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PubMed1980

Effects of lactate, pyruvate, butyrate and ammonia on gluconeogenesis from propionate by isolated rabbit liver cells.

The rate of gluconeogenesis in isolated rabbit liver cells has been measured from propionate, lactate, pyruvate and from the combination of propionate at different concentrations either with lactate or pyruvate. The glucose formed from propionate according to its concentration is about 74 to 87% of the glucose formed from lactate. No lag period was observed with preincubated cells and gluconeogenesis is linear at least from 90 min when the substrates are present at a concentration of 5 micrometers or more. Combinations of lactate + propionate increase the glucose formed as compared with propionate alone by a factor 1.5 - 1.7 according to substrates concentrations. Combinations of propionate + pyruvate decrease glucose formation in comparison with propionate alone. Conversion of pyruvate into lactate is enhanced by propionate. Glucose formation from lactate is strongly decreased by 14 micrometers quinolinate but has no significant effect on glucose formation from propionate. Amino-oxyacetate (0.2 micrometers) which decreases gluconeogenesis from lactate produced a slight enhancement of gluconeogenesis from propionate. 10 micrometers n-butylmalonate decreases gluconeogenesis by about 20-30% from three substrates. These observations are consistent with a predominant conversion of propionate into phosphoenolpyruvate intramitochondrially. Butyrate is rapidly metabolized by isolated rabbit liver cells with formation of ketone bodies. It inhibits glucose formation from propionate. 10 micrometers ammonium chloride + 2 micrometers ornithine in presence of propionate give an important ureogenesis and strongly decrease gluconeogenesis from propionate. At low concentration (0.5 micrometers), butyrate partially raises the inhibiting effect of ammonia on gluconeogenesis. This effect is progressively annulled as butyrate concentration rises to 10 micrometers. These observations are consistent with the fact that butyrate modifies the intramitochondrial ratio NADH/NAD and thereby the oxidation of malate formed from propionate.

Ammonia↗
PubMed1999

Inhaled fluticasone propionate: a review of its therapeutic efficacy at dosages < or = 500 microg/day in adults and adolescents with mild to moderate asthma.

UNLABELLED: Fluticasone propionate is a corticosteroid with comparatively high receptor affinity and topical activity. Inhaled fluticasone propionate < or =500 microg/day provided effective corticosteroid maintenance treatment in patients with mild to moderate asthma in randomised, controlled clinical studies of 4 to 24 weeks in duration. Dosages of 50 to 250 microg twice daily produced consistent improvement in spirometric measures of lung function, reduced the frequency of as-needed beta2-agonist bronchodilator use, asthma symptom scores and night-time wakenings, and prevented asthma exacerbations compared with placebo. Fluticasone propionate < or =250 microg twice daily provided significantly greater improvements in lung function than nedocromil 4 mg 4 times daily, theophylline (5 to 15 mg/L) or zafirlukast 20 mg twice daily. Health-related quality of life improved significantly with fluticasone propionate 88 microg twice daily, but not zafirlukast 20 mg twice daily or placebo. In comparative trials in which fluticasone propionate was given at half the dosage of beclomethasone dipropionate, budesonide or flunisolide, fluticasone propionate < or =250 microg twice daily produced equivalent or greater improvement in spirometric parameters and equivalent reductions in the use of as-needed beta2-agonists than beclomethasone dipropionate, budesonide or flunisolide. Fluticasone propionate 250 microg twice daily was generally more effective than triamcinolone acetonide 200 microg 4 times daily in two 24-week trials. The combination of inhaled fluticasone propionate < or =250 plus salmeterol < or =50 microg twice daily allowed for the use of lower dosages of the inhaled corticosteroid. The incidence of adverse events in patients receiving inhaled fluticasone propionate 50 to 250 microg twice daily was similar to that in beclomethasone dipropionate 168 to 500 microg twice daily and budesonide 100 to 600 microg twice daily recipients and greater than that in recipients of triamcinolone acetonide 200 microg 4 times daily in comparative trials. The incidence of oral candidiasis was < or =8% in patients treated with fluticasone propionate < or =250 microg twice daily or other agents. There was no evidence of clinically significant hypothalamo-pituitary-adrenal (HPA) axis suppression with fluticasone propionate < or =250 microg twice daily in comparative trials. CONCLUSIONS: Inhaled fluticasone propionate < or =500 microg/day is an effective antiinflammatory therapy for mild to moderate asthma in adolescents and adults. The drug is more effective than nedocromil, theophylline or zafirlukast and is at least as effective as other inhaled corticosteroids administered at twice the fluticasone propionate dosage. The addition of inhaled salmeterol allows the use of lower maintenance dosages of fluticasone propionate. The drug is well tolerated and there is no evidence of a clinically significant effect of this dosage on HPA axis function. Hence, fluticasone propionate < or =500 microg/day is a particularly suitable agent for patients with mild to moderate asthma.

