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Effect of amino group modification of ovine luteinizing hormone (oLH) by N-succinimidyl 6-[3-(2-pyridyldithio)propionate]hexanoate, a long chain N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) on immunological and biological properties: a comparative study with SPDP modified oLH.

The epsilon-NH2 groups of ovine luteinizing hormone has been modified with the long chain N-succinimidyl-3-(2-pyridyl dithiopropionate (LC-SPDP). The LC-SPDP modification primarily occurs in -NH2 groups of the alpha-subunit. Although, the sequential modification of lysine residue in alpha-subunit led to progressive reduction in the receptor binding and immunological properties but the steroidogenic activity was relatively unaffected. The immunoreactivity and receptor binding properties of LC-SPDP modified oLH molecule were more affected comparative to SPDP modified derivatives. This suggested that the increase in hydrophobic carbon chain in LC-SPDP-oLH molecules resulted into the drastic inhibition in the immunological and biological properties. However, the steroidogenic potential of LC-SPDP/or SPDP-oLH derivative was comparable. The present study clearly demonstrate that a single -NH2 group modification with LC-SPDP would generate the site for the conjugation to the toxin/carrier proteins and the resultant oLH-S-S-toxin conjugate would retain significant immunological and biological properties of the hormone molecule.

Amino Acids↗

[The modes of anti-inflammatory and analgesic actions of 2-[4-(3-methyl-2-butenyl) phenyl] propionic acid (TA-60) and 2-[4-(2,2-dichlorovinyl) phenyl] propionic acid (TA-668) and effect of TA-60 on the gastrointestinal tract].

TA-668 and TA-60, potent anti-inflammatory compounds, showed no inhibition against the dextran-, the serotonin- and the carrageenin + prostaglandin E2 (PGE2)-induced hind paw edemas in rats and neither did typical acidic non-steroidal anti-inflammatory drugs (ANSAIDs) such as indomethacin. On the other hand, salicylic acid, mepirizole and tiaramide X HCl inhibited the hind paw edema induced by carrageenin + PGE2 in rats. TA-668 and TA-60 as well as other ANSAIDs inhibited the arachidonic acid (AA)-induced erythema, but did not inhibit the PGE2-induced erythema. Mepirizole and tiaramide X HCl showed no inhibition against both the AA- and the PGE2-induced erythemas. TA-668 and TA-60 showed analgesic activities in the adjuvant-induced hind paw edematous rats. The analgesic activities of these compounds disappeared when PGE2 was injected into the inflamed paw as well as indomethacin and ibuprofen. It is concluded that anti-inflammatory and analgesic activities of both TA-668 and TA-60 were based on the inhibition of cyclo-oxygenase. TA-60 showed a protective effect against gastric necrosis induced by necrotizing agents such as HCl, NaOH or NaOH + EtOH. TA-60 showed about a 4 times less potent activity than ibuprofen in delay of occurring time of castor oil-induced diarrhea in rats. These results suggest that the slight ulcerating effect of TA-60 on the gastrointestinal tract might be attributed to its gastric protective effect and slight decreasing effect on the gastrointestinal level of PGE2.

Animals↗

A direct pathway for the conversion of propionate into pyruvate in Moraxella lwoffi.

