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Biomedical subjects

R D Murdoch

Publications and source records attributed to R D Murdoch.

At least 19 recordsLinked to original sources
PubMed2005

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.

Adrenal Cortex Hormones↗
PubMed2003

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.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

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.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

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).

Adolescent↗
PubMed2001

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.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

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.

Adult↗
PubMed2001

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.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Plasma concentrations and urinary excretion of histamine after inhalation and subcutaneous injection of histamine.

1. Increased histamine concentrations are found in the plasma and urine following allergen challenge in allergic subjects. This study compared a controlled challenge with clinically relevant doses of inhaled and injected histamine, as indicative of an allergic response, in an attempt to validate the use of urinary histamine or 1-methylhistamine measurements as an objective, non-invasive diagnostic test. 2. Inhalation of histamine produced peripheral vasodilation, increased heart rate, a fall in partial expiratory flow rate (pEFR) and blood pressure, 'tight chest' and cough. Subcutaneous injection produced vasodilation and headache but no change in heart rate or blood pressure. 3. Plasma histamine concentrations were similar in the two studies. Inhalation of increasing doses of histamine through a nebuliser (output 0.13 ml min-1) resulted in an increase from a mean of 0.30 to 1.65 ng ml-1, with return towards baseline within 20 min. Injection of 1 mg histamine s.c. produced an increase from 0.32 to 1.4 ng ml-1 within 5 min, remaining above 1 ng ml-1 for 30 min. 4. There was a significant increase of 15.2 ng mg-1 creatinine in urinary histamine concentration following the injection of histamine (P = 0.04) and an increase of 11.4 ng mg-1 creatinine when histamine was given by inhalation (P = 0.18). Histamine excretion rate increased by 108 ng min-1 (P = 0.04) after inhalation and by 37.2 ng min-1 (P = 0.09) after injection. Urinary 1-methylhistamine concentrations were significantly raised following both histamine inhalation (+ 238 ng mg-1 creatinine; P = 0.013) and injection (+ 180 ng mg-1 creatinine; P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Plasma histamine and clinical tolerance to infused histamine in normal, atopic and urticarial subjects.

Five subjects with a recent history of urticaria (U), five atopic (A) subjects and a non-atopic (NA) control group were given intravenous infusions of histamine starting at 0.05 micrograms/kg/min, increasing by 0.05 micrograms/kg/min every 30 minutes to a maximum of 0.35 micrograms/kg/min. Plasma histamine levels were monitored every 15 minutes. The infusion was stopped when an objective clinical endpoint was reached, involving either evidence of peripheral vasodilatation (rise of skin temperature by at least 1 degree C) or a 20% fall of peak expiratory flow rate. There were no significant differences in resting plasma histamine in the three groups. Those with urticaria reached the clinical endpoint at a lower infusion rate than non-atopic subjects (U 0.22 +/- 0.02 micrograms/kg/min; A 0.26 +/- 0.02 micrograms/kg/min; NA 0.32 +/- 0.2 micrograms/kg/min. p less than 0.008) they also received a lower total histamine dose (U 1.12 +/- 0.33 mg; A 1.42 +/- 0.38 mg, NA 2.2 +/- 0.51 mg, p less than 0.008). Atopic subjects with a history of asthma, eczema or rhinitis also tolerated histamine poorly, some subjects reaching a clinical endpoint while the plasma histamine level was still relatively low (U 1.52 +/- 0.4 ng/ml, A 0.85 +/- 0.19 ng/ml, NA 1.4 +/- 0.44 ng/ml, p = 0.05). After the histamine infusion was stopped, the fall in the blood level of histamine was slower in urticarial subjects than in the other two groups, with a half-life of 6.2 +/- 1.3 min (A 3.0 +/- 1.2 min, NA 4.0 +/- 0.7 min, p less than 0.02). There were thus differences in the metabolism of histamine in our non-atopic urticarial subjects and increased histamine sensitivity in atopic subjects which require further study.

Amine Oxidase (Copper-Containing)↗
PubMed1991

Efficacy and safety of granisetron in the prevention of chemotherapy-induced emesis in paediatric patients.

