Characterization of tumor imaging with microbubble-based ultrasound contrast agent, sonazoid, in rabbit liver

In order to investigate improvement of hepatic tumor detectability by Sonazoid with phase inversion imaging, the contrast effects on the liver of metastatic carcinoma-model rabbits were evaluated by videodensitometry and visual assessment. Correlation between the contrast enhancement of Sonazoid and histopathology was examined using the same animals. Electron microscopy was performed on hepatic tissue from another healthy rabbits to identify the distribution of Sonazoid microbubbles. As a result, all tumors were smaller than 12 mm in diameter, and after intravenous injection of Sonazoid, they were surrounded with a ring of enhanced signal during the early phase (up to 30 s), followed by a clear contrast defect during the delayed phase (after 10 min). Histopathologic observation revealed that the ring-enhancement was caused by neovasculature in the tumor, and the contrast defects corresponded to living and dead parts of tumors, which lack Kupffer cells. Videodensitometric differences between tumor and healthy tissue markedly increased at delayed phase, and visual detectability of tumors was improved when Sonazoid was used. Ultrastructural analysis showed microbubble-like structures in Kupffer cells, which indicated that Sonazoid microbubbles were taken up with these cells. In conclusion, Sonazoid, used with phase inversion imaging, greatly increases the detectability of small hepatic tumors by highlighting neovascularity at early phase and providing clear contrast defects due to absence of Kupffer cells, which take up Sonazoid microbubbles, at delayed phase.     

A respiration-metabolism chamber system and a GC-MS method developed for studying exhalation of perfluorobutane in rats after intravenous injection of the ultrasound contrast agent Sonazoid

Sonazoid is a new contrast agent for ultrasound imaging comprising an aqueous suspension of lipid-stabilised perfluorobutane (PFB) gas microbubbles. A respiration-metabolism chamber system was developed to collect exhaled air following intravenous administration of Sonazoid to rats. Analysis of PFB in the exhaled rat air was performed using a modified version of an earlier published method for blood samples, i.e. an automatic headspace gas chromatographic mass spectrometric (GC-MS) method using electron impact ionisation. The calibration standards were PFB diluted in air (2.5-1800 pg/ml). Perfluoropentane (PFP) was used as an internal standard and the MS detector was set to single ion monitoring of the base fragment ions of PFB (m/z 69 and 119) and PFP (m/z 69). The calibration curve, made by plotting the peak area ratios of PFB (m/z 69) to PFP (m/z 69) against the theoretical concentration of PFB, was fitted to a linear equation with weighting 1/y2 and found to be reproducible. The lower limit of quantification (LLOQ) was 2.5 pg PFB/ml. The between-day variation of the method was below 2.6% relative standard deviation (R.S.D.) and the within-day variation of the method was below 6.4% R.S.D. The accuracy of the method was evaluated and showed a relative error less than 5.2%. PFB was found to be stable for 14 days when stored in Tedlar sample bags at room temperature. An even lower detection limit may be obtained by using the more time-consuming process of solid-phase micro extraction; thus, by concentrating PFB on carboxen-PDMS fibres an LLOQ of 0.5 pg PFB/ml was obtained. When five rats were given an i.v. bolus injection of Sonazoid at a dose of 8 microl microbubbles/kg a mean recovery of 96% (range, 81-110%) was found during 24 h; more than 50% was exhaled during the first 30 min after injection.     

