Long-term regularly inhaled salbutamol

Seventeen asthmatic patients were allocated at random to one of two treatment regimens: prophylactic (10 patients), in which salbutamol inhaler was used regularly in a dose of 200 micrograms 4-times daily; or symptomatic (7 patients), in which a placebo inhaler was used regularly as 2 actuations 4-times daily. In both regimens, an 'escape' salbutamol inhaler was given to be used for symptomatic relief if and when needed. The study lasted 12 months, after a run-in period of 1 month to accustom patients to the trial procedure. At the end of the year, 16 patients transferred to the alternative regimen for a further 3 months. Both groups were well matched except that the group starting with the prophylactic regimen had more severe airways obstruction than the symptomatic group. Patients were assessed by daily scores of their asthmatic symptoms, twice daily PEFR measurements and the amount of anti-asthmatic medication used. Acute reversibility tests were performed every month at the clinic visits. Patients treated prophylactically had less seasonal variation in PEFR and generally lower symptom scores despite a lower mean PEFR. There was no evidence to suggest tolerance was developing either by acute reversibility tests or by an escalating use of symptomatic salbutamol or other anti-asthma medication. The prophylactic use of salbutamol seemed to provide a more stable control of asthma, offering potential benefit to patients.     

Status of lipid peroxidation and plasma iron level in bronchial asthmatic patients

Low antioxidant levels and oxidative stress due to airway inflammation may be determinant of asthma severity. The study was conducted to find the extent of lipid peroxidation and change in the levels of plasma iron in asthmatic patients with severity of disease. Study included 155 asthmatic and 156 healthy volunteers of the age groups 18-45 of either sex. Asthmatic patients were grouped into mild, moderate and severe groups on the basis of Forced Expiratory Volume in first second percent (FEV1%). Level of plasma malondialdhyde (MDA) was used as index of lipid peroxidation. A significant increase (P<0.01) in plasma MDA and plasma iron levels was found in asthmatic subjects as compared to controls. There was maximum increase in plasma MDA and iron levels in moderate asthmatic group. A positive correlation between plasma MDA and iron (r = +0.3) has been found in asthmatic patients. An increased plasma iron levels in asthmatics may contribute to aggravate lipid peroxidation.     

The pharmacokinetics of levosalbutamol: what are the clinical implications?

Salbutamol (albuterol) is a beta2-adrenoceptor agonist used as a bronchodilator for the treatment of asthma and as a uterine relaxant for the suspension of premature labour. Salbutamol has been marketed as a racemic mixture, although beta2-agonist activity resides almost exclusively in the (R)-enantiomer. The enantioselective disposition of salbutamol and the possibility that (S)-salbutamol has adverse effects have led to the development of an enantiomerically pure (R)-salbutamol formulation known as levosalbutamol (levalbuterol). Salbutamol is metabolised almost exclusively by sulphotransferase (SULT) 1A3 to an inactive metabolite. (R)-Salbutamol is metabolised up to 12 times faster than (S)-salbutamol. This leads to relatively higher plasma concentrations of (S)- salbutamol following all routes of administration, but particularly following oral administration because of extensive metabolism by the intestine. Enantiomer concentrations are similar for the first hour following an inhaled dose, reflecting the fact that salbutamol in the lung probably undergoes little metabolism. Subsequently, (S)-salbutamol predominates due to absorption and metabolism of the swallowed portion of the inhaled dose. Following oral or inhaled administration of enantiomerically pure salbutamol, a small amount (6%) is converted to the other enantiomer, probably by acid-catalysed racemisation in the stomach. Tissue binding of salbutamol is not enantioselective and plasma protein binding is relatively low. Both enantiomers are actively excreted into the urine. Compared with healthy individuals, patients with asthma do not have substantially different pharmacokinetics of the salbutamol enantiomers, but they do appear to have less drug delivered to the lung following inhaled administration because of their narrowed airways. Levosalbutamol elicits an equal or slightly larger response than an equivalent dose of the racemic mixture. This is probably due to competitive inhibition between the enantiomers at beta-adrenoceptors. Pharmacokinetic-pharmacodynamic relationships for levosalbutamol show relatively large interindividual variations. Functionally significant genetic polymorphisms have been identified for beta2-adrenoceptors, SULT1A3 and organic action transporters, all of which affect the disposition or action of levosalbutamol. Animal, in vitro and some clinical studies have reported deleterious effects of (S)-salbutamol on smooth muscle contractility or lung function. However, well-designed clinical studies in patients with asthma have failed to find evidence of significant toxicity associated with (S)-salbutamol. The clinical consequences of relatively higher plasma concentrations of (S)-salbutamol following administration of racemate remain unclear, but in the absence of clear evidence of toxicity the clinical superiority of levosalbutamol over racemic salbutamol appears to be small.     

