(4) inhibitor cilomilast improves FEV(1) in chronic obstructive pulmonary disease (COPD) patients. We investigated the acute bronchodilating effects of a single dose of cilomilast with or without concomitant administration of inhaled salbutamol and/or ipratropium bromide in 21 patients with COPD (mean (SD) age 64 (8.1) y, post-salbutamol FEV(1) 47.7 (13.2) %predicted). FEV(1) was measured before and up to 8 hourly intervals after intake of placebo, cilomilast, or cilomilast in combination with inhaled salbutamol 400 microg and/or ipratropium bromide 80 microg. Maximum increase in FEV(1) from pre-dose baseline was calculated after each treatment and differences between treatment arms were analyzed by ANOVA. The mean (SEM) maximum increase in FEV(1) was 139.6 (18.5) ml following cilomilast and 151.5 (18.5) ml following placebo (95% C.I. for mean difference between cilomilast and placebo: -67.3, 43.6 ml). Furthermore, combined treatment of cilomilast with salbutamol or ipratropium resulted in a maximum increase in FEV(1) of 280.7 (25.6) and 297.0 (25.9) ml, respectively, while this was 379.0 (24.6) ml following cilomilast with both salbutamol and ipratropium (p < 0.01). We conclude that a single dose of cilomilast does not produce acute bronchodilation in patients with COPD who otherwise respond to inhaled bronchodilators. Our results implicate that the change in lung function seen after long-term treatment with cilomilast is not the result of acute bronchodilation in patients with COPD.

5-HT moduline: an endogenous inhibitor of 5-HT(1B/1D)-mediated contraction in pulmonary arteries.

(1) 5-HT moduline (5-HTm) is tetrapeptide (Leu-Ser-Ala-Leu) previously shown to act as a specific endogenous antagonist to central 5-HT(1B/1D) receptors. Its effects were investigated in rat and rabbit pulmonary arteries (PAs). (2) In rabbit PAs, contractile responses to the 5-HT(1B/1D) receptor agonist 5-carboxamidotryptamine (5-CT) were inhibited by 1 and 10 micro M 5-HTm in a non-competitive fashion with the maximum contractile response (E(max), per cent of response to 50 mM KCl) being reduced from 65.6+/-7% (n=6) to 39.7+/-6.5% (n=6) and 25.2+/-7.9 (n=4), respectively. The ability of 5-HTm to inhibit responses to 5-CT was increased by the aminopeptidase inhibitor bestatin (10 micro M). (3) In the rabbit PAs, the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methylester (L-NAME) potentiated responses to 5-CT (E(max): 106+/-22.5 (n=4)) and this response was also inhibited by 10 micro M 5-HTm (E(max): 38+/-13% (n=8)). (4) 5-HTm (10 micro M) inhibited responses to 5-CT in rat PAs, the E(max) being reduced from 24.8+/-4.1% (n=7) to 15.5+/-3.7% (n=9). 5-HTm induced relaxation of 5-CT-pre-constricted rat PAs with a pIC(50) of 9.0+/-0.6 (n=9). (5) In PAs from chronic hypoxic, pulmonary hypertensive rats, the maximum response to 5-CT was increased to 80+/-8.5% (n=11). 5-HTm reduced this response to 34.4+/-6.3% (n=12). L-NAME markedly inhibited the ability of 5-HTm to inhibit responses to 5-CT (E(max) before 5-HTm: 100.5+/-16% (n=5), E(max) after 5-HTm: 107+/-11.3% (n=4)). (6) In conclusion we show here for the first time that 5-HTm is a non-competitive inhibitor of 5-HT(1B/1D) receptor-mediated constriction in PAs. In rat PAs, L-NAME can inhibit this effect of 5-HTm.

Motility activation and second messenger signalling in spermatozoa from rat cauda epididymidis.