肝脏MRI特异性对比剂Gd-EOB-DTPA在肝脏肿瘤诊断及鉴别诊断中的价值

目的研究肝脏MRI特异性对比剂Gd-EOB-DTPA在肝脏肿瘤诊断及鉴别诊断中的价值。方法回顾性分析2011年1月～2018年10月我院收治的肝脏肿瘤患者80例,且均经手术治疗或穿刺及病理检查并已明确诊断。比较使用特异性对比剂Gd-EOB-DTPA行MRI检查结果与病理结果的符合率及Kappa值。分析Gd-EOB-DTPA MRI及增强CT对肝肿瘤病灶的检出率。结果原发性肿瘤符合率为95.7%,Kappa值 0.8,具有高度一致性;继发性肿瘤符合率为96.4%,Kappa值 0.8,具有高度一致性;肝脏局灶性结节增生符合率80.0%,Kappa值 0.8,具有高度一致性。Gd-EOB-DTPA MRI对于1cm肝肿瘤病灶的检出率相比增强CT明显提高(P 0.05)。结论临床上对肝脏肿瘤患者行MRI检查时,采用特异性对比剂Gd-EOB-DTPA,具有较高的准确性,可为临床诊断及鉴别提供重要依据,值得在临床推广。     

实时灰阶超声造影结合超声造影剂 SonoVue在肝脏局灶性小病灶鉴别诊断中的应用

目的 探讨实时灰阶超声造影(CEUS)结合超声造影剂SonoVue(简称:CEUS新技术)对肝脏局灶性小病灶病变的诊断价值。方法 对行CEUS新技术检查的112例(143枚病灶)患者的临床资料进行回顾性分析,以病理结果为金标准,比较CEUS新技术诊断结果与病理结果的符合率。结果 CEUS新技术检出肝脏局灶性小病灶恶性肿瘤患者41例,与病理结果符合率为80.4%(41/51);检出肝脏局灶性小病灶良性肿瘤患者48例,与病理结果符合率为78.7%(48/61)。CEUS新技术检出肝脏局灶性小病灶恶性病灶67枚,与病理结果符合率为90.5%(67/74);检出肝脏局灶性小病灶良性病灶58枚,与病理结果符合率为84.1%(58/69)。CEUS新技术诊断肝脏局灶性小病灶恶性肿瘤患者的敏感性、特异性分别为75.9 %、82.8%。CEUS新技术诊断肝脏局灶性小病灶恶性病灶的敏感性、特异性分别为85.9%、89.2%。结论 CEUS结合第二代新型超声造影剂SonoVue能提高肝脏局灶性小病灶病变的检出率,对鉴别肝脏局灶性小病灶良恶性肿瘤亦有积极作用。     

Gd(ABE-DTTA), a novel contrast agent, at the MRI-effective dose shows absence of deleterious physiological effects in dogs

The physiological effects of a novel MRI contrast agent, Gd(ABE-DTTA), were investigated in dogs, monitoring parameters in blood samples. Each animal (n = 8 in the short-term, n = 4 in the long-term group) underwent isoflurane anesthesia followed by the generation of myocardial infarction and received a contrast agent at the MRI effective dose. Blood samples were collected 24 and 48 h, and 7, 14, 28, 35, 49 and 56 days after contrast agent administration. No significant changes exceeding the normal range were detected in any of the investigated parameters except in alanine aminotransferase (ALT). ALT enzyme activity increased in the short-term group 24 and 48 h after agent administration as expected from the effect of isoflurane anesthesia. Between days 7 and 56 no elevation in ALT was observed. In dogs no substantial short- or long-term effect was observed on the investigated, physiological parameters after Gd(ABE-DTTA) administration at the MRI effective dose.     

In vitro stability analyses as a model for metabolism of ferromagnetic particles (Clariscan), a contrast agent for magnetic resonance imaging

