scholarly journals Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists

Thorax ◽  
2001 ◽  
Vol 56 (7) ◽  
pp. 529-535
Author(s):  
H J van der Woude ◽  
T H Winter ◽  
R Aalbers
Keyword(s):  
Single Dose ◽  
Partial Agonist ◽  
Forced Expiratory Volume ◽  
Intrinsic Activity ◽  
High Dose ◽  
Double Blind ◽  
Long Term Treatment ◽  
Long Acting

BACKGROUNDIn vitro the long acting β2 agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other β2 agonists. To study this in vivo, the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists.METHODSA randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV1) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV1 of 20% or more (PC20) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 μg twice daily by Turbuhaler), salmeterol (100 μg twice daily by Diskhaler), or placebo a methacholine provocation test was performed and continued until there was at least a 30% decrease in FEV1. Salbutamol (50 μg) was administered immediately thereafter, followed by ipratropium bromide (40 μg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation.RESULTSThere was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV1 of ⩾30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The difference between formoterol and salmeterol was statistically significant: 0.7 doubling dose steps (95% CI 0.1 to 1.2, p=0.016). The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p<0.0003 for both). Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8%, 7.3%, and 5.5% for placebo, formoterol and salmeterol, respectively (equivalent to increases of 26%, 14%, and 12%, respectively, from the lowest FEV1after methacholine). At 30 minutes significant differences remained, but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups.CONCLUSIONFormoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent, indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo. Irrespective of this, prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally, indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol. Patients on regular treatment with long acting β2 agonists should be made aware that an additional single dose of a short acting β2 agonist may become less effective.

scholarly journals Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1210
Author(s):  
Xieguo Yan ◽  
Shiqiang Wang ◽  
Kaoxiang Sun
Keyword(s):  
Drug Loading ◽  
Entrapment Efficiency ◽  
In Vitro Dissolution ◽  
Dissolution Behavior ◽  
In Vivo Evaluation ◽  
Long Term Treatment ◽  
Long Acting

Schizophrenia, a psychiatric disorder, requires long-term treatment; however, large fluctuations in blood drug concentration increase the risk of adverse reactions. We prepared a long-term risperidone (RIS) implantation system that can stabilize RIS release and established in-vitro and in-vivo evaluation systems. Cumulative release, drug loading, and entrapment efficiency were used as evaluation indicators to evaluate the effects of different pore formers, polymer ratios, porogen concentrations, and oil–water ratios on a RIS implant (RIS-IM). We also built a mathematical model to identify the optimized formulation by stepwise regression. We also assessed the crystalline changes, residual solvents, solubility and stability after sterilization, in-vivo polymer degradation, pharmacokinetics, and tissue inflammation in the case of the optimized formulation. The surface of the optimized RIS microspheres was small and hollow with 134.4 ± 3.5 µm particle size, 1.60 SPAN, 46.7% ± 2.3% implant drug loading, and 93.4% entrapment efficiency. The in-vitro dissolution behavior of RIS-IM had zero-order kinetics and stable blood concentration; no lag time was released for over three months. Furthermore, the RIS-IM was not only non-irritating to tissues but also had good biocompatibility and product stability. Long-acting RIS-IMs with microspheres and film coatings can provide a new avenue for treating schizophrenia.

scholarly journals Micro RNA Expression after Ingestion of Fucoidan; A Clinical Study

Marine Drugs ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 143 ◽  
Author(s):  
Nuri Gueven ◽  
Kevin J. Spring ◽  
Sandra Holmes ◽  
Kiran Ahuja ◽  
Raj Eri ◽  
...  
Keyword(s):  
Single Dose ◽  
Biological Activities ◽  
Micro Rna ◽  
Cell Surface Receptor ◽  
Sulfated Polysaccharides ◽  
Analysis Tool ◽  
Brown Macroalgae ◽  
Double Blind

Fucoidans are a class of fucose-rich sulfated polysaccharides derived from brown macroalgae that exert a range of biological activities in vitro and in vivo. To generate an unbiased assessment of pathways and processes affected by fucoidan, a placebo-controlled double-blind pilot study was performed in healthy volunteers. Blood samples were taken immediately before and 24 h after ingestion of a single dose of 1 g of Undaria pinnatifida fucoidan (UPF) or placebo. Levels of isolated miRNAs were analyzed using Taqman Open Array Human MicroRNA panels. Out of 754 miRNAs screened, UPF affected a total of 53 miRNAs. Pathway analysis using the TALOS data analysis tool predicted 29 different pathways and processes that were largely grouped into cell surface receptor signaling, cancer-related pathways, the majority of which were previously associated with fucoidans. However, this analysis also identified nine pathways and processes that have not been associated with fucoidans before. Overall, this study illustrates that even a single dose of fucoidans has the potential to affect the expression of genes related to fundamental cellular processes. Moreover, it confirms previous data that fucoidans influence immunity, cancer cells, inflammation, and neurological function.