The effects of ketotifen on beta-adrenergic activity in asthmatics

Summary In order to examine a possible mechanism of action of ketotifen in asthma, a double-blind study was undertaken to determine whether ketotifen showed any effects on the beta-adrenergic system in asthmatic patients. The effects of ketotifen 1 mg b.i.d. for one month on the changes in spirometry, plasma potassium and serum glucose levels induced by sequential doses of inhaled, nebulized salbutamol was compared with placebo. In addition the degree of inhibition caused by local salbutamol on the wheal volume due to intradermal prostaglandin E and bradykinin, was compared following ketotifen and placebo.Nebulized salbutamol produced consistent improvements in spirometry and changes in potassium and glucose levels. Local salbutamol significantly decreased the wheal volume induced by intradermal prostaglandin E and bradykinin. However, none of these salbutamol-induced effects were altered following ketotifen or placebo. Ketotifen, in the doses used, has no demonstrable effect on the beta-adrenergic system in asthmatic patients.     

A dose response study comparing Duovent vs salbutamol

The dose response profiles of Duovent (fenoterol 0.1 mg/ipratropium 0.04 mg per puff) and salbutamol (0.1 mg per puff) were determined in a double-blind, controlled study. Twenty-one patients with asthma and nine patients with chronic bronchitis received 1, 2, 4, and 6 puffs of either Duovent or salbutamol on separate days. FEV1, pulse and tremor were recorded at baseline and up to 360 minutes after inhalation of test medication. Duovent and salbutamol produced an effective bronchodilator response at all dose levels, however, at 2, 4 and 6 puffs, the improvement with Duovent was significantly greater than with salbutamol alone in both asthmatic and chronic bronchitic patients. Two puffs of Duovent produced a significantly greater bronchodilation than all doses of salbutamol. There was no difference in the bronchodilator response between 1-6 puffs of salbutamol indicating maximal dose was achieved with one puff. There was an incremental improvement in FEV1 with 1, 2, and 4 puffs of Duovent but no difference between 4 and 6 puffs. There was no difference in pulse rate or tremor between salbutamol or Duovent at any dose level. We conclude that Duovent produces a greater and more prolonged bronchodilator response than salbutamol in both asthmatic and chronic bronchitic patients.     

Beta(2)-adrenergic receptor polymorphisms and response to salbutamol among Indian asthmatics*

INTRODUCTION: The beta(2)-adrenergic receptor (beta(2)AR or ADRbeta(2)) is the target for beta(2)-agonist drugs used for bronchodilation in asthma and other respiratory diseases. The aim of this study was to identify common single nucleotide polymorphisms (SNPs) and haplotypes in asthmatics and healthy individuals from an Indian population, and determine the influence of beta(2)AR SNPs in responsiveness to beta(2)-agonist therapy in asthma patients. METHODS: Ten variable SNP sites within a span of 2.193 kb were identified in the beta(2)AR gene by sequencing and genotyping 374 bronchial asthma patients and healthy individuals from an Indian population. Spirometry tests were performed on 80 unrelated patients before and after administration of 200 microg of salbutamol. A post-bronchodilator forced expiratory volume in one second (FEV(1)) change of >or= 15.3% was considered a good response, and a change of<15.3% was defined as a poor response, to salbutamol. RESULTS: The pattern of linkage disequilibrium between the ten SNPs showed a single, linked SNP block consisting of sites -468, -367, -47, -20, and 79 having strong linkage disequilibrium, while the SNPs at sites -1023, -654, 46, 252, and 523 showed very low linkage with one another and with the linked region. The SNPs were found to be organized into 16 haplotypes in the studied population. We found that patients with a homozygous Arg-16 form at nucleotide position 46 are poor responders with probability of 0.81, and patients with a homozygous Gly-16 form are good responders with a probability of 0.73. The responder status to salbutamol treatment and the genotype at nucleotide position 46 in beta(2)AR gene of an asthmatic patient are significantly associated in the studied Indian population (chi2=9.98, df=2, p=0.0068). Most importantly, this association for responsiveness to salbutamol at nucleotide position 46 is independent of other SNPs in the beta(2)AR gene. CONCLUSION: This study suggests that the SNP at nucleotide position 46 has particular relevance to pharmacogenetics in the Indian population studied.     