Administration, Inhalation↗
PubMed2000

Effect of oral antibiotics on intestinal production of propionic acid.

BACKGROUND: Propionic acid derived from colonic bacterial fermentation contributes substantially to overall propionate load in children with disorders of propionate metabolism, and its reduction is important for adequate metabolic control. AIMS: To evaluate the in vitro and in vivo effects of antibiotic treatment on propionate production by colonic bacteria, and plasma propionate concentrations in a child with propionic acidaemia. METHODS: In vitro fermentation techniques were used to study the effects of addition of antibiotics (metronidazole, clindamycin, erythromycin, and vancomycin) on net faecal production of short chain fatty acids including propionic acid. Courses of oral antibiotics of 7 days duration were used to assess the in vivo effects on faecal propionate production and metabolic control including plasma propionate concentrations. RESULTS: Metronidazole produced the largest and most consistent reduction (77-84%) in the production in vitro of propionate from faecal homogenates. Oral administration of metronidazole reduced faecal propionate production by 43% within 24 hours of treatment; a 7 day course virtually eliminated it for the next 3 weeks. These reductions were accompanied by substantially lowered plasma propionate concentrations during the same period. CONCLUSIONS: Intermittent courses of oral metronidazole might be as effective as continuous treatment in reducing gut propionate production in children with disorders of propionate metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Disappearance and passage of propionic acid from the rumen of the beef steer.

Studies were conducted to define steady state pH, propionic acid concentrations and fluid turnover in the rumen of steers fed every 3 h and to determine whether rates of ruminal propionic acid disappearance were linearly related to their in situ production rates. Ruminally fistulated beef steers (326 +/- 11 kg; n = 3) were fed eight times daily a 54% mixed hay: 46% corn-based concentrate diet to meet maintenance energy requirements. Maximal acceptable variations from the mean at steady state conditions of pH, propionic acid concentrations and specific activity, and liquid flow (Cr marker concentrations) were defined as 4%, 20%, 30% and 10%, respectively, across 4 h of observation. In situ production of propionic acid, determined by pulse-continuous infusion of 1-14C-propionic acid, was 142 mmol/h (CV = 8.4%). The ruminal half-life of propionic acid was estimated to be 1.5 h and the liquid flow rate was 3.8 liters/h. Propionic acid production rates subsequently were elevated by continuous intraruminal infusion of buffered propionic acid. Irrespective of production (basal and infusion) rate, approximately 66% disappeared (i.e., presumed absorption) and 34% passed from the rumen to the lower tract in the liquid phase. Ruminal disappearance of propionate was linearly related with its production rate, and propionate concentrations and production rates also were linearly related. Liquid passage was linearly related to production rate, but there was insufficient evidence to conclude that fractional dilution rate or ruminal volume were similarly related. When ruminal production of propionic acid is elevated, the rumen has additional absolute capacity to remove propionate, but the fractional removal appears to be constant. The digestive tract distal to the rumen is likely an important site of propionate absorption in cattle when propionate production is high.

Absorption↗
PubMedDate not supplied

The efficacy of fluticasone propionate aqueous nasal spray for allergic rhinitis and its relationship to topical effects.