In vivo administration of a GnRH antagonist to male mice: effects on pituitary gonadotropin secretion in vitro

1989 ◽  
Vol 120 (3) ◽  
pp. 308-314
Author(s):  
A. M. Ultee-van Gessel ◽  
G.J. van Steenbrugge ◽  
F. G. Leemborg ◽  
F. H. Schroeder ◽  
F. H. de Jong
Keyword(s):  
Gnrh Antagonist ◽  
Term Treatment ◽  
Plasma Testosterone ◽  
High Dose ◽  
Male Mice ◽  
Short Term Treatment ◽  
Gonadotropin Secretion ◽  
Long Term Treatment

Abstract. The potent luteinizing hormone-releasing hormone antagonist [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]GnRH (4 mg/kg) was administered sc once or daily for 21 days to immune-deficient (nude) and normal immune-competent (NIC) male mice derived from the same genetic background. Effects of in vivo pretreatment with the antagonist on gonadotropin secretion from hemipituitary glands from both types of mice were studied in vitro in the presence or absence of synthetic GnRH. Treatment with the GnRH antagonist caused differential effects on release of FSH and LH from and amounts of FSH and LH in hemipituitary glands. Pituitary FSH secretion was effectively inhibited, whereas effects on pituitary LH were less evident or nonsignificant under these experimental conditions. Long-term treatment with the antagonist caused larger effects on pituitary secretion and content of FSH, when compared with short-term treatment. No significant effects of duration of treatment on secretion or pituitary content of LH were detected. Addition of synthetic GnRH to the incubation medium caused stimulation of gonadotropin release. Therefore, it was concluded that the high doses of this GnRH antagonist were not able to block GnRH receptors effectively in the pituitary glands of nude and NIC male mice. The incomplete suppression of LH secretion by this high dose of the GnRH antagonist may partly explain the inability of the antagonist to suppress plasma testosterone levels and the growth of androgen-dependent tumours in male mice.

scholarly journals Autologous Red Blood Cell Delivery of Betamethasone Phosphate Sodium for Long Anti-Inflammation

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 286 ◽  
Author(s):  
Xiumei Zhang ◽  
Mingfeng Qiu ◽  
Pengcheng Guo ◽  
Yumei Lian ◽  
Enge Xu ◽  
...  
Keyword(s):  
Side Effects ◽  
Osmotic Fragility ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Anti Inflammatory ◽  
Loading Amount ◽  
Long Acting ◽  
Inflammatory Effect

Although glucocorticoids are highly effective in treating various types of inflammation such as skin disease, rheumatic disease, and allergic disease, their application have been seriously limited for their high incidence of side effects, particularly in long term treatment. To improve efficacy and reduce side effects, we encapsulated betamethasone phosphate (BSP) into biocompatible red blood cells (RBCs) and explored its long acting-effect. BSP was loaded into rat autologous erythrocytes by hypotonic preswelling method, and the loading amount was about 2.5 mg/mL cells. In vitro, BSP loaded RBCs (BSP-RBCs) presented similar morphology, osmotic fragility to native RBCs (NRBCs). After the loading process, the loaded cells can maintain around 70% of Na+/K+-ATPase activity of natural cells. In vivo, a series of tests including survival, pharmacokinetics, and anti-inflammatory effect were carried out to examine the long-acting effect of BSP-RBCs. The results shown that the loaded cells could circulate in plasma for over nine days, the release of BSP can last for over seven days and the anti-inflammatory effect can still be observed on day 5 after injection. Totally, BSP-loaded autologous erythrocytes seem to be a promising sustained releasing delivery system with long anti-inflammatory effect.

A Proposal that Herpesviruses are Co-Factors of HIV Disease

1995 ◽  
Vol 6 (6_suppl) ◽  
pp. 17-21 ◽  
Author(s):  
P. D. Griffiths
Keyword(s):  
Human Herpesvirus ◽  
High Dose ◽  
Hiv Disease ◽  
Double Blind ◽  
Herpesvirus Type ◽  
Hiv Coinfection ◽  
Human Herpesvirus Type ◽  
Simplex Virus