舒喘灵扩张试验对支气管哮喘及慢性喘息性支气管炎患者小气道功能的影响

用舒喘灵扩张试验判断支气管哮喘及慢性喘息性支气管炎(慢喘支)患者小气道功能的变化。用最大呼气平均流量(MEFV)曲线测定小气道功能。结果表明,舒喘灵对23例支气管哮喘患者FEF75％、FEF25％～75％、FEF75％～85％有明显的改善作用,而对16例慢喘支患者的各项指标无明显影响,表明支气管哮喘患者的小气道功能异常是可逆的,而慢喘支是不可逆的,同时也表明β_2-受体激动剂对支气管哮喘敏感,而对慢喘支不敏感。     

哮喘患者血浆白细胞介素-18水平测定及其临床意义的研究

目的探讨白细胞介素(IL)-18在支气管哮喘发病机制中的作用。方法收集30例哮喘患者和15名健康对照者的血浆,采用酶联免疫吸附试验(ELISA)检测血浆中IL-18、IL-12和IL-13的水平。结果哮喘组血浆IL-18、IL-13水平明显高于对照组,IL-12水平则显著低于对照组,差异有显著性(P<0.01)。哮喘组IL-18和IL-13呈显著正相关(P<0.05)。结论IL-18可能参与了哮喘的发病过程,它通过调节Th1/Th2的活性及细胞因子的产生,在哮喘的发病过程中发挥作用。     

Single dose and steady-state pharmacokinetics of 4 mg and 8 mg oral salbutamol controlled-release in patients with bronchial asthma

Summary Fifteen patients with asthma were given salbutamol controlled-release (SCR) 4 mg or 8 mg twice daily for seven days, in a randomised double-blind cross-over design. Plasma salbutamol levels were measured after the first and fifteenth doses for a 12 h period following drug ingestion.At steady-state the geometric mean values for C_max were 8.2 ng/ml for 4 mg, and 16.1 ng/ml for 8 mg. Median t_max values were 300 and 240 min respectively. The geometric mean AUC (0–12) were 4507 ng·min·ml^–1 and 8980 ng·min/ml. Peak to trough fluctuation ratios were 0.577 and 0.572.There were no significant differences between 4 mg or 8 mg formulations, for any of the parameters measured, after appropriate corrections for dose. The concentration-time profiles at steady-state showed little fluctuation in plasma salbutamol levels over the twelve hour dosing interval. These results show that 4 mg and 8 mg formulations of SCR provide smooth plasma profiles at steady-state with a twice daily dosing regime.Part of this paper has been presented in abstract form to the British Thoracic Society, Newcastle, July 1988     

沙丁胺醇联合丙酸倍氯米松治疗成人哮喘的疗效观察

目的观察沙丁胺醇联合丙酸倍氯米松治疗成年人哮喘的疗效。方法将我院呼吸内科收治的60例成人哮喘患者随机分为3组,每组各20例。其中两组患者分别给予沙丁胺醇和丙酸倍氯米松治疗,另外一组患者联合两种药物治疗。对3组患者的疗效进行观察。结果 3组患者在经过治疗后与治疗前性比较哮喘症状都有改善,但是单独使用沙丁胺醇和丙酸倍氯米松组的疗效较联合用药组要差。结论联合使用沙丁胺醇和丙酸倍氯米松治疗成人哮喘效果优于单独用药组,值得临床推广使用。     

Plasma leptin and adiposity during antipsychotic treatment of schizophrenia.