Fluticasone propionate aqueous nasal spray is an intranasal corticosteroid for the treatment of patients with allergic rhinitis. This double-masked, double-dummy, parallel-group study was conducted to confirm that the efficacy of fluticasone propionate nasal spray is attributable to topical rather than systemic effects. A total of 304 patients with documented seasonal allergic rhinitis were randomly assigned to receive fluticasone propionate nasal spray 200 micrograms once daily (n = 77), oral fluticasone propionate 5 mg once daily (n = 73), oral fluticasone propionate 10 mg once daily (n = 77), or placebo (n = 77) for 14 days. Plasma fluticasone propionate concentrations were determined at baseline and after 14 days of treatment (day 15). Nasal symptoms were recorded daily by patients and assessed weekly by clinicians. On day 15, more patients in the oral fluticasone propionate 5-mg or 10-mg groups, compared with patients in the fluticasone propionate nasal spray group or the placebo group, had detectable plasma fluticasone propionate concentrations, and mean concentrations were higher in the oral fluticasone propionate groups. Both clinician- and patient-rated total and individual nasal symptom scores for obstruction, rhinorrhea, sneezing, and itching were significantly lower in the fluticasone propionate nasal spray group compared with either of the oral fluticasone propionate groups or the placebo group. With few exceptions, oral fluticasone propionate (5 mg or 10 mg) was not significantly different from placebo on any measures of efficacy. These findings indicate that the efficacy of fluticasone propionate nasal spray (200 micrograms once daily) in the treatment of allergic rhinitis results from direct topical effects rather than from indirect effects after systemic absorption.

Absorption↗
PubMed2005

The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma.

BACKGROUND: For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid (ICS) therapy, the preferred treatment is to add an inhaled long-acting beta2-agonist vs increasing the ICS dose. OBJECTIVE: To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting beta2-agonist salmeterol with that of fluticasone propionate used alone in children aged 4 to 11 years with persistent asthma. METHODS: A randomized, multicenter, double-blind, active-controlled, parallel-group study in 203 children with persistent asthma who were symptomatic during ICS therapy. Patients received fluticasone propionate-salmeterol (100/50 microg) or fluticasone propionate (100 microg) alone twice daily for 12 weeks. RESULTS: The safety profile of fluticasone propionate-salmeterol was similar to that of fluticasone propionate alone. The overall incidence of adverse events was 59% for fluticasone propionate-salmeterol and 57% for fluticasone propionate. Both treatments were well tolerated. Two patients receiving fluticasone propionate-salmeterol and 5 receiving fluticasone propionate withdrew from the study because of worsening asthma. Changes in heart rate, blood pressure, and laboratory variables were infrequent and were similar between treatments. No patients had clinically significant abnormal electrocardiographic findings during treatment. Geometric mean 24-hour urinary cortisol excretion at baseline and after 12 weeks of treatment was comparable within and between groups; no patient in either group had abnormally low 24-hour urinary cortisol excretion after 12 weeks of treatment. The incidence of withdrawals due to asthma exacerbations was 2% in the fluticasone propionate-salmeterol group and 5% in the fluticasone propionate group. CONCLUSIONS: In pediatric patients with persistent asthma, fluticasone propionate-salmeterol twice daily was well tolerated, with a safety profile similar to that of fluticasone propionate used alone.

Adrenergic beta-Agonists↗
PubMed1985

Metabolism of propionate to acetate in the cockroach Periplaneta americana.

Carbon-13 NMR and radiotracer studies were used to determine the precursor to methylmalonate and to study the metabolism of propionate in the cockroach Periplaneta americana. [3,4,5-13C3]Valine labeled carbons 3, 4, and 26 of 3-methylpentacosane, indicating that valine was metabolized via propionyl-CoA to methylmalonyl-CoA and served as the methyl branch unit precursor. Potassium [2-13C]propionate labeled the odd-numbered carbons of hydrocarbons and potassium [3-13C]propionate labeled the even-numbered carbons of hydrocarbons in this insect. This labeling pattern indicates that propionate is metabolized to acetate, with carbon-2 of propionate becoming the methyl carbon of acetate and carbon-3 of propionate becoming the carboxyl carbon of acetate. In vivo studies in which products were separated by HPLC showed that [2-14C]propionate was readily metabolized to acetate. The radioactivity from sodium [1-14C]propionate was not incorporated into succinate nor into any other tricarboxylic acid cycle intermediate, indicating that propionate was not metabolized via methylmalonate to succinate. Similarly, [1-14C]propionate did not label acetate. An experiment designed to determine the subcellular localization of the enzymes involved in converting propionate to acetate showed that they were located in the mitochondrial fraction. Data from both in vivo and in vitro studies as a function of time indicated that propionate was converted directly to acetate and did not first go through tricarboxylic acid cycle intermediates. These data demonstrate a novel pathway of propionate metabolism in insects.

Acetates↗
PubMed1969

Acceleration of gluconeogenesis from propionate by Dl-carnitine in the rat kidney cortex.