There is now extensive evidence that herpesviruses can interact with human immunodeficiency virus (HIV) in vitro. To determine if such interactions could be operative in vivo, evidence from AIDS autopsy series are reviewed. Using basic histopathological techniques, cytomegalovirus (CMV) and HIV coinfection of various individual ceils has been demonstrated. Using cell culture, CMV has been detected in 66% and herpes simplex virus in 11% of patients. Using immunocytochemistry, human herpesvirus type 6 (HHV-6) has been found in virtually all tissue sections. The hypothesis that these viruses contribute to the death of individuals with AIDS is supported by the results of two double-blind, placebo-controlled randomized trials of high-dose aciclovir and an observational study of the same drug. All three studies have shown improved survival. Thus, the case is made that herpesviruses act as co-factors of HIV disease, and that inhibition of such infections represents a potential way of reducing mortality in those with AIDS. This paper was presented as the case for in a debate on ‘Herpesviruses as co-factors of HIV disease’. The case against was made by Don Jeffries (see page 22)

scholarly journals A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes

2016 ◽  
Vol 120 (9) ◽  
pp. 1011-1017 ◽  
Author(s):  
A. J. Simpson ◽  
J. R. Bood ◽  
S. D. Anderson ◽  
L. M. Romer ◽  
B. Dahlén ◽  
...  
Keyword(s):  
Mast Cell ◽  
Single Dose ◽  
Cell Activation ◽  
Standard Dose ◽  
Forced Expiratory Volume ◽  
Mast Cell Activation ◽  
Double Blind ◽  
Dry Air ◽  
Prostaglandin F

Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11β-prostaglandin F2α (11β-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12–20)% (median and interquartile range) following placebo was attenuated to 7 (5–9)% with the administration of terbutaline ( P < 0.001). EVH caused a significant increase in 11β-PGF2α from 41 (27–57) ng/mmol creatinine at baseline to 58 (43–72) ng/mmol creatinine at its peak post-EVH following placebo ( P = 0.002). The rise in 11β-PGF2α was inhibited with administration of terbutaline: 39 (28–44) ng/mmol creatinine at baseline vs. 40 (33–58) ng/mmol creatinine at its peak post-EVH ( P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

Acute pre-exercise supplementation of combined carnosine and anserine enhances initial maximal power of Wingate tests in humans

2021 ◽  
Author(s):  
Laura Blancquaert ◽  
Inge Everaert ◽  
Audrey Baguet ◽  
Tine Bex ◽  
Silvia Barbaresi ◽  
...  
Keyword(s):  
Human Plasma ◽  
Biochemical Properties ◽  
Wingate Test ◽  
High Dose ◽  
In Vitro Experiments ◽  
Double Blind ◽  
Highly Active ◽  
Novel Strategy

Classic in vitro experiments (Severin's phenomenon) demonstrated that acute carnosine supplementation may potentiate muscle contractility. However, upon oral ingestion, carnosine is readily degraded in human plasma by the highly active serum carnosinase-1 (CN1). We developed a novel strategy to circumvent CN1 by pre-exercise ingestion of combined carnosine (CARN) and anserine (ANS), the methylated analog with similar biochemical properties but more resistant to CN1. First, in vitro hydrolysis was tested by adding carnosine and anserine to human plasma, alone or in combination. Secondly, 5 subjects were supplemented with 25mg/kg anserine or 25mg/kg of each anserine and carnosine to test in vivo bioavailability. Thirdly, two double-blind, placebo-controlled, crossover studies investigated the effect of pre-exercise ANS+CARN (20mg/kg BW of each) supplementation on performance during a single all-out Wingate test following 6-minute high-intensity cycling (study A) or 3 repeated Wingate tests (study B). In vitro experiments demonstrated slower degradation of anserine vs carnosine, which was further slowed by simultaneously adding carnosine. In vivo bioavailability of plasma anserine was more prominent (2.5-fold increased AUC) when ANS+CARN vs ANS was ingested. Study A showed significantly higher (+6±11%; p=0.04) power in the first 5s of the Wingate test following ANS+CARN (12.8±2.4W/kg) vs placebo (12.1±2.2W/kg). Study B demonstrated increased peak power (+3%) throughout 3 consecutive Wingate tests (ANS+CARN 10.5±0.6W/kg vs placebo 10.2±9.9W/kg). These experiments reveal a novel acute nutritional method to effectively raise plasma anserine and carnosine by high-dose combined supplementation. This approach led to improved initial cycling power, revealing a new nutritional strategy to increase exercise performance.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

THYROID STIMULATORS AND THYROID STIMULATION

1971 ◽  
Vol 66 (3) ◽  
pp. 558-576 ◽  
Author(s):  
Gerald Burke
Keyword(s):  
Regulatory System ◽  
Control Site ◽  
Thyroid Cell ◽  
Primary Control ◽  
Physico Chemical ◽  
Site Of Action ◽  
Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

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