Absorption of moisture by sodium cromoglycate and mixtures of sodium cromoglycate and lactose

The presence of up to about 15% w/w moisture has little effect on the tensile and shear properties of sodium cromoglycate and of 1:1 mixtures of sodium cromoglycate and lactose. Analysis of their adsorption and desorption isotherms using equations developed by Young and Nelson shows that this is because most of the moisture is absorbed into the interior of the sodium cromoglycate leaving little adsorbed moisture on the surfaces of the particles concerned.     

The nasal absorption of sodium cromoglycate in the albino rat

The intranasal absorption of sodium cromoglycate has been investigated in the adult male COBS/Wistar rat. Sodium cromoglycate (1 mg kg-1) was instilled into the nasal cavities and for comparison animals were also similarly dosed intravenously or sub-lingually. Serial samples of blood or bile were collected. After intravenous administration, the area under the plasma concentration curve (AUC0-infinity) was 32 micrograms min ml-1 corresponding to a plasma clearance of 13 ml min-1 and an elimination rate constant of 0.049 min-1. Plasma concentrations of radioactivity after intranasal administration rose to a mean peak of 0.3 micrograms ml-1 approximately 20 min after dosing and fell to 0.03 micrograms min ml-1 at 3 h. The AUC0-3 was 19 micrograms min ml-1 corresponding to an absorption of 60% over 3 h. The absorption rate constant (ka) was 0.059 min-1. The total amount of sodium cromoglycate excreted in bile after intravenous administration was 56%. The amount of compound excreted in the bile was 30% after intranasal administration corresponding to an absorption of 53%. Plasma and bile data therefore show good agreement. Total excretion in the bile over 3 h after sub-lingual administration was 3%, demonstrating that this route made no significant contribution to the intranasal results. The absorption of sodium cromoglycate is independent of variations in the technique including changes in the orientation of the rat or blocking of the nasopalatine. The techniques used minimized other competing nasal clearance processes such as mucociliary clearance.     

The prolonged retention of sodium cromoglycate in the rabbit eye

The retention of sodium cromoglycate in the rabbit eye over a 6 h period following its administration in two different vehicles is reported. When formulated as a dispersion in a hypo-allergenic acetylated lanolin/paraffins base, prolonged retention was observed. Thus, the concentration of sodium cromoglycate in the tears, conjunctiva and cornea 6 h after administration equalled or exceeded the concentration obtained with an aqueous solution 1 h post-instillation.     

Comparison of a lactose-free formulation of sodium cromoglycate and sodium cromoglycate plus lactose in the treatment of asthma

A double-blind, parallel group, 7-centre trial was carried out to compare the clinical efficacy and patient acceptability of two formulations of sodium cromoglycate for inhalation in patients suffering from asthma. Each single-dose capsule for use in a breath-actuated inhaler contained either a blend of sodium cromoglycate (20 mg) plus lactose (20 mg) or a lactose-free pelletized formulation of sodium cromoglycate (20 mg). Data were summarized from 529 asthmatic patients who had been using the blend formulation for at least 3 months previously. Two hundred and sixty-five patients then received pelletized sodium cromoglycate and 264 patients remained on sodium cromoglycate plus lactose for at least 3 months. Regular assessments were made by patients and clinicians during the trial period of treatment effectiveness. No clinically significant differences were observed between the two formulations after 3 months on test treatment. After a treatment period of 6 months, the pelletized formulation was shown to have some advantages over the blend formulation which were not observed at 3 months, with a significantly higher proportion of 'very effective' assessments being recorded by both patients and clinicians. The capsules of pelletized sodium cromoglycate required significantly less inhalations to empty compared to the capsules of the blend. No differences were observed between the two formulations with regard to the incidence of transient cough and throat irritation after inhalation.     