1. The rate of gluconeogenesis from propionate in rat kidney-cortex slices was stimulated up to 3.5-fold by dl-carnitine and by bicarbonate, and was inhibited by inorganic phosphate or high concentrations of propionate (above 3mm). 2. The stimulatory effect of carnitine was dependent on the bicarbonate concentration and could be replaced at low propionate concentration by addition of 25mm-bicarbonate-carbon dioxide buffer. At low bicarbonate concentration the carnitine concentration can be rate-limiting. 3. All observations are in accordance with the view that the action of carnitine is in principle the same as that established for other fatty acids in other tissues, namely that carnitine promotes the appearance of propionyl-CoA within the mitochondrion by acting as a carrier. 4. The accelerating effects of carnitine and bicarbonate and the inhibitory effect of phosphate can be explained on the basis of the known properties of key enzymes of propionate metabolism, i.e. the reversibility of the reactions leading to the formation of methylmalonyl-CoA from propionyl-CoA. 5. 5mm-Propionate caused a five- to ten-fold fall in the free CoA content of the tissue. This fall can account for the inhibition of respiration and gluconeogenesis caused by high propionate concentration. 6. Relatively large quantities of propionyl-l-carnitine (15% of the propionate removed) were formed when dl-carnitine was present; thus the ;activation' of propionate proceeded at a faster rate than the carboxylation of propionyl-CoA. The metabolism of added propionyl-l-carnitine was accompanied by glucose synthesis. 7. The appearance of radioactivity from [2-(14)C]propionate in both glucose and carbon dioxide was as expected on account of the randomization of C-2 and C-3 of propionate, i.e. the formation of succinate as an intermediate. 8. The maximum rate of glucose synthesis from propionate (93.3+/-3.3mumoles/g. dry wt./hr.) was not affected by dietary changes aimed at varying the rate of caecal volatile fatty acid formation in the rat. 9. Inhibition of gluconeogenesis by high propionate concentration was not found in those species where the rate of caecal or ruminal propionate production is high under normal conditions (rabbit, sheep and cow).

Animals↗
PubMed2006

Propionate challenge tests have limited value for investigating bovine metabolism.

Two experiments were designed to assess the potential utility of the propionate challenge test (PCT) as an index of gluconeogenic capacity. In Expt. 1, the dose-response to jugular propionate infusion was assessed in a duplicated 4 x 4 Latin square experiment with 8 lactating dairy cows. Sodium propionate (4.5 mol/L, pH 7.4) was infused in an intrajugular bolus at 0 (saline), 0.52, 1.04, or 1.56 mmol/kg body weight (BW), and jugular blood was sampled over the following 2 h. Peak propionate concentration in plasma and area under the curve for plasma glucose both increased linearly with increasing propionate dose (P < 0.01). Plasma free fatty acid (FFA) concentration was elevated by all propionate treatments at 20 min postinfusion (P = 0.03), and plasma cortisol concentration tended to increase (P < 0.10) after propionate infusions. Experiment 2 was designed to study the effect of short-term differences in fed state on responses to propionate infusion. Lactating dairy cows (n = 8) were included in a duplicated 4 x 4 Latin square design with a 2 x 2 factorial arrangement of treatments. Sodium propionate (1.04 mmol/kg BW) or saline was infused either before feeding (0900) or 2 h after feeding (1300). Fed cows consumed 4.4 +/- 1.4 kg dry matter before the PCT. Although fed cows had a significantly higher preinfusion plasma propionate concentration, fed state did not influence postinfusion changes in plasma propionate, glucose, insulin, glucagon, or FFA concentrations. Liver glycogen concentration decreased significantly after propionate, but not saline infusion (P < 0.05). Short-term differences in fed state do not affect the physiological responses to PCT. However, glucagon release after jugular administration of propionate is likely supraphysiologic, and postinfusion lipolysis and glycogenolysis suggest that stress responses may alter PCT measurements. Although the PCT may help to diagnose liver dysfunction, it is not a useful index with which to assess differences in gluconeogenic capacity.

Animals↗
PubMed1989

Volatile fatty acid uptake and propionate metabolism in ruminant hepatocytes.

