Safety pharmacology of the respiratory system: Techniques and study design

The known effects of drugs from a variety of pharmacologic/therapeutic classes on the respiratory system and worldwide regulatory requirements support the need for conducting respiratory evaluations in safety pharmacology. The objective of these studies is to evaluate the potential for drugs to cause secondary pharmacologic or toxicologic effects that influence respiratory function. Changes in respiratory function can result either from alterations in the pumping apparatus that controls the pattern of pulmonary ventilation or from changes in the mechanical properties of the lung that determine the transpulmonary pressures (work) required for lung inflation and deflation. Defects in the pumping apparatus are classified as hypo- or hyperventilation syndromes and are evaluated by examining ventilatory parameters in a conscious animal model. The ventilatory parameters include respiratory rate, tidal volume, minute volume, peak (or mean) inspiratory flow, peak (or mean) expiratory flow, and fractional inspiratory time. Defects in mechanical properties of the lung are classified as obstructive or restrictive disorders and can be evaluated in animal models by performing flow-volume and pressure-volume maneuvers, respectively. The parameters used to detect airway obstruction include peak expiratory flow, forced expiratory flow at 25 and 75% of forced vital capacity, and a timed forced expiratory volume, while the parameters used to detect lung restriction include total lung capacity, inspiratory capacity, functional residual capacity, and compliance. Measurement of dynamic lung resistance and compliance, obtained continuously during tidal breathing, is an alternative method for evaluating obstructive and restrictive disorders, respectively, and is used when the response to drug treatment is expected to be immediate (within minutes post-dose). The species used in the safety pharmacology studies conducted in our laboratory are the same as those used in toxicology studies since pharmacokinetic and toxicologic/pathologic data are available in these species. These data can be used to help select test measurement intervals and doses and to aid in the interpretation of functional change. The techniques and procedures for measuring respiratory function parameters are well established in guinea pigs, rats, and dogs.     

Evaluation of the safety of a non-animal stabilized hyaluronic acid (NASHA – Q-Medical, Sweden) in European countries: a retrospective study from 1997 to 2001

BACKGROUND: In Europe, several filler devices are currently on the market for use in aesthetic dermatology and some of them cause severe, permanent, adverse reactions. Since 1996 a non-animal stabilized hyaluronic acid (NASHA) from Q-Medical, Sweden, has been introduced and is becoming a leading product in aesthetic dermatology. Hyaluronic acid has no species specificity and skin testing is not recommended before treatment. OBJECTIVE: Our purpose was to evaluate the incidence of adverse reactions from 1997 to 2001 and the safety of NASHA after injections into the skin for aesthetic reasons. METHOD: Surveys were sent to physicians in European countries that agreed to participate. This is a retrospective study. A total of 12 344 syringes were sold by the Q-Medical to these physicians and we evaluated the total number of patients treated to 35% of this number (4320). We separated immediate hypersensitivity reactions from delayed reactions and analysed infectious and other types of reactions. RESULTS: From 1997 until 2001, 34 cases of hypersensitivity were reported: 16 cases of immediate hypersensitivity and 18 cases of delayed. The global risk of sensitivity is 0.8%. Since 2000, the amount of protein in the raw product has decreased and the incidence of hypersensitivity reactions is around 0.6%. As 50% of these reactions are immediate and resolved within less than 3 weeks, the risk of strong but transient, delayed reaction is around 0.3%. Four cases of abscess were reported. They were all sterile. No bacterial infection was found. Herpetic recurrence is possible after lip augmentation according to the technique of injection. No systemic reactions were reported. CONCLUSION: NASHA is a very useful and safe filler product. Skin testing does not seem to be necessary.     

