Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma.

The pharmacokinetic and pharmacodynamic effects of inhaled corticosteroids (ICS) have shaped the efficacy and safety of these agents in the treatment of asthma. Important pharmacokinetic and pharmacodynamic characteristics that can enhance the efficacy of ICS include small particle size, high glucocorticoid-receptor-binding affinity, long pulmonary residence time and lipid conjugation. These characteristics can increase or prolong the anti-inflammatory effects of an ICS. Important pharmacokinetic characteristics that can enhance the safety of ICS include on-site activation in the lung, low oropharyngeal exposure, negligible oral bioavailability, high protein-binding and rapid systemic clearance. The degree of oropharyngeal exposure is relevant to local side-effects, such as oropharyngeal candidiasis, dysphonia and coughing. Pharmacokinetic properties that influence the degree of systemic exposure are relevant to the pharmacodynamic effect of ICS-induced hypothalamic-pituitary-adrenal axis suppression and cortisol suppression, an indicator of potential long-term systemic side-effects, such as reduced growth velocity and bone density, fractures, and skin bruising and thinning. Therefore, significant differences in the pharmacokinetic and pharmacodynamic characteristics of the currently available inhaled corticosteroids warrant careful consideration when used in clinical practice as they may result in differences in efficacy and local and systemic safety profiles.     

抗真菌药物的药物代谢动力学/药效学及其合理应用

抗真菌药物的临床应用越来越广泛，加之多数药物特异性不强，在作用于真菌细胞的同时也易对人体细胞产生毒性作用；此外，临床治疗真菌感染的药物有限，且用药剂量较大、疗程长、不良反应较多及毒性较大，影响了临床应用。近年来新靶向剂型、新作用靶位的药物相继上市，但真正安全有效的为数尚少。掌握各类抗真菌药物的代谢动力学和药效学（PK／PD）特点及不良反应，对于临床合理选择和应用至关重要。     

从药代学和药效学的观点看什么是理想的吸入性激素

吸入性激素（ICS）是支气管哮喘（简称哮喘）长期治疗的一线药物。糖皮质激素（简称激素）是目前最有效的哮喘抗炎药物，但因为全身性不良反应使其长期应用受限。但ICS治疗哮喘的疗效仍不甚理想，全球哮喘防治创议（GINA）中推荐ICS单独使用仅适用于轻度持续哮喘。研究ICS的药代学和药效学规律对认识ICS治疗哮喘的有效性和安全性，指导临床用药和开发新型ICS极为重要。     

Sex-related differences in pharmacokinetics and pharmacodynamics of anti-hypertensive drugs

Sex-specific differences in pharmacokinetics and pharmacodynamics have been reported to have important clinical consequences. In this review, some representative sex-specific differences in absorption and transporters (that is, P-glycoprotein (P-gp)), metabolic processes (that is, those that involve cytochrome P450 (CYP)), clearance (Cl) processes (for example, renal excretion or other pharmacokinetic parameters) and involvement of sex hormones (that is, estrogen and testosterone) in the regulation of some metabolic enzymes are introduced for each of the following categories of anti-hypertensive drugs: calcium-channel blockers, angiotensin-receptor blockers and angiotensin-converting enzyme inhibitors, diuretic agents, and β-adrenergic-receptor blockers (β-blockers). In many cases, female sex is a risk factor for adverse effects or attenuated clinical responses because of lower Cl, smaller distribution volumes, higher activity of some metabolic enzymes (especially hepatic CYP3A4), or presence of sex hormones. Additionally, some of these factors often co-contribute to the sex-specific differences. Furthermore, pharmacodynamic variability among individuals is often larger than pharmacokinetic variability; in other words, it could become a predominant determinant of interindividual differences in therapeutic responses. Thus, studies of sex-specific differences in pharmacokinetics and pharmacodynamics should be conducted. However, sex-related disparities in pharmacokinetics may not necessarily correspond to clinically significant differences in therapeutic response. There are still large gaps in our knowledge of sex-specific differences in clinical pharmacology and much more research is needed.     