Previous reports have demonstrated that butyrate inhibits metabolism of propionate by liver cells isolated from sheep and goats. Our objectives were to examine some possible mechanisms for this inhibition and to test for this inhibition in the bovine animal. Incorporation of label from 2.5 mM [2-(14)C]propionate into glucose (nmol propionate/mg cell DM/h) in the presence of 0, 1.25, and 2.5 mM butyrate was 107, 66, and 62 by goat hepatocytes and 79, 25, and 29 by calf hepatocytes; therefore, butyrate inhibited propionate metabolism at least as effectively in calves as in goats. In goat hepatocytes 1.25 mM butyrate reduced 1.25 mM propionate uptake to 46% of control, and 1.25 mM [2-(14)C] propionate incorporation into glucose to 44% of control. Propionate had no effect on butyrate uptake. Isovalerate and valerate tended to be cleared from the media to a greater extent than butyrate but had no effect on propionate uptake. Therefore, inhibition of propionate conversion to glucose by butyrate is specific and is not due to a general competition among VFA for metabolism. Butyrate inhibits hepatic propionate utilization generally, not specifically propionate conversion to glucose. Butyrate also inhibited propionate utilization by goat liver homogenates, indicating that butyrate inhibits propionate metabolism at a step subsequent to propionate transport across the hepatocyte plasma membrane.

Animals↗
PubMed1988

Hypocholesterolaemic effects of dietary propionate: studies in whole animals and perfused rat liver.

In adult male rats fed a non-purified diet supplemented with 5% sodium propionate, plasma cholesterol concentrations were significantly depressed. Although liver cholesterol was increased by feeding propionate, rates of hepatic cholesterol and fatty acid synthesis were unchanged. Tissue concentrations and rates of synthesis of cholesterol were also unaffected by dietary propionate in stomach, small intestine and caecum. Concentrations of propionate in hepatic portal venous plasma were raised by feeding the supplemented diet but the increase was low in comparison to the dietary intake. Examination of the gut contents revealed concentrations of total volatile fatty acids (VFA) of 19 mumol/ml in the stomach contents of control rats and 148 mumol/ml (of which propionate contributed 116 mumol/ml) in those fed the supplemented diet. Duodenal and ileal concentrations of VFA were very low and were only slightly raised in the propionate-fed rats while caecal VFA were the same in both groups with a combined mean of 159 mumol/ml. These data indicate that in the rat, the absorption of dietary propionate appears to occur in the stomach. In pigs fed a standard ration hepatic portal venous VFA remained low for the first 4 h after feeding but then rose with the onset of large bowel fermentation. Feeding the diet supplemented with propionate caused hepatic portal venous plasma concentrations to rise by approximately 0.4 mumol/ml. This increase was apparent 30 min after feeding and was sustained for 3 h but subsequently there was no difference to controls. As in the rat, the absorption of dietary propionate appeared to occur in the upper gastrointestinal tract. The transport of propionate via the porcine hepatic portal vein also appeared insufficient to account for the dietary intake and suggests metabolism of the acid by the upper gastrointestinal tract. Further studies with perfused livers from fed rats indicated that propionate at a concentration of 1 mumol/ml did not alter cholesterol synthesis but that inhibition occurred at 18 mumol of propionate/ml. It appears that a redistribution of cholesterol from the plasma to the liver, rather than inhibition of hepatic and intestinal cholesterol synthesis, is responsible for the hypocholesterolaemic effects of dietary propionate. Because the absorption and transport of dietary propionate appears to follow a time course which differs considerably to that of the acid produced by the large bowel microflora, we conclude also that VFA produced by such fermentation would not seem to be responsible for the hypocholesterolaemic effects of certain water-soluble plant fibres.

Animals↗
PubMed1993

Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma.