Comparison of a lactose-free formulation of sodium cromoglycate and sodium cromoglycate plus lactose in the treatment of asthma

Summary

A double-blind, parallel group, 7-centre trial was carried out to compare the clinical efficacy and patient acceptability of two formulations of sodium cromoglycate for inhalation in patients suffering from asthma. Each single-dose capsule for use in a breath-actuated inhaler contained either a blend of sodium cromoglycate (20?mg) plus lactose (20?mg) or a lactose-free pelletized formulation of sodium cromoglycate (20?mg). Data were summarized from 529 asthmatic patients who had been using the blend formulation for at least 3 months previously. Two hundred and sixty-five patients then received pelletized sodium cromoglycate and 264 patients remained on sodium cromoglycate plus lactose for at least 3 months. Regular assessments were made by patients and clinicians during the trial period of treatment effectiveness. No clinically significant differences were observed between the two formulations after 3 months on test treatment. After a treatment period of 6 months, the pelletized formulation was shown to have some advantages over the blend formulation which were not observed at 3 months, with a significantly higher proportion of ‘very effective’ assessments being recorded by both patients and clinicians. The capsules of pelletized sodium cromoglycate required significantly less inhalations to empty compared to the capsules of the blend. No differences were observed between the two formulations with regard to the incidence of transient cough and throat irritation after inhalation.     

Color reactions for identification of sodium cromoglycate

Chromone-2-carboxylic acid (3) reacts with aminopyrazolone (2) in methanolic hydrochloric acid to yield the orange-red polymethine dye 4. Treating dimethyl cromoglicate (6) with compound 2 and perchloric acid leads to the tetraperchlorate 7 of the red azamerocyanine 8. The phenol 9, obtained from alkaline hydrolysis of sodium cromoglicate (1a), couples with diazotized sulfanilic acid to form the red azo dye 10. The chromone 6 condenses with 1,3-dimethylbarbituric acid (DMBA) in acetic anhydride/acetic acid to the red oxonole 12. Cromoglicinic acid (1b) reacts under these conditions to yield the yellow polymethine dye 14, whose structure is elucidated by X-ray analysis.     

Bradykinin-induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate.

1. The effects of inhaled nedocromil sodium and sodium cromoglycate on bradykinin-induced bronchoconstriction have been studied in a double-blind, placebo controlled study, in eight mild asthmatic subjects. 2. The subjects attended on four occasions. Fifteen minutes after drug pre-treatment a bradykinin challenge was performed. Increasing concentrations were inhaled until a greater than 40% fall in expiratory flow at 30% of vital capacity from a partial flow volume manoeuvre (V p30) was demonstrated. 3. Inhaled bradykinin (0.06-8.0 mg ml-1) caused dose-related bronchoconstriction with the geometric mean cumulative dose causing a 40% fall in V p30 (PD40) of 0.035 (95% CI: 0.02-0.07) mumol, after placebo inhalation, which was similar to that measured before the trial (0.04: 0.02-0.09 mumol). 4. Both nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) gave significant protection (P less than 0.05) against bradykinin-induced bronchoconstriction (PD40 0.37: 0.19-0.72 mumol after nedocromil sodium and 0.22: 0.11-0.49 after sodium cromoglycate). 5. Since bradykinin-induced bronchoconstriction is probably neurally mediated we conclude that both nedocromil sodium and sodium cromoglycate have an action on neural pathways which may be useful in the control of asthma symptoms.     

The effect of nedocromil sodium and sodium cromoglycate on antigen-induced bronchoconstriction in the Ascaris-sensitive monkey.

Nedocromil sodium inhibited the bronchoconstriction caused by antigen challenge in Ascaris-sensitive monkeys and in addition it prevented the release of histamine from mast cells lavaged from sensitive monkeys. Sodium cromoglycate was relatively inactive in both these systems. It is suggested that nedocromil sodium can stabilize both mucosal and connective tissue mast cells and may represent a new type of drug.     

Inhaled sodium metabisulphite induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate.

1. The effects of nedocromil sodium and sodium cromoglycate on bronchoconstriction induced by inhaled sodium metabisulphite have been studied in eight atopic subjects, three of whom had mild asthma. 2. Nedocromil sodium (4 mg, 7.8 X 10(-6) M), sodium cromoglycate (10 mg, 24.1 X 10(-6) M) and matched placebo were administered by identical metered dose inhalers 30 min before a dose-response to sodium metabisulphite (5-100 mg ml-1) was performed. 3. Maximum fall in sGaw after placebo pre-treatment was -43.9 +/- 3.3% baseline (mean +/- s.e. mean). At the same metabisulphite concentration maximum fall in sGaw after sodium cromoglycate was -13.0 +/- 3.6% and after nedocromil sodium was +4.3 +/- 6.8%. Nedocromil sodium prevented any significant fall in sGaw even after higher concentrations of metabisulphite. 4. Both nedocromil sodium, 4 mg, and sodium cromoglycate, 10 mg, inhibited sodium metabisulphite induced bronchoconstriction but nedocromil sodium was significantly more effective. Relative in vivo potency of the two drugs is broadly in line with other in vivo and in vitro studies.     

