A clinical trial of oral clenbuterol (NAB 365) in chronic airways obstruction

Brusasco, Vito; Crimi, Emanuele; Mangini, S. G.; Vibelli, C

doi:10.1185/03007998009109466

Cited by 6 publications

(2 citation statements)

References 9 publications

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“…This working hypothesis is elaborated in the discussion section. Images were taken from Servier Medical Art (smart.servier.com) microgram range, which are generally assumed safe for treatment of asthma [20][21][22]. Demonstration of effectiveness of clenbuterol at much lower doses than was previously studied is important, since reducing the dose of the drug may diminish potential side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Clenbuterol has an unfavourable reputation for its misuse in high doses by bodybuilders and fitness enthusiasts because of its hypertrophic effects in muscles and lipolytic effects in adipose tissues. However, clenbuterol in lower doses is generally assumed to be safe [20][21][22] and is used in humans for asthma treatment in a number of countries. The current study was performed on a well-established model of type 2 diabetes, DIO mice, which are characterised by obesity, glucose intolerance, insulin resistance and hepatic steatosis.…”

Section: How Might This Impact On Clinical Practice In the Foreseeablmentioning

confidence: 99%

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Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

et al. 2020

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Aims/hypothesis Chronic stimulation of β 2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of β 2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β 2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg −1 day −1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and Anastasia Kalinovich and Nodi Dehvari contributed equally to this study.

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Section: Discussionmentioning

confidence: 99%

Section: How Might This Impact On Clinical Practice In the Foreseeablmentioning

confidence: 99%

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

et al. 2020

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Bronchodilating activity of oral clenbuterol in asthmatic children after single administration of different dosages

Boner

Bennati

Castellani

et al. 1987

Pediatric Pulmonology

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The dose-response activity of clenbuterol, a new long-acting beta 2-agonist, was evaluated in 12 children aged 5 to 11 years with moderate to severe asthma. The study was a double-blind cross-over comparison of three oral dose levels: 0.5, 1.0, and 1.5 micrograms/kg and placebo all in the form of syrup. Pulmonary function, heart rate, blood pressure, and tremor were evaluated at 30, 60, 90, and 120 min, then hourly for 8 hr, following the ingestion of the drug. The bronchodilating effect of clenbuterol, evaluated as percentage changes in expiratory flow rates was significantly different from placebo. The overall fall-off in the effect of 1.0 micrograms/kg and 1.5 micrograms/kg doses after 8 hr was small. The results of the 1.0 micrograms/kg dose often overlapped those of the 1.5 micrograms/kg dose, suggesting that a single 1.0 micrograms/kg dose of clenbuterol is most advisable in children, assuring the most favorable risk/benefit ratio. Even the highest dose of clenbuterol caused only a marginal increase in tremor, not statistically different from that induced by placebo.

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Analysis of the beta1 and beta2 adrenoceptor interactions of the partial agonist, clenbuterol (NAB365), in the rat jugular vein and atria

Cohen

Wiley

Bemis

1982

Naunyn-Schmiedeberg's Arch. Pharmacol.

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The potent bronchodilator, clenbuterol, was compared to other beta adrenoceptor agonists with regard to affinity and efficacy for interaction with beta 1, and beta 2 adrenoceptors in the rat jugular vein and atria. Clenbuterol was a potent partial beta adrenoceptor agonist in both tissues based on the following observations: 1. Maximal relaxation of the jugular vein and increases in atrial rate to clenbuterol were less than maximal responses to other beta adrenoceptor agonists. 2. Clenbuterol antagonized responses to the stronger agonist, isoproterenol, in both tissues and 3. the equilibrium dissociation constant for clenbuterol approximated the ED50 concentration for vascular relaxation and increases in atrial rate, a characteristic of some, but not all, partial agonists. Relative to other beta adrenoceptor agonists, clenbuterol showed high affinity toward both beta 1 and beta 2 adrenoceptors and selectively toward beta 2 adrenoceptors. Equilibrium dissociation constants were 38 and 6.3 nM for beta 1 and beta 2 adrenoceptors, respectively. The high affinity of clenbuterol toward beta 1 and beta 2 adrenoceptors was coupled to a low relative efficacy of clenbuterol to activate either beta 1 or beta 2 adrenoceptors. Most beta 2 adrenoceptor agonists such as isoproterenol or salbutamol require approximately 1-3% adrenoceptor occupation for 40-50% relaxation of the jugular vein whereas clenbuterol required approximately 100% adrenoceptor occupation for a similar response. Thus, based on our analysis, the high agonist potency of clenbuterol results primarily from the high affinity toward beta adrenoceptors rather than efficient activation of the adrenoceptor as occurs with isoproterenol or salbutamol.

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A clinical trial of oral clenbuterol (NAB 365) in chronic airways obstruction

Cited by 6 publications

References 9 publications

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

Bronchodilating activity of oral clenbuterol in asthmatic children after single administration of different dosages

Analysis of the beta1 and beta2 adrenoceptor interactions of the partial agonist, clenbuterol (NAB365), in the rat jugular vein and atria

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