This study was designed to compare the efficacy and safety of a new inhaled corticosteroid, fluticasone propionate at a total daily dose of 200 micrograms, with beclomethasone dipropionate 400 micrograms/day in childhood asthma. A total of 398 asthmatic children (aged 4-19 years) were randomised to receive either fluticasone propionate 200 micrograms daily or beclomethasone dipropionate 400 micrograms daily for six weeks inhaled via a spacer device from a metered dose inhaler. During the study the patients recorded morning and evening peak expiratory flow rate (PEFR), symptom scores, and use of beta 2 agonist rescue medication. In addition, clinic visit PEFR and forced expiratory volume in one second were measured. Safety was assessed by recording all adverse events and by performing routine biochemistry and haematology screens including plasma cortisol concentration before and after treatment. For the purposes of analysis the diary card data were grouped into three periods: week 3 (days 15-21), week 6 (days 36-42), and weeks 1-6 (days 1-42). The results showed no significant difference between treatments on most efficacy parameters. However, there were significant differences in changes from baseline in favour of fluticasone propionate for % predicted morning PEFR both at week 3 (fluticasone propionate 6.1%, beclomethasone dipropionate 3.9%) and at week 6 (fluticasone propionate 8.3%, beclomethasone dipropionate 5. 9%) and % predicted evening PEFR at week 6 (fluticasone propionate 7.3%, beclomethasone dipropionate 4.9% and over weeks 1-6 (fluticasone propionate 5.5%, beclomethasone dipropionate 3.6%. Comparison between groups showed that the group receiving fluticasone propionate had a lower % of days with symptom-free exercise at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 81%) and % days without rescue medication at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 80%) and over weeks 1-6 (fluticasone propionate 80%, beclomethasone dipropionate 73%). Except for a higher incidence of sore throat in the fluticasone propionate group, the two treatments did not differ with regard to safety. There was no evidence of adrenal suppression with either treatment. In conclusion, fluticasone propionate 200 microgram daily ws at least as effective and as well tolerated as beclomethasone dipropionate 400 microgram daily in childhood asthma.

Administration, Inhalation↗
PubMed2000

Inhaled salmeterol/fluticasone propionate combination: a review of its use in persistent asthma.

UNLABELLED: The long-acting beta2-agonist salmeterol and the corticosteroid fluticasone propionate are available as a combination inhalation device for the treatment of persistent asthma. Well designed studies in adults, adolescents and children aged > or =4 years, demonstrate that combined salmetero/fluticasone propionate 50/100, 50/250 and 50/500 microg administered via a dry powder inhaler (DPI) is clinically equivalent to concurrent delivery of the same dosages of the 2 drugs via separate DPIs. In adults and adolescents, combined salmeterol/fluticasone 50/100 and 50/250 microg twice daily produced rapid improvements in lung function that were consistently greater than those in patients receiving monotherapy twice daily salmeterol 50 microg, fluticasone propionate 100 or 250 microg or placebo in 2 well designed studies. Recipients of the combination had a significantly greater probability of completing 12 weeks of treatment than patients receiving monotherapy or placebo. The combination also produced significant improvements between baseline and end-point in all secondary outcome variables (morning and evening peak expiratory flow, daytime symptom scores, days and nights without asthma symptoms and requirements for as-needed beta-agonists) and health-related quality of life (QOL). Combination therapy was superior to monotherapy with salmeterol and placebo for all outcomes in both studies, and was superior to fluticasone propionate 100 microg for all but 1 outcome (nights without awakenings) in 1 study. Similar results were obtained in patients who had previously been using short acting beta2-agonists alone. Combined twice daily salmeterolfluticasone propionate 50/100 and 50/250 microg produced greater improvements in lung function than inhaled budesonide at higher dosages than fluticasone propionate in the combination. Combined salmeterol/fluticasone propionate 50/250 microg produced similar improvements in lung function to concurrent budesonide 800 microg plus formoterol 12 microg when given twice daily for 12 weeks. In another 12-week trial, combined salmeterol/fluticasone propionate 50/100 microg was more effective than oral montelukast 10 mg/day plus fluticasone propionate 100 microg twice daily in patients with suboptimally controlled asthma. Salmeterol/fluticasone is more cost effective than monotherapy with fluticasone propionate or budesonide. The most frequent adverse events associated with salmeterol/fluticasone propionate are headache, throat irritation, hoarseness and candidiasis. CONCLUSION: Combined salmeterol/fluticasone propionate is as effective as the 2 drugs given concurrently via separate inhalers and significantly more effective than either drug given alone at the same nominal dosage. The combination is also significantly more effective than montelukast plus fluticasone propionate or monotherapy with inhaled budesonide. Furthermore, the combination is more cost effective than inhaled corticosteroid monotherapy.

Administration, Inhalation↗
PubMed2000

Inhaled salmeterol/fluticasone propionate combination. A pharmacoeconomic review of its use in the management of asthma.