1. The identity of the organism previously known as Vibrio O1 (N.C.I.B. 8250) with a species of Moraxella is established. 2. The ability of cells to oxidize propionate is present only in cells with an endogenous respiration and this ability is increased 80-fold when the organism is grown with propionate. 3. Isocitrate lyase activity in extracts from propionate-grown cells is the same as that in extracts from lactate-grown cells, about tenfold greater than that in extracts from succinate-grown cells and slightly greater than half the activity in extracts from acetate-grown cells. 4. With arsenite as an inhibitor conditions were found in which the organism would catalyse the quantitative oxidation of propionate to pyruvate. When propionate was completely utilized pyruvate was metabolized further to 2-oxoglutarate. 5. The oxidation of propionate by cells was incomplete both in a ;closed system' with alkali to trap respiratory carbon dioxide and in an ;open system' with an atmosphere of oxygen+carbon dioxide (95:5). Acetate accumulated. Under these conditions [2-(14)C]- and [3-(14)C]-propionate gave rise to [(14)C]acetate. The rate of conversion of [2-(14)C]propionate into (14)CO(2), although much less than the rate of conversion of [1-(14)C]propionate into (14)CO(2), was slightly greater than the rate of conversion of [3-(14)C]propionate into (14)CO(2). 6. The oxidation of propionate by cells was complete in an ;open system' with an atmosphere of either oxygen or air. Under these conditions very little [1-(14)C]propionate was converted into (14)C-labelled cell material. The conversion of [2-(14)C]- and [3-(14)C]-propionate into (14)C-labelled cell material occurred at an appreciable rate, the rate for the incorporation of [3-(14)C]propionate being slightly more rapid. In the absence of a utilizable nitrogen source part of the [(14)C]propionate was incorporated into some reserve material, which was oxidized when added substrate had been completely utilized. 7. [(14)C]-Pyruvate produced from [(14)C]propionate was chemically degraded. The C((1)) of propionate was found only in C((1)) of pyruvate. At least 86% of C((2)) of pyruvate was derived from C((2)) of propionate and at least 92% of C((3)) of pyruvate from C((3)) of propionate. 8. These results are incompatible with the operation of any of the previously described pathways for propionate metabolism except the direct one, perhaps via an activated acrylate.

Carbon Dioxide↗

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

UNLABELLED: Asthma guidelines recommend an inhaled corticosteroid plus a long-acting inhaled beta(2)-agonist (beta(2)-adrenoceptor agonist) as the preferred maintenance therapy for moderate and severe persistent asthma. Advair/Seretide Diskus also registered as Accuhaler is fixed-dose salmeterol (a long-acting inhaled beta(2)-agonist) and fluticasone propionate (a corticosteroid) administered via a single powder inhalation device. The clinical effectiveness of salmeterol/fluticasone propionate in patients with persistent asthma symptoms has been established in comparative clinical trials. Pharmacoeconomic analyses, based on data from these clinical trials, have been conducted from a healthcare payer perspective in various countries. In patients with asthma not controlled with inhaled corticosteroids, salmeterol/fluticasone propionate was associated with more favourable (lower) cost-effectiveness ratios than fluticasone propionate monotherapy, oral montelukast plus inhaled fluticasone propionate, inhaled budesonide, and inhaled formoterol plus budesonide. As the initial maintenance therapy in patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate was cost effective relative to montelukast monotherapy. Although the total cost of asthma management tended to be slightly higher with salmeterol/fluticasone propionate than with fluticasone propionate or montelukast monotherapy, salmeterol/fluticasone propionate consistently had a more favourable cost-effectiveness ratio in terms of per successfully treated week or symptom-free day and/or was associated with small incremental costs to achieve significant additional clinical benefits. In clinical practice, salmeterol plus fluticasone propionate was associated with lower asthma-related costs than treatment with other maintenance therapies.In patients with asthma symptoms despite treatment with inhaled corticosteroids, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall Asthma Quality of Life Questionnaire (AQLQ) scores relative to salmeterol or placebo monotherapy, in emotional function domain scores relative to fluticasone propionate or budesonide, and in asthma symptoms domain scores relative to budesonide. In patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall AQLQ scores compared with fluticasone propionate or montelukast. CONCLUSIONS: Pharmacoeconomic analyses indicate that salmeterol/fluticasone propionate administered via a single inhaler represents a cost-effective treatment option (relative to fluticasone propionate at the same nominal dosage, budesonide, formoterol plus budesonide and montelukast plus fluticasone propionate) in patients with asthma not controlled with inhaled corticosteroid therapy. In patients with asthma not controlled with short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate is a cost effective treatment relative to monotherapy with montelukast. Importantly, salmeterol/fluticasone propionate is also associated with improvements in health-related quality of life.

Albuterol↗

Administration of propionate to day-old turkeys.

