Prodrug Of Terbutaline Research Articles

Preparative HPLC separation of bambuterol enantiomers and stereoselective inhibition of human cholinesterases

We separated and characterized the enantiomers of bambuterol (5-[-(tert-butylamino)-1-hydroxyethyl]-m-phenylene-bis(dimethylcarbamate) hydrochloride), which is used in racemic form as a prodrug of terbutaline, a beta(2)-adrenoceptor agonist. The enantioseparation was attempted on several chiral HPLC columns, and the most effective separation was achieved on the amylose-based Chiralpak AD column. Since in vivo conversion of bambuterol into terbutaline involves hydrolysis by butyrylcholinesterase (EC 3.1.1.8), we studied the reaction of enantiomers with eight human BChE variants. Both enantiomers inhibited all studied BChE variants; however, the rate of inhibition with the (R)-enantiomer was about five times faster than with the (S)-enantiomer. (R)-bambuterol inhibition rate constants for homozygous usual (UU), fluoride-resistant (FF) or atypical (AA) variant ranged from 6.4 to 0.11 min(-1)microM(-1). The inhibition rates for heterozygotes were between the respective constants for the corresponding homozygotes.

Comparison of Oral Bambuterol and Terbutaline in Elderly Patients with Chronic Reversible Airflow Obstruction

Bambuterol, a carbamate prodrug of terbutaline, is the first once-daily oral β2-agonist. The effect/side effect ratio of bambuterol oral solution was compared with terbutaline mixture in elderly patients with chronic reversible obstructive airways disease. The study was of a double-blind, crossover, randomized design and consisted of a 4-7-day run-in period followed by four consecutive treatment periods each of 2 weeks. The treatments were bambuterol solution 20 mg nocte (B20), 10 mg nocte (B10), terbutaline mixture 3 mg t.i.d., (T), and placebo solution (P). Patients measured daily peak expiratory flow rate (PEFR), asthma symptoms, use of inhaled β2-agonist, and tremor. Of 84 patients, 66 completed all periods. Mean age was 67 years (60-90), basal FEV11.49 L, and reversibility of FEV1 30%. Ninety-four percent of the patients used inhaled/oral steroids in constant dosage. All treatments were significantly more effective than placebo. B20 resulted in higher morning PEFR than T (306 × 2.9 L/min vs. 297 × 2.9 L/min), while B10 gave equivalent results to T. No differences were seen in the use of inhaled β-agonist. Less shortness of breath was experienced during the night with B20 and during the day with B10 compared with placebo. Both B20 and T produced more tremor than B10 and P. In elderly patients with chronic reversible airways obstruction once-daily bambuterol (10-20 mg) has a better effect/side effect ratio than 3 mg terbutaline thrice daily.

ABC of Asthma. Treatment of chronic asthma.

The first line of treatment of mild intermittent asthma is one of the selective s2-stimulants taken by inhalation. s-stimulants are the most effective bronchodilator in asthma. They start to work quickly—salbutamol and terbutaline take effect within 15 minutes and last for four to six hours. If more than one daily dose is usually required then additional treatment must be considered. The dose response varies among patients as does the dose that will produce side effects, such as tremor. Patients should be taught to monitor their inhaler use and to understand that if they need it more or its effects lessen, these are danger signals. They indicate deterioration in asthmatic control and the need for further treatment. s-stimulants Some patients worry that s-stimulants may become slightly less effective with time, particularly if the dose is high. There is little evidence of appreciable tachyphylaxis for the airway effects in asthmatics. If it exists it is a minor effect that is quickly reversed either by stopping the treatment temporarily or by taking corticosteroids. Tremor, palpitations, and muscle cramps may occur but are rarely troublesome if the drug is inhaled and these adverse effects outside the lung often become less of a problem with continued treatment. The regular use of s-stimulants has in some studies been associated with increased bronchial reactivity, worsening asthma control, and accelerated decline of lung function. When the steps in the guidelines are followed, however, s-stimulants are not used regularly unless needed for control of symptoms. Bronchodilator response to oral salbutamol 200 μg (solid line) and inhaled salmeterol 50 μg (broken line). Long acting preparations of oral s-agonists have been available for some years. They are effective in nocturnal asthma but are associated with more adverse effects than inhaled agents. The oral agent bambuterol, a prodrug of terbutaline, provides a …