Cost estimates from developed countries indicate that asthma accounts for up to 2% of the economic cost of all diseases. A large proportion of asthma-related costs are attributable to poor asthma control. Treatment strategies which improve clinical outcomes in patients with asthma, therefore, have the potential for significant economic benefits, and it is important to evaluate new asthma therapies for cost effectiveness. Several studies have established that salmeterol and fluticasone propionate combined in a single dry powder inhalation device are at least as effective as a combination of the 2 drugs administered via separate dry powder inhalers and more effective than monotherapy with fluticasone propionate or budesonide. Importantly, pharmacoeconomic analysis of several of these studies show that the salmeterol/fluticasone propionate combination is cost effective relative to monotherapy with fluticasone propionate or budesonide. Although the total cost of asthma management tended to be slightly higher with salmeterol/fluticasone propionate than with inhaled corticosteroid monotherapy, in most cases mean cost-effectiveness ratios were lower (i.e. more favourable) for salmeterol/fluticasone propionate than either fluticasone propionate or budesonide. Cost effectiveness was assessed according to 3 end-points: successfully treated weeks, symptom-free days and episode-free days. Mean cost-effectiveness ratios consistently favoured salmeterol/fluticasone propionate over the comparator drug for the end-point successfully treated weeks, and in most cases the other 2 end-points also favoured the combination product over the comparator. In a further study, salmeterol/fluticasone was also less costly than therapy with formoterol and budesonide administered via 2 separate inhalers. Studies of health-related quality of life (HR-QOL) using the Asthma Quality of Life Questionnaire indicate that salmeterol/fluticasone propionate produces clinically meaningful improvements in overall HR-QOL relative to salmeterol monotherapy or placebo. Improvements in overall HR-QOL were statistically significantly greater for salmeterol/fluticasone propionate than with fluticasone propionate or budesonide alone, although the differences between treatments did not exceed the threshold for clinical significance. In conclusion, short term cost-effectiveness data show that salmeterol/fluticasone propionate is more cost effective than the inhaled corticosteroids budesonide and fluticasone propionate alone. The combination product also appears to improve HR-QOL relative to placebo or salmeterol alone.

Albuterol↗
PubMed2005

Propionate is not an important regulator of plasma leptin concentration in dairy cattle.

Propionate was recently shown to increase leptin synthesis in rodents. To determine if a similar effect occurs in ruminants, propionate was administered to lactating dairy cows. In experiment 1, 31 cows were given an intrajugular Na propionate bolus (1,040 micromol/kg body weight), increasing plasma propionate from 160 to 5,680 microM and plasma insulin from 6.8 to 77.8 microIU/mL. Plasma leptin concentration decreased from 2.11 ng/mL before bolus to 1.99 ng/mL after dosing (P<0.05) with no differences in leptin concentrations at 20, 50, and 100 min post-bolus (P>0.10). In experiment 2, 12 cows were used in a duplicated 6 x 6 Latin square experiment to assess the dose-response effect of ruminal propionate infusion on plasma leptin concentration. Sodium propionate was infused at rates of 0, 260, 520, 780, 1040, or 1,300 mmol/h, while total short-chain fatty acid infusion rate was held constant at 1,300 mmol/h by addition of Na acetate to the infusate. Coccygeal blood was sampled following 18 h of infusion. Increasing the rate of propionate infusion linearly increased plasma propionate concentration from 180 to 330 microM (P<0.001) and plasma insulin concentration from 6.7 to 9.1 microIU/mL (P<0.05). There was a quadratic response in plasma leptin concentration (P=0.04) with a maximum at 780 mmol/h propionate, but leptin concentrations increased by no more than 8% relative to the 0 mmol/h propionate infusion. Leptin concentrations were correlated with insulin concentrations but not with propionate concentrations in plasma. Propionate is not a physiological regulator of leptin secretion in lactating dairy cows.

Animals↗
PubMed1995

Effects of intraruminal infusion of propionate on the concentrations of ammonia and insulin in peripheral blood of cows receiving an intraruminal infusion of urea.