Fracture risk in patients with chronic lung diseases treated with bronchodilator drugs and inhaled and oral corticosteroids

BACKGROUND: Chronic lung diseases and drugs used to treat patients with chronic lung diseases may be associated with an increased fracture risk. METHODS: The design was a case-control study of all patients with a fracture (n=124,655) in the year 2000 in Denmark as case subjects. For each case subject, three age- and gender-matched control subjects were randomly drawn from the general population (n=373,962). RESULTS: Chronic lung diseases such as COPD (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.13 to 1.25), emphysema (OR, 1.31; 95% CI, 1.16 to 1.48), and other chronic lung diseases (OR, 1.20; 95% CI, 1.00 to 1.44) were associated with a higher relative risk of any fracture than asthma (OR, 1.06; 95% CI, 1.01 to 1.12). Oral corticosteroids were associated with a dose-dependent increased risk of fractures. Inhaled short-acting beta-agonists were associated with an increase in fracture risk that was not dose dependent and was seen already at low doses. Oral beta-agonists were associated with an increase in fracture risk at low doses but not at higher doses. Other bronchodilators (inhaled long-acting beta-agonists, inhaled beta-agonists plus inhaled corticosteroids, inhaled beta-agonists plus antimuscarinic substances, inhaled antimuscarinic substances, inhaled cromoglycate and cromoglycate-like substances, oral theophylline, and oral leukotriene receptor antagonists), and inhaled corticosteroids were not associated with fracture risk. CONCLUSIONS: The increase in fracture risk seen with inhaled short-acting beta-agonists may be linked to the severity of the underlying lung disease rather than with the beta-agonists, per se, as other types of beta-agonists were not associated with fractures.     

吸入性糖皮质激素预防肺癌的研究进展

肺癌是严重危害人类健康的疾病,且预后差,约2/3的患者确诊时已失去手术机会。糖皮质激素具有强大的抗炎作用,可显著改善 COPD 患者的临床症状,加快病情好转,缩短住院时间,减少急性发作次数,改善生活质量。长期规律应用吸入性糖皮质激素有很好的通过抑制气道炎症从而达到预防肺癌的前景。     

The importance of pharmacokinetics and pharmacodynamics in the clinical evaluation of antiarrhythmic drugs

Many pharmacokinetic and pharmacodynamic factors affect clinical evaluation of antiarrhythmic agents. The route of administration and the duration of treatment are variables that influence the study outcome. Due to metabolic differences and pharmacodynamic factors, different results may be obtained depending on whether drugs are administered orally or intravenously. Moreover the achievement of steady state blood level does not insure the achievement of adequate myocardial drug level nor does it indicate that a steady state effect has been achieved. There may be significant delay in the accumulation of antiarrhythmic drugs in the myocardium. Only when the metabolic profile and pharmacodynamic characteristics of a drug are understood can the most efficient testing protocol be designed for a particular antiarrhythmic agent.     

Safety of inhaled corticosteroids

Systemic bioavailability from the gastrointestinal tract is reduced with newer inhaled corticosteroids (ICSs) such as fluticasone, but systemic absorption still occurs via the lung. Observational studies have shown an association between ICS use and several adverse outcomes such as cataracts, glaucoma, and adrenal failure, and prospective controlled studies have confirmed a causal relationship between ICS use and bruising, reduction in bone mineral density, and reduced growth velocity. The evidence suggests that the effect of ICSs on bone mineral density is small in the short term but that patients taking moderate or high doses for long periods will be at increased risk of fractures and that this could be an appreciable public health problem. There is also evidence to suggest that the risk of long-term adverse effects is likely to differ between ICSs. The clinical message that follows is that ICSs should be used widely because they reduce the need for courses of oral corticosteroids and improve quality of life, but that they need to be managed carefully to reduce the risk of adverse effects with long-term use.     

Possibilities of formoterol to enhance the peripheral lung deposition of the inhaled liposome corticosteroids

The pulmonary distribution and clearance of 99m-Tc-labelled beclomethasone dipropionate (Bec)--dilauroylphosphatidylcholine (DLPC) were compared in nine asthmatic patients on inhaled steroids after a 1-week medical treatment period of long-acting beta2-agonist formoterol. The patients were given formoterol 12 microg (OxisTurbuhaler) twice daily in addition to their own regular inhaled corticosteroid therapy. Gamma lung scintigraphy and lung function tests were performed before and after formoterol treatment.The bronchodilating effect ofthe combined therapy was significant: 1-week usage of inhaled formoterol enhanced peripheral lung deposition of beclomethasone liposome and thus diminished central/peripheral deposition ratio (C/P ratio). All measured lung function values except FEV1/FVC% improved after the medication period, although statistically significant levels were not reached. A systemic positive connection was seen between enhanced lung functions and greater lung deposition measured as AUC(0-24h)/24 Beclomethasone liposome formulation maintained its long-lasting effect in connection with formoterol treatment. At the 4-h measurement, 76% of the liposome-entrapped radioactivity still remained in the lungs before and 75% after the medication period.     