Heart rate response to breathing: dependency upon breathing pattern

Summary. Heart rate responses to stepwise and periodic changes in lung volume were studied in seven young healthy males. Stepwise inspiration and expiration both resulted in an increase in heart rate followed by a rapid decrease in heart rate. The fastest heart rate was reached in 1·6 ± 0·5 s and in 3·6 ± 1·4 s in response to inspiration and expiration, respectively (P < 0·01). The slowest heart rate was reached in 4·8± 1·0 s and in 7·6± 1·9 s in response to inspiration and expiration, respectively (P < 0·01). Following this biphasic change the heart rate returned to a steady level. The difference between the fastest and the slowest heart rates was significantly larger in response to inspiration (21·7 ± 7·3 beats per minute) than in response to expiration (12·0±7·3 beats per minute; P < 0·01). Periodic changes in lung volume were performed with frequencies from 3·0 to 12·0 respirations per minute (r.p.m.). The changes in heart rate showed a constant amplitude in the frequency range below 5·5 r.p.m. Maximal heart rate changes were found at frequencies of 5·5 to 7·0 r.p.m. Changes in heart rate decreased in a linear manner on a log-log scale in the frequency range above 7·0 r.p.m. The relation between frequency and changes in heart rate is explained by interference between the transient changes in heart rate induced both by inspiration and by expiration. It is concluded that if heart rate changes in response to periodic changes in lung volume are to be used as a measure of vagal function a number of factors have to be taken into consideration and to simplify the analysis of heart rate responses to breathing we recommend, instead, the use of the transient changes in heart rate induced by stepwise changes in lung volume.     

加替沙星序贯治疗下呼吸道细菌感染的药物经济学评价

目的对加替沙星序贯治疗下呼吸道细菌感染进行药物经济学评价。方法将69例下呼吸道细菌性感染患者，随机分为A组（34例）、B组（35例），其中A组采用加替沙星注射液400mg静脉滴注，每天1次，连用10天；B组先用加替沙星注射液400mg静脉滴注，每天1次，3—4天后改为口服400mg，每天1次，连用6—7天，然后对两种方案进行成本-效果分析。结果两组在临床疗效、不良反应发生率及细菌清除率方面差异无统计学意义（P〉0．05）；但A组的医疗费用却高于B组（P〈0．01）。结论加替沙星序贯疗法与单纯静脉滴注相比更安全，更经济合理。     

SARS死亡病例的实验室检查特点

目的：了解严重急性呼吸综合征(SARS)死亡病例的临床特点，为SARS重症病例的诊断、治疗及预后判断提供帮助。方法：对我院2003年1月至4月底收治的102例确诊非典患者中的5例死亡病例的流行病学及实验室检查资料进行回顾性分析。结果：死亡病例均为男性，平均49岁，从发病到入院平均7．6d，从住院到确诊平均1．2d；从住院到死亡平均14．4d，从发病到死亡平均为22d。死亡病例粒细胞总数和百分比均明显升高，多数患者淋巴细胞计数和百分比降低(4／5)，血红蛋白均呈进行性下降。死亡患者除已见报道的ALT、AST、LDH、CK升高及低钙血症外，GLU均明显高于正常而ALB均明显降低；大多数患者TP、PA等多项生化指标均出现明显下降而脱氧血红蛋白百分率(HHb)明显上升，同时伴有低磷、低镁血症。结论：SARS死亡病例多项实验室指标均会出现明显异常，动态监测这些指标有助于SARS患者的诊断、治疗及预后判断。     