The effects of salts of propionic acid on newly hatched turkeys were examined. In Experiment 1, poults were injected with .25 mL of 1 M solutions of either sodium propionate or calcium propionate. After a 24-h holding period, the poults were killed and assayed for blood glucose, liver weight, and liver glycogen. Sodium propionate increased blood glucose concentration but did not alter liver weight or liver glycogen compared with controls. Calcium propionate had no effect on blood glucose but increased liver weight and liver glycogen compared with controls. There was no mortality in saline-injected controls or sodium propionate poults; 4 of 10 poults injected with calcium propionate died. In Experiment 2, poults were administered 0 or 4% sodium propionate in the feed or 0 or 2% sodium propionate in the drinking water in a 2 x 2 factorial arrangement. Propionate depressed feed intake and body weight by both routes of administration. Propionate in the feed, but not drinking water, depressed liver weight and liver glycogen. Plasma uric acid was increased by propionate in either the feed or the water but was not above control amounts when propionate was given in both the feed and water at the same time. Plasma propionic acid was increased by propionate in the water but not by propionate in the feed. We conclude that the use of propionate in injectibles, drinking water, or feed of newly hatched turkeys is contraindicated.

Animals↗

Salmeterol and fluticasone propionate given as a combination. Lack of systemic pharmacodynamic and pharmacokinetic interactions.

OBJECTIVE: To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects. METHODS: Twenty-eight healthy subjects received salmeterol 100 microg, salmeterol 100 microg/fluticasone propionate 500 microg and fluticasone propionate 500 microg via a Diskus dry powder inhaler twice daily for 11 days according to a randomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 microg on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and glucose levels] and fluticasone propionate (on 24-h urinary cortisol and morning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta2-adrenoceptors and beta2-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10. Dosing continued on the evening of day 10 and on day 11, and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol (up to a total dosage of 3,200 microg) was evaluated. RESULTS: All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences between the single-dose and repeat-dose salmeterol groups. The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate. Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary cortisol excretion (22.4 microg compared with 48.6 microg with placebo), but this was unaffected by the co-administration of salmeterol. Morning plasma cortisol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta2-adrenoceptors and no correlation of beta2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only during the first half-hour after dosing. Co-administration of fluticasone propionate did not affect the peak plasma concentration (Cmax) of salmeterol. For fluticasone propionate, there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax, plasma concentration at the end of the dosing interval (Ct), terminal elimination half-life (t1/2) or time to Cmax (tmax). The area under the concentration-time curve within a dosing interval (AUCt) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher (about 8%) than after inhalation of fluticasone propionate alone (P=0.0135). However, the 90% confidence intervals (CIs) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). CONCLUSION: These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.

Administration, Inhalation↗

Contribution of propionate to glucose synthesis in sheep.

1. The production rate of propionate in the rumen and the entry rate of glucose into the body pool of glucose in sheep were measured by isotope-dilution methods. Propionate production rates were measured by using a continuous infusion of specifically labelled [(14)C]propionate. Glucose entry rates were estimated by using either a primed infusion or a continuous infusion of [U-(14)C]glucose. 2. The specific radioactivity of plasma glucose was constant between 4 and 9hr. after the commencement of intravenous infusion of [U-(14)C]glucose and between 1 and 3hr. when a primed infusion was used. 3. Infusion of [(14)C]propionate intraruminally resulted in a fairly constant specific radioactivity of rumen propionate between about 4 and 9hr. and of plasma glucose between 6 and 9hr. after the commencement of the infusion. Comparison of the mean specific radioactivities of glucose and propionate during these periods allowed estimates to be made of the contribution of propionate to glucose synthesis. 4. Comparisons of the specific radioactivities of plasma glucose and rumen propionate during intraruminal infusions of one of [1-(14)C]-, [2-(14)C]-, [3-(14)C]- and [U-(14)C]-propionate indicated considerable exchange of C-1 of propionate on conversion into glucose. The incorporation of C-2 and C-3 of propionate into glucose and lactate indicated that 54% of both the glucose and lactate synthesized arose from propionate carbon. 5. No differences were found for glucose entry rates measured either by a primed infusion or by a continuous infusion. The mean entry rate (+/-s.e.m.) of glucose estimated by using a continuous infusion into sheep was 0.33+/-0.03 (4) m-mole/min. and by using a primed infusion was 0.32+/-0.01 (4) m-mole/min. The mean propionate production rate was 1.24+/-0.03 (8) m-moles/min. The conversion of propionate into glucose was 0.36 m-mole/min., indicating that 32% of the propionate produced in the rumen is used for glucose synthesis. 6. It was indicated that a considerable amount of the propionate converted into glucose was first converted into lactate.