Possible molecular basis for the pharmacokinetics and pharmacodynamics of three membrane-active drugs: propranolol, nimodipine and amiodarone

The interactions of propranolol, nimodipine, and amiodarone with membrane lipids were examined in an effort to explain their different pharmacokinetic and pharmacodynamic properties. Propranolol and nimodipine, which bind with high affinity to plasmalemmal beta-adrenergic and calcium channel receptors, respectively, have membrane partition coefficients of approximately 1200 and 5000 and are readily washed out of membranes with which they had been equilibrated. X-ray and neutron diffraction studies showed that after partitioning into lipid membranes, both propranolol and nimodipine are located approximately 6 A from the phosphate headgroup region of the membrane bilayer, near the hydrocarbon core/water interface. Amiodarone, which blocks Na and K channels with less site specificity than propranolol and nimodipine, has a much higher partition coefficient of approximately 1,000,000, resists washout from membrane bilayers, and is located deeper in the membrane, approximately 12 A from the phosphate headgroup region of the bilayer, nearer to the terminal methyl groups of the fatty acyl chains. The shorter durations of clinical action of propranolol and nimodipine may be related to the reversibility of their interactions with the region of the bilayer exposed to the aqueous media near the hydrocarbon core/water interface, whereas the much longer duration of clinical action of amiodarone may reflect a location more deeply within the fatty acyl region of the bilayer where this hydrophobic drug interacts avidly with the hydrocarbon core of the membrane.     

Safety of inhaled corticosteroids: room for improvement

Inhaled corticosteroids (ICS) are the standard of care in asthma and are widely used in the treatment of patients with chronic obstructive pulmonary disease. High-dose regimens and long-term use of ICS in predisposed individuals may be associated with a variety of side effects, similar to those observed with systemic corticosteroid therapy. Side effects associated with long-term ICS use include reduction in growth velocity, cataracts, glaucoma, osteoporosis, and fractures. Fear of unwanted complications may be of concern in all patients using ICS, particularly in age- and gender-specific populations that are more prone to develop side effects or to reduce treatment adherence because of physical, behavioral, or psychological problems. In addition to concerns about ICS safety, dosing regimens that are difficult to follow may further reduce a patient's ability to comply with treatment. Ciclesonide, a new-generation ICS with unique pharmacokinetic properties, was developed to provide effective anti-inflammatory control for asthma with once-daily administration to improve patient adherence and a high safety profile to reduce the occurrence of local and systemic side effects.     

五种抗结核新药在小鼠体内的药代动力学/药效学初步研究

目的 在BALB/c小鼠结核病模型中,研究普托马尼(pretomanid,PA-824)、德拉马尼(delamanid,Dlm)、氯法齐明(clofazimine,Cfz)、贝达喹啉(bedaquiline,Bdq)、PBTZ-169共5种抗结核药物在不同给药剂量下的药代动力学/药效学(pharmacokinetic/pharmacodynamics,PK/PD)。方法 BALB/c小鼠经气溶胶感染结核分枝杆菌标准株H37Rv,5种药物分为高中低3个剂量组灌胃给药。在给药4周和8周时,解剖小鼠,取脾、肺脏进行菌落单位(colony forming unit,CFU)计数以评价药物疗效,同时在4倍测定最低抑菌浓度(minimum inhibitory concentration,MIC)的含药培养板上,挑取单菌落并测定MIC值。在各给药组给予最后一个剂量3h后,通过眼眶采血,用液相色谱-质谱法测定血浆药物浓度。结果 以各药物引起小鼠肺部CFU计数下降且与对照组差异有统计学意义为标准,得到最低有效剂量分别为PA-824 30mg/kg,Dlm 5mg/kg,Cfz 5mg/kg,Bdq 6.25mg/kg,PBTZ-169 20mg/kg。自最低有效剂量起,各药物均使得小鼠肺CFU计数下降,其中Bdq与PA-824高剂量组小鼠肺CFU计数分别下降2.99和2.66 log₁₀值。5种药物给药8周时,在最低有效剂量下的血药浓度(C_3h)分别为PA-824(7.60±1.28)μg/ml,Dlm(0.20±0.05)μg/ml,Cfz(0.26±0.02)μg/ml,Bdq(0.22±0.07)μg/ml,PBTZ-169(74.56±17.80)ng/ml。各药物高剂量时,C_max/MIC大于特定数值,即PA-824 100mg/kg时,C_max/MIC>147;Dlm 10mg/kg时,C_max/MIC>100;Cfz 20mg/kg时,C_max/MIC>2;Bdq 25mg/kg时,C_max/MIC>13.6;PBTZ-169 20mg/kg时,C_max/MIC>150,不易产生药物耐受性/表型抗性。结论 5种抗结核药物在有效剂量下,血药浓度随药物剂量增加而上升,CFU计数与给药剂量呈负相关,C_max/MIC是与疗效呈良好相关性的PK/PD参数,可为这些药物的临床使用提供指导。