Effects of buffering in hypercapnia and hypercapnic hypoxemia

Anesthetized, paralyzed and mechanically ventilated pigs were exposed to extreme hypercapnia (Paco_2-20 kPa) at Fio₂ 0.4 for 480 min, with (n = 6) or without (n = 6) continuous infusion of isotonic buffers (bicarbonate and trometamol). Arterial pH was higher in buffered animals than controls, 7.21 ±0.01 vs 7.01±0.01 (mean ± s.e.mean, P < 0.01). Serum osmolality and Paco₂ did not differ between groups throughout the experiment. The hemodynamic response to hypercapnia was attenuated in the buffered group, who had lower heart rate, 133 ± 6 vs 189±12 min^-1 (P < 0.01), mean arterial pressure (MAP) 109 ± 4 vs 124 ± 4 mmHg (14.5 ± 0.5 vs 16.5 ± 0.5 kPa) (P < 0.05), mean pulmonary arterial pressure 16±1 vs 23 ± 1 mmHg (2.1 ±0.1 vs 3.1 ±0.1 kPa) (P < 0.01), and pulmonary vascular resistance (PVR) 249 ± 21 vs 343 ± 20 dyn s-cm^-5 (2490±210 vs 3430±200 μN-s-cm^-5) (P < 0.01), compared with the control group. Subsequently, both groups were exposed to hypercapnic hypoxemia by stepwise increases in Fio₂ (0.15, 0.10, 0.05) at 30-min intervals, while Fico₂ was kept at 0.2. PVR increased in both groups (P < 0.05) but, except for heart rate, all hemodynamic differences between the groups disappeared during hypoxia. At Fio₂ 0.15, buffered animals had higher arterial oxygen saturation (73 ± 5%) than the controls (55 ± 5%), (P < 0.05). The control animals died after 1–29 min (mean 14 min) at Fio₂ 0.10, while all buffered animals survived Fio₂ 0.10 with stable MAP (122 ± 14 mmHg (16.3 ± 1.9 kPa). The buffered animals died after 4–22 min (mean 15 min) at Fio₂ 0.05. We conclude that buffering to a pH of 7.21 attenuates the observed hemodynamic response in extreme hypercapnia and improves survival in hypercapnic hypoxemia.     

Comparative effects of enoximone and theophylline on plasma catecholamines and haemodynamics in cardiosurgical patients

Summary The release of endogenous catecholamines in aorto-coronary bypass graft patients receiving either 0.5 mg/kg enoximone (n=10), 4.0 mg/kg theophylline (n=10) or saline solution (control,n=10) has been studied, as well as certain haemodynamic parameters. Adrenaline (A) and noradrenaline (NA) concentrations were not significantly changed by the administration of enoximone. Theophylline caused a small increase in NA (+ 40% in the 1st min) and a marked increase in A (approximately + 7000% in the 1st min), which still remained elevated at the end of the investigation period (+ 220% in the 30th min). The major haemodynamic effects of enoximone were a significant increase in cardiac index (CI; + 35%) and a decrease in pulmonary capillary wedge pressure (PCWP; −27%), pulmonary artery pressure (PAP; −21%), RVEDV and RVESV, while the heart rate (HR) remained almost unchanged. The dominant haemodynamic effects of theophylline were an increase in HR (+ 26%; arrhythmia in 3 patients), PAP (+ 22%), and RVEDV (+ 19%), while REVESV (+ 26%), MAP (−16%), CI (−14%), and RVEF (−15%) fell significantly. It is concluded that the haemodynamic actions of enoximone are not mediated by catecholamine release, whereas the adverse cardiovascular effects of theophylline might partly be explained by the significant increase in plasma adrenaline.     

Adverse events in phase one studies: a study in 430 healthy volunteers

Summary All the clinical, laboratory and electrocardiographic adverse events detected during 24 Phase I studies in the same unit over a 5 y period are reported here. 430 healthy male volunteers were involved, corresponding to 5488 days of follow-up.The overall incidence of adverse events was 13.5%, with a significant difference between active drug (15.3%) and placebo (7.4%) treatments. There were 69 distinct types of adverse events. Headache was the most frequent symptom (2%). There were severe adverse events in 20 cases (0.36%), with an incidence of 20/430 per subject (4.6%). There were no deaths or life-threatening events.Although the main objective of Phase I studies is to determine the maximum dose tolerated, cause-effect relationships with adverse events are hard to establish, because of the frequency of adverse events with placebo, and because of the limited number of subjects included such studies.