This study examined molecular mechanisms involved in the activation of motility in spermatozoa from the cauda epididymidis of rats. A 1.05-fold dilution of semen from the cauda epididymidis with 300 mmol sucrose l(-1) did not activate motility in spermatozoa. Addition of dibutyryl cAMP, pentoxifylline or Ca(2+) to the sucrose activated motility in the short term (<30-60 min). A fivefold dilution of semen from the cauda epididymidis with a modified Tyrode's medium (BWW) activated and sustained vigorous motility that could not be attenuated with kinase inhibitors. This motility was associated with a transient increase in intracellular cAMP during the first 60 s of activation. Lower motility was activated in Ca(2+)-deficient media but this was not associated with an increase in cAMP. A fivefold dilution with plasma from the cauda epididymidis did not activate motility. The addition of Ca(2+) to the sucrose induced an increase in cAMP of similar duration but lower magnitude to that associated with dilution in BWW. The results from this study indicate that the cAMP and Ca(2+) signal transduction pathways are involved in activation of sperm motility, and that the increase in intracellular cAMP in rat spermatozoa from the cauda epididymidis undergoing motility activation is Ca(2+)-dependent. This is the first study to report a Ca(2+)-dependent increase in cAMP associated with motility activation in immotile mammalian spermatozoa. In light of these data, a model is proposed whereby cAMP and Ca(2+) act as synarchic messengers, initiating a signal transduction cascade, which is independent of protein kinase A-mediated phosphorylation of flagella proteins in immotile spermatozoa from the cauda epididymidis.

Cilomilast (Ariflo) does not potentiate the cardiovascular effects of inhaled salbutamol.

We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled beta(2)-agonist salbutamol and cilomilast (Ariflo), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma. This was a randomised, double-blind, placebo-controlled, multiple-dose, three-period crossover study involving non-smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly assigned to receive cilomilast plus nebulised salbutamol, cilomilast plus nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose of cilomilast or placebo was followed 1 h later with a single dose of nebulised salbutamol (2.5 mg) or placebo. Primary variables were average change from pre- to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12-lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen volunteers completed the study. There was no evidence of a clinically important pharmacodynamic interaction between cilomilast and salbutamol in healthy volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic effects associated with salbutamol inhalation were unaffected by co-administration of cilomilast.

An overview of the pharmacokinetics of cilomilast (Ariflo), a new, orally active phosphodiesterase 4 inhibitor, in healthy young and elderly volunteers.

The oral pharmacokinetics of cilomilast (Ariflo) were investigated in five separate studies in healthy volunteers. Cilomilast was rapidly absorbed, and pharmacokinetics were dose proportional after single and repeat dosing. The elimination half-life was 7 to 8 hours; accordingly, steady state was reached on the 3rd day of dosing. The degree of accumulation following repeat twice-daily dosing was predictable from the data following a single dose. Although systemic exposure (AUC) was, on average, 21% higher in elderly (65-84 years) compared with young subjects, values for Cmax and t(1/2) were similar, and no difference in tolerability was noted. Single and repeat doses of cilomilast up to and including 15 mg (dosed before or taken between meals) were well tolerated. Dosing with food reduced the rate of absorption without affecting total bioavailability. Hence, tolerability was optimal in the fed state; repeat doses up to and including 30 mg twice daily aftermeals were well tolerated following dose titration.

Cilomilast: pharmacokinetic and pharmacodynamic interactions with digoxin.

BACKGROUND: Cilomilast is an orally active, selective phosphodiesterase 4 inhibitor currently in clinical development for the treatment of chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this study was to examine the tolerability and steady-state pharmacokinetics of cilomilast and digoxin when coadministered at standard therapeutic doses in healthy adults. METHODS: In an initial, open-label phase, healthy young adults received cilomilast 15 mg BID for 5 days. After a 7-day washout period, subjects entered a double-blind, crossover phase during which they received oral digoxin (375 microg once daily) for 2 consecutive 14-day periods with no intervening washout period. Cilomilast 15 mg BID or placebo was coadministered during the first 14-day period. Subjects then crossed over to the alternative treatment for the second 14-day period. Blood and urine samples were collected at appropriate times for evaluation of digoxin and cilomilast steady-state pharmacokinetic parameters. The size of the study was sufficient to achieve 90% power to correctly exclude an effect of cilomilast. RESULTS: Twelve of the 16 subjects enrolled completed the study. There were 4 withdrawals--1 due to noncompliance, 1 due to a positive drug screening, and 2 due to adverse events. At steady state, cilomilast 15 mg BID had no significant effect on the steady-state pharmacokinetic parameters of digoxin, with 90% CIs for both primary end points--area under the plasma concentration-time curve (AUC) over a 24-hour dosing interval and minimum plasma concentration--completely contained within the specified interval for equivalence (0.80-1.25). A mean reduction in maximum observed plasma concentration of digoxin of 11% was observed during coadministration with cilomilast, and time to maximum concentration was delayed by a median of 1 hour, suggesting a small reduction in the rate of digoxin absorption. Digoxin did not appear to markedly affect cilomilast steady-state pharmacokinetics. The most frequently reported adverse event was headache. CONCLUSIONS: Cilomilast 15 mg BID had no clinically significant effect on steady-state AUC or on predose trough plasma concentrations of digoxin (375 microg once daily). The steady-state pharmacokinetics of cilomilast 15 mg BID were similar whether administered alone or with digoxin at steady state (375 microg once daily).

Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast.

STUDY OBJECTIVE: To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers. SETTING: Clinical pharmacology unit. DESIGN: Five prospective pharmacokinetic studies: one single-blind, dose-escalating, placebo-controlled trial; four open-label, randomized studies. SUBJECTS: Ninety-six healthy adult volunteers who were nonsmokers. INTERVENTION: In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15-mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide. MEASUREMENTS AND MAIN RESULTS: After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose-proportional manner; the half-life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2-hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), but the area under the concentration-time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or coadministration of antacid. CONCLUSION: The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.

Warfarin pharmacodynamics unaffected by cilomilast.

OBJECTIVE: To demonstrate a lack of effect of steady-state concentrations of cilomilast, a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease, on warfarin-induced anticoagulation. METHODS: This 28-day, randomized, double-blind, placebo-controlled, parallel-group study involved 36 healthy men. All volunteers received warfarin once daily on days 1 through 24 of the study. After a standard 5-mg loading dose on days 1 and 2, the warfarin dose was titrated between days 3 and 10 to achieve a stable prothrombin time, expressed as international normalized ratio (INR). Volunteers received either cilomilast 15 mg twice daily or placebo on days 18 through 24. The primary end point was the INR on day 24. RESULTS: On day 24, the mean +/- SEM INR in subjects receiving concurrent warfarin and cilomilast was 1.35 +/- 0.05, compared with 1.38 +/- 0.07 in those receiving concurrent warfarin and placebo. The point estimate (90% CI) for the difference in day 24 INR values between cilomilast and placebo (adjusted for baseline) was 0.02 (90% CI-0.13 to 0.17), which translates to an INR ratio of 1.02 (90% CI 0.91 to 0.13). The 90% confidence interval for the ratio of mean INR (cilomilast:placebo) on day 24 was completely contained within the 25% equivalence range, indicating a lack of interaction between warfarin and cilomilast. The adverse event profiles of warfarin/placebo and warfarin/cilomilast were similar and favorable. CONCLUSIONS: The pharmacodynamics of warfarin are unaffected by coadministration of cilomilast at steady-state concentrations in healthy volunteers.

A mesoscale phytoplankton bloom in the polar Southern Ocean stimulated by iron fertilization.

Changes in iron supply to oceanic plankton are thought to have a significant effect on concentrations of atmospheric carbon dioxide by altering rates of carbon sequestration, a theory known as the 'iron hypothesis'. For this reason, it is important to understand the response of pelagic biota to increased iron supply. Here we report the results of a mesoscale iron fertilization experiment in the polar Southern Ocean, where the potential to sequester iron-elevated algal carbon is probably greatest. Increased iron supply led to elevated phytoplankton biomass and rates of photosynthesis in surface waters, causing a large drawdown of carbon dioxide and macronutrients, and elevated dimethyl sulphide levels after 13 days. This drawdown was mostly due to the proliferation of diatom stocks. But downward export of biogenic carbon was not increased. Moreover, satellite observations of this massive bloom 30 days later, suggest that a sufficient proportion of the added iron was retained in surface waters. Our findings demonstrate that iron supply controls phytoplankton growth and community composition during summer in these polar Southern Ocean waters, but the fate of algal carbon remains unknown and depends on the interplay between the processes controlling export, remineralisation and timescales of water mass subduction.

In vitro culture of brushtail possum (Trichosurus vulpecula) epididymal epithelium and induction of epididymal sperm maturation in co-culture.

A medium modified from eutherian systems was used to culture epididymal epithelial cells of the brushtail possum (Trichosurus vulpecula) for more than 2 months. Epididymal tubule fragments from the caput, corpus and cauda epididymides were used to generate cell monolayers. All three epididymal cell culture systems supported maturational changes in marsupial spermatozoa and enabled immature possum spermatozoa to differentiate from a T-shape to a streamlined shape, accompanied by the development of progressive motility after co-culture with 7-day-old cultured epididymal cell monolayers. This epididymal cell and sperm co-culture system for marsupial species may facilitate the identification of specific epithelial factors that affect sperm maturation, particularly in a species in which morphological maturation is readily visible.