Effects on Lipid and Glucose Metabolism of the Long-Acting β2-Adrenergic Drug Precursor Bambuterol in Patients with Non-Insulin-Dependent Diabetes Mellitus

Metabolic and adverse effects of the long-acting β2-adrenergic prodrug of terbutaline, bambuterol (20mg tablet once nightly), were examined in a randomised 2 × 6-week double-blind, placebo-controlled crossover study in 19 patients with non-insulin-dependent diabetes mellitus. Compliance was assessed by tablet counts and measurement of plasma terbutaline. Three patients withdrew because of adverse effects (2 on bambuterol, 1 on placebo). Of the 16 remaining patients, 14 were on either dietary regulation alone (n = 8) or dietary regulation plus oral antidiabetic agents (n = 6), and 2 had discontinued oral antidiabetic drugs 1 week before study entry. Compliance was excellent (94 to 100%). Triglyceride levels fell more after bambuterol [0.48 (3 weeks) and 0.50 mmol/L (6 weeks)] than after placebo [0.17 (3 weeks) and 0.28 mmol/L (6 weeks)], the reduction being significant only at 3 weeks. HDL cholesterol increased from 1.06 mmol/L (baseline) to 1.18 (placebo) and 1.26 mmol/L (bambuterol). After 6 weeks, LDL cholesterol increased from 4.04 mmol/L (baseline), by 0.07 mmol/L after 6 weeks of placebo, but decreased by 0.14 mmol/L after 6 weeks of bambuterol (both cases statistically significant). There were minor increases in blood glucose of 0.6 and 0.5 mmol/L after 3 and 6 weeks of bambuterol, respectively, as compared with placebo. Neither treatment had any effect on glucose disposal in response to intravenous insulin, implying that insulin sensitivity was unchanged. Reported and recorded adverse reactions were all well-known β2-agonist effects.

Determination of bambuterol, a prodrug of terbutaline, in plasma and urine by gas chromatography/mass spectrometry

(R,S)-Bambuterol was isolated from plasma and urine by solid-phase extraction and analysed as its trimethylsilyl derivative by gas chromatography/chemical ionization mass spectrometry with ammonia as the reagent gas. Deuterium-labelled bambuterol was used as internal standard. An esterase inhibitor was added to plasma to prevent hydrolysis of bambuterol in the plasma sample. Bambuterol could be measured in plasma down to 1 nmol l-1 with a within-day variation of less than 5% (coefficient of variation). The lower limit of measurement in urine was judged to be 8 nmol l-1, a concentration at which the within-day variation was 5.4% (coefficient of variation).

Effects of ibuterol, a beta-2 adrenergic prodrug, on intraocular pressure.

Ibuterol, a prodrug of terbutaline, was approximately 100 times more potent than terbutaline in producing ocular hypotension in the treated eye of normal and sympathectomized (SX) rabbits. In normal rabbits, ibuterol produced no change in IOP of the contralateral eye whereas in unilaterally SX rabbits a rise in IOP occurred in the SX (contralateral) eye when the normal eye was treated with ibuterol. Ibuterol also suppressed ocular hypertension induced by water loading and delayed the IOP recovery rate although its onset of action was delayed. Aqueous flow was increased significantly at 1 hr after ibuterol in fluorophotometric studies in normal rabbits. Pretreatment with forskolin antagonized rather than enhanced ibuterol-induced ocular hypotension. Pretreatment with diclofenac failed to suppress the development of tachyphylaxis to the ocular hypotensive effect of ibuterol. Although ibuterol is an effective ocular hypotensive agent in rabbits, the effects of this agent on aqueous flow are complex and tachyphylaxis to the ocular hypotensive effect develops fairly rapidly.