In an open ascending-dose study, granisetron, a specific 5-HT3 receptor antagonist, was administered to 24 paediatric patients (17 male, 7 female, mean age 6.2, range 3-15 years) who were receiving moderately or highly emetogenic chemotherapy for malignant disease. Single doses of 10, 20 and 40 micrograms/kg were administered by intravenous infusion 1 h before chemotherapy. Each dose level was studied in a group of 8 patients. With the 40 micrograms/kg dose, 5 of 8 patients experienced no nausea or vomiting in the 24 h after granisetron treatment. With 20 micrograms/kg, a similar response was seen, but with 10 micrograms/kg only 2 of 8 patients experienced complete antiemetic protection despite additional prophylactic chlorpromazine in this group. Granisetron was very well tolerated, and there were no clinically important changes in pulse rate, blood pressure or Holter electrocardiogram. It is concluded that granisetron was very well tolerated by paediatric patients. In addition, there was clear evidence of a major antiemetic effect for at least 24 h after a single intravenous dose of 20 or 40 micrograms/kg.

Adolescent↗
PubMed1991

The antiemetic effect of granisetron in lower hemibody radiotherapy.

Radiotherapy-induced emesis is poorly controlled with existing antiemetics. 5-Hydroxytryptamine (5HT3) receptor antagonists are a new class of antiemetics which have been demonstrated to be effective in controlling cytotoxic-induced emesis. We have prospectively studied the antiemetic efficacy of the 5HT3 receptor antagonist granisetron in an open non-randomized efficacy and toxicity study, at two dose levels, in patients receiving lower hemibody radiotherapy for multiple bone metastases. Of the 22 patients studied, 13 patients received 20 micrograms/kg and nine patients 40 micrograms/kg of granisetron, administered as an intravenous infusion 1 h before radiotherapy. Radiotherapy was administered as a single exposure to the lower half body to a midline dose of 8 Gy. A complete response (no nausea or vomiting) was observed in 9/13 patients at the lower dose level and 6/9 patients at the higher level. No major adverse events were recorded. We conclude that granisetron is a well-tolerated and effective antiemetic agent in radiotherapy-induced emesis. Formal comparison with conventional antiemetic agents in this situation is required.

Aged↗
PubMed1989

Symptomatic dermographism: wealing, mast cells and histamine are decreased in the skin following long-term application of a potent topical corticosteroid.

Clobetasol propionate 0.05% ointment and an otherwise identical steroid-free base were applied topically to a 10 cm2 area on the anterior thighs of six patients with symptomatic dermographism for 6 weeks. Four patients showed a significantly decreased wealing response to stroking of steroid pretreated skin compared to that of control sites. There was a parallel decrease in mast cell numbers and histamine levels in skin biopsies taken from the steroid treated areas. At 6 weeks two patients demonstrated a decrease in flare areas following the intradermal injection of compound 48/80 in steroid pretreated skin compared to base treated sites. Flare areas following intradermal injection of histamine in these two patients were equivalent in base and steroid treated skin.

Administration, Cutaneous↗
PubMed1989

The effect of the castor bean toxin, ricin, on rat IgE and IgG responses.

IgE responses are closely regulated in non-atopic humans and low IgE responder animals. After an initial period of IgE production following antigen exposure, IgE synthesis appears to be actively suppressed. Inhalation of the dust of castor beans induces persistent IgE responses in atopic and non-atopic humans alike. This phenomenon was investigated in animals. Hooded Lister rats were immunized intraperitoneally with different preparations of castor bean. These had been heated for different lengths of time, 60 and 15 mins, to inactivate the toxin ricin. Immunization with as much as 100 micrograms of the extract heated for 60 min failed to produce an IgE response, while injection of 100 micrograms of the extract heated for 15 min produced a marked IgE response to castor bean proteins. Thus the component of castor bean extract which induces the IgE response appears to be heat labile. The IgE potentiating component in castor bean was found to enhance IgE responses to other antigens such as ovalbumin and when 0.8 microgram of an unheated castor bean extract was administered together with an optimal dose of ovalbumin, there was a substantial increase in ovalbumin-specific IgE but not IgG in all animals. In addition, total serum IgE but not IgG increased up to 20-fold. The effect of castor bean was more sustainable than that of an established IgE-specific adjuvant, Bordetella pertussis, and was able to boost an IgE response that had diminished and maintain an ongoing IgE response when re-administered at weekly intervals. In addition, it was possible to reproduce the IgE potentiating effects with purified castor bean ricin at 25 ng/rat. The way that it produces this effect is not known but it is possible that ricin blocks the normal IgE suppressive mechanisms that regulate IgE responses.