双氯灭痛在正常人体内的药物动力学研究

采用反相高效液相色谱法测定了１０例健康人单剂量口服７５ｍｇ双氯灭痛片剂后血浆药浓度，研究了该药物在中国人体内药物动力学。经用ＰＫＢＰ－Ｎ＿１程序包在计算机上拟合计算表明，双氯灭痛口服给药多数人表现为二房室模型。其主要药动学参数分别为：Ｔ＿（α１／２）＝０．４０±０．１１ｈ，Ｔ＿（β１／２）＝１．７７±０．５ｈ，Ｔ＿（ｍａｘ）＝１．７８±０．３２ｈ，Ｃ＿（ｍａｘ）＝１．８７±０．９μｇ／ｍｌ，ＡＵＣ＝３．８１±１．７μｇ／（ｍｌ·ｈ）。结果表明，中国人体内的药动学参数与所报道的外国人体内相似。     

The pharmacokinetics of sodium cromoglycate in man after intravenous and inhalation administration.

The pharmacokinetics of sodium cromoglycate in four healthy volunteers after slow intravenous infusion have been evaluated following measurement of plasma concentrations by radioimmunoassay. The results confirm earlier findings that sodium cromoglycate is rapidly eliminated from the body and that the data can be fitted to a two compartment open model. The pharmacokinetic parameters derived from the intravenous administration were used to evaluate the pharmacokinetics after inhalation administration via the Spinhaler. A model for absorption from the lungs is described which involves absorption at two different rates; this gives a better fit to the observed data than a single absorption rate. A fast absorption rate constant with a mean value of 0.54 min-1 and a slower rate constant with a mean value of 0.0097 min-1 were found. Of a mean total of 2.84 mg absorbed from a 20 mg inhaled dose, 0.68 +/- 0.15 (s.e. mean) mg were absorbed at the fast rate and 2.17 +/- 0.37 mg at the slower rate. These rates probably reflect absorption from different sites within the lungs. The results may have important implications for interpretation of clinical findings.     

The action of sodium cromoglycate on ''C'' fibre endings in the dog lung

Khat leaves, widely used as a stimulant in East Africa and the Arab Peninsula, contain the alkaloid, (-)-cathinone. The effects of this substance on the locomotor activity of rats were compared to those of (+)-amphetamine. Both substances were found to induce a similar degree of hypermotility. Furthermore, the effect of (-)-cathinone on the locomotor behaviour of hypophysectomized rats was analogous to that reported for (+)-amphetamine in such animals. The results support the claim that the symptoms caused by the chewing of khat are amphetamine-like.     

The effect of nedocromil sodium, sodium cromoglycate and codeine phosphate on citric acid-induced cough in dogs.

1. The effects of nedocromil sodium, sodium cromoglycate and codeine phosphate on citric acid-induced cough have been studied in conscious tracheostomised dogs. 2. Nedocromil sodium (approximately 15 mg given as an aerosol) and codeine phosphate (5 mg kg-1, i.v.) significantly increased the time to the first cough when dogs were challenged with citric acid aerosol. The mean number of coughs in the initial period of coughing fell after treatment of dogs with nedocromil sodium or with codeine phosphate, but this reduction in mean cough number was not statistically significant. 3. Neither sodium cromoglycate (approximately 15 mg given as an aerosol) nor saline had significant effect on a citric acid challenge. 4. It is concluded that nedocromil sodium, but not sodium cromoglycate, possesses an anti-tussive action that may result from inhibition of sensory nerve activity in the lung. Nedocromil sodium may prove useful in the treatment of unproductive cough in situations where the use of a centrally-acting antitussive is undesirable.