Animals↗

Metabolism of propionate by sheep-liver mitochondria. Evidence for rate control by a specific succinate oxidase.

1. Metabolism of propionate by sheep-liver mitochondria was stimulated catalytically by alpha-oxoglutarate, pyruvate, citrate and isocitrate. Succinate was stimulatory at higher concentrations, but fumarate and malate were inert. These effects were all independent of the presence of ATP, succinate being less effective when ATP was present. 2. Compared with the metabolism of added succinate, propionate metabolism was resistant to malonate inhibition, but only in the presence of added ATP. In the absence of ATP propionate metabolism was more sensitive to malonate inhibition than was the metabolism of succinate. 3. In the absence of malonate, and at malonate concentrations in the range 5-100mm, alpha-oxoglutarate increased the rate of fixation of [2-(14)C]propionate by about 50% without altering the nature of the fixation products. 4. Metabolism of [1-(14)C]-propionate in the presence of 50mm-malonate was accompanied by accumulation of about half the propionate consumed as succinate. When alpha-oxoglutarate was present in addition part of the alpha-oxoglutarate was metabolized and the rate of propionate consumption was increased. The total succinate that accumulated corresponded to the alpha-oxoglutarate consumed plus about half the propionate metabolized. 5. When [1-(14)C]propionate was metabolized in the absence of malonate about 70% of the generated succinate was oxidized to fumarate or beyond. The addition of malonate decreased the rate of propionate metabolism, and decreased to about half the fraction of generated succinate oxidized. 6. When propionate and 10mm-succinate were metabolized together, the total oxidation of succinate was greater than that with 10mm-succinate alone. The increment in succinate oxidation corresponded to about half the propionate metabolized in the presence or absence of malonate or ATP. 7. It is suggested that the metabolism of propionate is specifically limited by the rate of oxidation of the generated succinate, and that the succinate oxidase concerned is distinct from that responsible for the oxidation of added succinate. 8. The results are discussed in terms of the mode of action of certain stimulants and inhibitors of propionate metabolism. It is suggested that many of these act by stimulation or inhibition of the specific succinate oxidase that limits propionate metabolism.

Adenosine Triphosphate↗

Effects of intraruminal infusion of sodium, potassium, and ammonium on hypophagia from propionate in lactating dairy cows.

The objective of this experiment was to evaluate effects of salt type on hypophagic effects of intraruminal infusion of propionate in lactating dairy cows. Our working hypothesis is that oxidative metabolism of propionate causes satiety by increasing hepatic ATP concentration and decreasing the discharge rate of the hepatic vagus. We hypothesized that hypophagic effects of propionate are reduced by ammonium and potassium. We speculated that ammonium infusion lowers hepatic ATP concentration because ATP is used for urea synthesis and potassium increases the discharge rate of the hepatic vagus. Eight ruminally cannulated Holstein cows in midlactation were used in a duplicated 4 x 4 Latin square design experiment. Treatments were intraruminal infusion of propionic acid, ammonium propionate, sodium propionate, and potassium propionate. Treatment solutions were 0.93 M for propionate and 0.67 M for salts among the treatments except for propionic acid. Treatment solutions were infused over 14 h starting 2 h before feeding at 17.9 ml/min, which is equivalent to 16.7 and 11.9 mmol/min for propionate and salts, respectively. Infusion of ammonium propionate decreased dry matter intake compared with sodium propionate and potassium propionate (P < 0.04; 11.0 vs. 14.0 and 13.9 kg/12 h) by decreasing meal frequency without affecting meal size, indicating that ammonium delayed the sense of hunger. No difference in DMI and feeding behavior was observed between infusion of sodium and potassium propionate. Contrary to the hypothesis, ammonium infusion did not reduce hypophagic effects of propionate, possibly because the urea cycle indirectly stimulated oxidative metabolism in the liver by generating oxidizable carbon from amino acid catabolism.

Adenosine Triphosphate↗