Animals↗
PubMed1988

Prostaglandin D2 and histamine release in cold urticaria unaccompanied by evidence of platelet activation.

Six patients with acquired primary cold urticaria and six normal control subjects were challenged with a 5-minute immersion of an arm in cold water, at 10 degrees C, to induce cold urticaria. Venous blood draining the arm was sampled before and at 5 and 20 minutes after challenge. Prostaglandin D2 levels in the serum increased significantly after cold challenge but did not correlate with the severity of the urticaria. Significant elevations in histamine after cold challenge tended to be higher in the patients with a low threshold to cold reaction. Two markers of platelet activation, platelet factor 4 and beta-thromboglobulin, remained at basal levels 5 minutes and 20 minutes after challenge.

Adult↗
PubMed1988

A comparison of mediator and catecholamine release between exercise- and hypertonic saline-induced asthma.

Serum neutrophil chemotactic activity (NCA) and plasma histamine concentrations were measured in 9 asthmatic subjects with exercise-induced asthma after inhalation challenge with ultrasonically nebulized 3.6% hypertonic saline, which was administered either in a dose-dependent manner (HSDR) or as a continuous single dose (HSC), and after cycle ergometer exercise. The mean decreases in FEV1 elicited by HSDR, HSC, and exercise were 26, 27, and 25%, respectively, and were not significantly different. There was an approximate 300% maximal increase in NCA detected after both HSC and exercise challenges. Gel filtration chromatography on columns of Ultragel ACA 34 indicated that the NCA released after HSC provocation and exercise were 600 to 700 kDa. There was an approximate 100% maximal increase in NCA after HSDR challenge, and this was significantly less (p = 0.016) than that after HSC and exercise. Exercise but not hypertonic challenge was associated with a basophilia and a significant increase in plasma histamine. There was a significant increase in plasma norepinephrine concentrations after exercise but not after HSC challenge in 7 asthmatics. Epinephrine concentrations did not change after exercise or HSC inhalation. NCA was measured in 5 subjects subjected to 2 HSC challenges that were separated by 60 min. There was an increase in NCA detected after both provocations. The increase after the second challenge was significantly greater (p = 0.27 x 10(-4)) than that observed after the initial provocation, despite a substantially reduced bronchoconstrictor response after the second challenge.

Adolescent↗
PubMed1987

Development of a microassay for histamine release.

A microassay has been developed to measure histamine release from both washed human leucocytes and whole blood, in which blood samples can be diluted down to 1:20 without affecting their sensitivity to antigen. The sensitivity and reproducibility of the single isotope histamine radioenzymatic assay [REA] was compared to the conventional spectrofluorometric histamine assay. The limit of detection was 0.2 and 2.0 ng/ml, respectively, and the agreement between the two assays was good (r = 0.94). There was also a good qualitative agreement between skin-prick test and histamine release (92%). In order to see if this assay was suitable for small volumes of blood, we measured histamine release to antigen from both diluted whole blood taken by a thumb prick (as a model of the heel prick used in obtaining paediatric blood samples), and undiluted venous blood. There was complete agreement between a positive or negative histamine release response to antigen by diluted thumb prick and undiluted venous blood samples. Leucocyte sensitivity to antigen increased slightly upon dilution, but remained within a ten-fold antigen dilution. The micro-histamine release assay described here offers an opportunity to measure basophil sensitivity to allergens where the availability of the blood is limited (in young babies for example) as well as making possible multiple allergen testing.

Adult↗