Alterations in plasma leptin have been reported in schizophrenia patients treated with antipsychotics, suggesting the hypothesis that impairments in leptin secretion or signaling might play a role in antipsychotic-induced weight gain. Plasma leptin was measured in 72 schizophrenia patients chronically treated with olanzapine (n=27), risperidone (n=24) or typical antipsychotics (n=21) and 124 healthy adult control subjects. ANCOVA was used to test effects of adiposity (body mass index kg/m2; BMI), subject group (treated patients vs untreated controls), and treatment group (specific medication groups and untreated controls) on plasma leptin concentrations. Additional analyses were performed in a subset of patients and controls individually matched for BMI to further assess group differences in plasma leptin independent of adiposity. BMI strongly predicted plasma leptin concentrations in the overall sample. In addition, a significant three-way interaction between BMI, subject group, and gender was observed. In the individually BMI-matched sample, modestly reduced plasma leptin levels (effect size 0.4 SD) were observed in treated patients in comparison to the BMI-matched healthy controls, with both groups including males and females. However, no differences in plasma leptin levels were observed in the matched sample when separately comparing male patients vs untreated male controls and female patients vs untreated female controls. Plasma leptin in chronically treated patients with schizophrenia is strongly predicted by adiposity, similar to untreated healthy individuals despite adequate power to detect a difference. The results argue against a role for defective leptin secretion or sensitivity in the weight gain induced by antipsychotic medications.     

Monitoring saliva concentrations of methaqualone, codeine, secobarbital, diphenhydramine and diazepam after single oral doses

A preliminary investigation was undertaken to determine the feasibility of monitoring saliva levels of drugs for forensic purposes. Single oral doses of the title compounds were administered to healthy volunteers. Plasma and saliva levels were measured and ratios calculated for all drugs except diazepam. Saliva/plasma ratios for methaqualone, diphenhydramine and secobarbital were all less than one and reasonably consistent between collection times and subjects. The saliva/plasma ratios for codeine were more variable, but always greater than one. Although more detailed investigation is necessary, saliva may be a useful medium for forensic monitoring of drug ingestion.     

Levalbuterol hydrochloride

Racemic salbutamol (racemic albuterol) ameliorates symptoms of asthma by activating beta-adrenoceptors on nerve, smooth muscle and inflammatory cells within the airways. Racemic salbutamol comprises equal proportions of 2 isomers: (S)-salbutamol and (R)-salbutamol, with the latter being exclusively responsible for activation of beta-adrenoceptors. Accordingly, within racemic salbutamol it is (R)-salbutamol that efficiently relieves obstruction of asthmatic airways and affords highly effective protection from bronchoconstrictor stimuli, including allergens. During regular use of racemic salbutamol, there is a progressive decline of protective efficacy and a corresponding intensification of airway responsiveness. This decline is largely absent during regular use of (R)-salbutamol. Consequently, bronchodilator responses to sub-maximal doses of (R)-salbutamol exceed responses to the equivalent dose of (R)-salbutamol given as the racemate. For example, in asthmatics with baseline FEVs 相似文献   

茶色素治疗支气管哮喘的疗效

目的探讨茶色素对哮喘患者氧化/抗氧化系统的影响及其对哮喘的治疗作用。方法选择80例哮喘患者随机分为A、B组,各40例,并与正常对照组比较。A组应用茶色素治疗及按需吸入沙丁胺醇气雾剂,B组仅按需吸入沙丁胺醇气雾剂,3周后观察治疗前后哮喘患者外周血超氧化物歧化酶(SOD)、脂质过氧化物终产物丙二醛(MDA)、CAMP/CGMP含量及症状、体征、肺功能指标的变化。结果哮喘患者血清SOD水平及CAMP/CGMP明显低于正常人,而MDA水平明显高于正常人(均P<0.01)。A组比B组治疗后患者SOD水平增高(P<0.05),而MDA水平降低(P<0.05),症状、体征评分下降(P<0.05),FEV1、PEF升高(P<0.05)。结论支气管哮喘患者存在氧化/抗氧化失衡,茶色素能明显改善氧化/抗氧化失衡,改善临床症状。     