To test the hypothesis that propionate can reduce hepatic capacity to detoxify ammonia, effects of the inclusion of propionate in intraruminal infusions of urea on the concentrations of ammonia, other metabolites and insulin in peripheral blood were investigated in two experiments with non-lactating dairy cows. Both experiments were of a 4 x 4 Latin square design with four animals, four treatments and four experimental periods of 7 d; feed was given in two equal meals each day, all intraruminal infusions were given for 1 h at the time of the morning feed, and propionic acid was partly neutralized with NaOH. In Expt 1, the treatments were a basal diet of pelleted lucerne and chopped hay alone or with the following infusions (g/d): urea 80, propionic acid 350, urea 80 plus propionic acid 350. The inclusion of propionate in the urea infusion markedly increased (P < 0.001) the concentration of ammonia in plasma compared with infusion of urea alone. Moreover, the inclusion of urea with the propionate infusion abolished (P < 0.01) the increase in blood insulin level seen with the infusion of propionate alone. In Expt 2, less severe treatments were imposed, the aim being to reproduce metabolic loads of propionate and ammonia that might be expected from a diet of high-protein grass silage rich in lactic acid. The treatments were a basal diet of grass silage alone or with the following infusions (g/d): NaCl 145, NaCl 145 plus urea 50, propionic acid 200, urea 50 plus propionic acid 200. Effects were less pronounced than in Expt 1 but, in the period immediately after infusion, similar effects were seen. It is concluded that propionate-ammonia interactions may have potentially important effects on milk production especially for diets with high proportions of grass silage containing high levels of protein and lactic acid.

Ammonia↗
PubMed1988

Propionate metabolism in the rat heart by 13C n.m.r. spectroscopy.

High-resolution 13C n.m.r. spectroscopy has been used to examine propionate metabolism in the perfused rat heart. A number of tricarboxylic acid (TCA) cycle intermediates are observable by 13C n.m.r. in hearts perfused with mixtures of pyruvate and propionate. When the enriched 13C-labelled nucleus originates with pyruvate, the resonances of the intermediates appear as multiplets due to formation of multiply-enriched 13C-labelled isotopomers, whereas when the 13C-labelled nucleus originates with propionate, these same intermediates appear as singlets in the 13C spectrum since entry of propionate into the TCA cycle occurs via succinyl-CoA. An analysis of the isotopomer populations in hearts perfused with [3-13C]pyruvate plus unlabelled propionate indicates that about 27% of the total pyruvate pool available to the heart is derived directly from unlabelled propionate. This was substantiated by perfusing a heart for 2 h with [3-13C]propionate as the only available exogenous substrate. Under these conditions, all of the propionate consumed by the heart, as measured by conventional chemical analysis, ultimately entered the oxidative pathway as [2-13C] or [3-13C]pyruvate. This is consistent with entry of propionate into the TCA cycle intermediate pools as succinyl-CoA and concomitant disposal of malate to pyruvate via the malic enzyme. 13C resonances arising from enriched methylmalonate and propionylcarnitine are also detected in hearts perfused with [3-13C] or [1-13C]propionate which suggests that 13C n.m.r. may be useful as a non-invasive probe in vivo of metabolic abnormalities involving the propionate pathway, such as methylmalonic aciduria or propionic acidaemia.

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PubMed1997

Uptake and metabolism of propionate in the liver isolated from sheep treated with glucagon.

The uptake and metabolism of propionate in the isolated perfused caudal lobe of the liver and in isolated hepatocytes were examined following treatment of sheep with glucagon or saline. Glucagon or sterile saline was infused at 9.8 micrograms/min for 3 h into the jugular vein and then the caudal lobe of the liver was removed surgically under anaesthesia. The caudal lobe was used either to prepare hepatocytes or in a non-recirculating perfusion experiment. Uptake and metabolism of propionate were studied using [2-14C]propionate. In studies using the non-recirculation perfusion of the caudal lobe of the sheep liver it was shown that the treatment of sheep with glucagon resulted in an increased rate of gluconeogenesis from propionate and in an increased net uptake of propionate by the caudal lobe. The uptake of propionate into the hepatocytes was saturable, concentrative and exhibited a K(m) for propionate of 0.24 (SE 0.07) mM and a maximal rate of uptake (Vmax) of 6.7 (SE 0.6) nmol/mg dry cells per min and was unaffected by glucagon treatment of sheep. After incubation of cells in medium containing 0.5 mM-[2-14C]propionate for 10 min, the rate of gluconeogenesis from propionate was 22% higher in the hepatocytes isolated from glucagon-treated sheep. Concentrations in the medium of 1.35 mM butyrate and 1 mM-caproate inhibited propionate uptake by about 50% and abolished the glucagon-induced stimulation of gluconeogenesis from propionate. The results are consistent with a regulatory role for glucagon in the gluconeogenesis from propionate in the sheep liver.

Animals↗