维生素D联合沙丁胺醇治疗小儿支气管哮喘的疗效研究

目的 研究维生素D联合沙丁胺醇治疗小儿支气管哮喘的效果。方法 选择2014年1月-2016年12月郑州大学附属儿童医院的79例小儿支气管哮喘患儿,随机分为两组。对照组（n=40）采用压缩雾化吸入沙丁胺醇治疗,观察组（n=39）在对照组基础上联合口服维生素D。治疗90 d,比较两组的治疗有效率、喘憋症状消失时间、咳嗽缓解时间、肺部哮鸣音消失时间和肺部湿啰音消失时间。结果 观察组患儿的有效率明显高于对照组,差异有统计学意义（P<0.05）。治疗后两组的血清25-羟维生素D3水平均明显升高,嗜酸细胞阳离子蛋白（ECP）及血清特异性IgE水平均明显降低,同组治疗前后比较差异均有统计学意义（P<0.05）;且观察组更为明显,组间比较差异有统计学意义（P<0.05）。观察组的喘憋症状消失时间、咳嗽缓解时间、肺部哮鸣音消失时间和肺部湿啰音消失时间均明显短于对照组,差异有统计学意义（P<0.05）。结论 维生素D联合沙丁胺醇对小儿支气管哮喘具有较为满意的治疗效果,可以有效改善患儿的临床症状,其作用机制可能与提高血清25-羟维生素D3水平,降低ECP和Ig E水平有关。     

血浆纤维蛋白原和鳞状细胞癌抗原在宫颈癌中的临床价值

目的 探讨血浆纤维蛋白原(FIB)和鳞状细胞癌抗原(SCCA)在宫颈癌中的变化及对于诊断的临床价值.方法 选取经病理证实的宫颈癌患者62例(宫颈癌组),检测术前空腹血浆FIB和SCCA水平,同期选择宫颈良性病变患者50例(宫颈良性病变组)及健康体检者50例(健康对照组),观察各组血浆FIB和SCCA水平,并进行比较.同时,宫颈癌患者手术一周后再次检测血浆FIB和SCCA水平的变化.结果 宫颈癌患者血浆FIB和SCCA水平分别为(4.40±1.29)g·L-1和(6.62±-1,显著高于宫颈良性病变组及健康对照组,差异有统计学意义(F=53.772、132.072,P<0.05);血浆FIB和SCCA水平与宫颈癌恶性程度相关,分期Ⅲ~Ⅳ期患者血浆D二聚体水平明显高于l~Ⅱ期患者(P<0.01);在手术1周后宫颈癌患者血浆FIB和SCCA水平较术前显著降低.结论 宫颈癌患者手术前后其体内血浆FIB和SCCA水平变化显著,并且血浆FIB和SCCA水平变化趋势与宫颈癌的恶性程度呈正相关,因此血浆FIB和SCCA可以作为宫颈癌患者诊断、疾病监测及预后的指标.     

The dispositional enantioselectivity of indobufen in man.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen (2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a novel platelet aggregation inhibitor, have been studied in male healthy volunteers given either the racemic compound or the S-enantiomer (200 mg racemate, 100 mg S-enantiomer). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. After administration of the racemate, the pharmacokinetic behaviour of the R- and S-enantiomers differed, the plasma levels of the S form declining more rapidly [half-lives = 6.2 hr (S), 8.7 hr (R)]. No substantial differences were observed in terms of plasma level profile of S-indobufen when administered alone and in the racemic mixture. A statistically significant difference between the two enantiomers after administration of the racemate was found in the area under the curve (AUC), peak plasma levels (Cmax) and elimination half-life (t1/2 beta) whereas no statistically significant difference was detected in the time of peak (tmax). When the pharmacokinetic parameters Cmax, AUC, t1/2 beta and tmax of S-indobufen administered alone or as racemate were compared, there were no statistically significant differences between treatments as well as between periods and sequences. The urinary excretion of total S-indobufen (free + glucuronide) and of total R-indobufen after administration of the racemate was essentially the same. No difference was observed either in the urinary excretion of total S-indobufen after administration of the racemate or of the S-enantiomer.     

哮喘儿童血浆神经肽Y与心率变异性相关性分析

目的 探讨哮喘儿童血浆神经肽Y（NPY）含量与其心率变异性（HRV）的关系。方法 随机选择哮喘儿童35例与健康儿童40例测定其空腹血浆NPY浓度，同时做24h动态心电图并进行HRV时域分析。结果 HRV中反映迷走神经张力指标的高频（HF）、rMSSD和pNN50在哮喘儿童组数值明显高于正常对照组（P〈0．01），而反映交感神经张力的主要指标低频（LF）、SDNN和SDANN则明显低于对照组。哮喘儿童血浆NPY明显升高（P〈0．01），NPY与rMSSD（r=0．76）、pNN50（r=0．71）呈正相关。结论 哮喘儿童血浆NPY与其HRV密切相关。     

唯尔本注射液对哮喘病人T淋巴细胞亚群的影响

对40例接受唯尔本注射液治疗的哮喘病人治疗前后的T淋巴细胞亚群进行了检测,并设对照组20例进行了比较。结果证实唯尔本注射液可以提高哮喘患者外周血T抑制细胞的数目,提示唯尔本是一种可以提高细胞免疫功能的防治哮喘药物。     

Evaluation of the effect on heart rate variability of a beta2-adrenoceptor agonist and antagonist using non-linear scatterplot and sequence methods

AIMS: To examine the impact on heart rate variability (HRV), of agonism or antagonism at the cardiac beta2-adrenoceptor in healthy volunteers, using standard time-domain summary statistics and non-linear methods (scatterplot and quadrant analysis). METHODS: Under double-blind and randomised conditions (Latin square design), 17 normal volunteers received placebo, salbutamol (beta2-adrenoceptor partial agonist), ICI 118,551 (specific beta2-adrenoceptor antagonist), or salbutamol plus ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22.30 h, with HRV assessed from the sleeping heart rates. RESULTS: Salbutamol reduced the long-term (SDNN: 135 ms [120, 156], SDANN: 107 ms [89, 124]) time-domain indicators of HRV compared with placebo (SDNN: 39 [24, 55], SDANN 42 [29, 56], [mean difference [95% confidence intervals of difference]]). Alone, ICI 118,551 did not effect HRV, but in combination blocked the actions of salbutamol. Scatterplot length (944 ms [869, 1019]) and area (222*10(3) ms2 [191, 253]) were reduced by salbutamol compared with placebo; (length difference (164 [98, 230]) and area difference 59 [36, 83]). Scatterplot width (dispersion) was lower at both low (width RR-1 25% salbutamol 277 ms [261, 293]: salbutamol minus placebo 14 ms [0, 28]) and high (width 75% salbutamol 417 [391, 443]: salbutamol minus placebo 41 [20, 62]) heart rates. ICI 118,551 alone did not alter scatterplot parameters but in combination blocked the effect of salbutamol. Cardiac acceleration episodes (i.e. consecutive deltaRR and deltaRRn+1 shorten) were increased following salbutamol 7288 [6089, 8486] compared with placebo -1890 [-2600, -1179]; the beat-to beat difference (deltaRRn+1) was reduced after salbutamol compared with the other treatments. ICI 118,551 did not effect acceleration episodes but reduced the effect of salbutamol when used in combination. CONCLUSIONS: Agonism at the cardiac beta2-adrenoceptor in healthy volunteers with salbutamol altered autonomic balance towards sympathetic dominance; this re-balancing was blocked by ICI 118,551 given in combination with salbutamol. However antagonism at the beta2-adrenoceptor with ICI 118,551 alone did not significantly alter the HRV. The beta2-adrenoceptor modulates HRV in healthy volunteers; the implications of agonism and antagonism at the beta2-adrenoceptor in cardiovascular disease states warrants further investigation.