Clariscan is a new contrast agent for magnetic resonance imaging. It is an aqueous suspension of ferromagnetic particles injected for blood pool and liver imaging. Previous experiments showed that particles made of 59Fe were taken up by the mononuclear phagocytic system and then solubilised. The present work aims at explaining a possible mechanism for the dissolution of these ferromagnetic particles in the body. The particles were diluted in 10-mM citrate or 10-mM acetate buffers at pH 4.5, 5.0 and 5.5 and incubated at 37 degrees C for up to 22 days, protected from light. The mixtures were analysed at different times during this incubation period using photon correlation spectroscopy, magnetic relaxation, visible spectroscopy and reactivity of the iron with the chelator, bathophenanthroline disulphonic acid. The data obtained with these techniques showed that the particles were almost completely solubilised within 4-7 days when incubated in 10 mM citrate, pH 4.5. Incubation in 10 mM citrate buffer, pH 5.0 revealed a slower solubilisation of the particles, as the changes observed after 72 h of incubation at pH 5.0 were 43-71% of the changes observed at pH 4.5. Incubation in 10 mM citrate, pH 5.5 revealed an even slower solubilisation of the particles, as the changes observed after 72 h of incubation at pH 5.5 were 12-34% of those observed at pH 4.5. Incubation of the particles in 10 mM acetate at pH 4.5, 5.0 and 5.5, as well as incubation of the particles in water pH adjusted to pH 5.1, resulted in only minor or no solubilisation of the particles. The results indicate that the low pH of endosomes and lysosomes, as well as endogenous iron-complexing substances, may be important for the solubilisation of these ferromagnetic particles following i.v. injection of Clariscan.     

Hemodynamic and electrophysiological effects of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin in a halothane-anesthetized canine model

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. We investigated the QT-prolonging effects of mitemcinal using a halothane-anesthetized canine model. Intravenous administration of mitemcinal at doses of more than 8.3 mg/kg per 10 min significantly prolonged the QT interval corrected by Fridericia's corrections. Mitemcinal exhibited a bradycardiac effect and produced significantly greater prolongation in monophasic action potential duration (MAP(90)) at sinus rhythm compared with MAP(90) at pacing and showed reverse use-dependent prolongation of repolarization, suggesting that the negative chronotropic effect of mitemcinal potentiates the prolongation of the repolarization period. A technique using MAP/pacing electrodes allowed measurements of both MAP(90) and effective refractory period (ERP) simultaneously at the same ventricular site. Although mitemcinal slightly prolonged the MAP(90(CL400)) and ERP in comparison with the control group at the dose of 25 mg/kg per 10 min, the terminal repolarization period, the difference between MAP(90(CL400)) and ERP, did not increase suggesting the absence of a proarrhythmic effect even with a 7000-fold for the therapeutic blood concentration as free level. The electrophysiological results from mitemcinal in this study indicate that the risk of serious arrhythmia such as torsades de pointes, a major clinical concern related to QT interval prolongation, might be low.     

Vascular effects in dogs of pinacidil (P 1134), a novel vasoactive antihypertensive agent

In pentobarbital sodium-anaesthetized dogs, pinacidil was infused for approximately 5 min into the carotid, coronary, femoral or renal artery at a rate of 10 micrograms/kg per min. The infusion, which did not affect systemic blood pressure, rapidly and markedly increased blood flow to any of the regions studied. When given i.v., 0.2 mg/kg pinacidil caused a moderate reduction in mean arterial blood pressure (15-20 mmHg) associated with an increase in coronary and renal blood flow while femoral and carotid blood flow remained unchanged; 0.5 mg/kg led to a marked (40-60 mmHg) reduction in blood pressure associated with an increase in coronary blood flow whereas renal, carotid and femoral blood flow stabilized at control levels. Indomethacin (2.5 mg/kg i.v.) failed to reverse the hypotension induced by pinacidil. The results are in accord with the concept that the vascular effect of pinacidil is due to direct smooth muscle relaxation which does not depend on prostaglandin synthesis.     

RGD靶向超声造影剂对大鼠2期压力性损伤创面的靶向性研究

目的 检测大鼠2期压力性损伤模型中整合素αvβ3的表达情况,制备精氨酸-甘氨酸-天冬氨酸（RGD）靶 向超声造影剂,观察其对大鼠2期压力性损伤模型的靶向性。方法 将36只大鼠随机分为实验组、对照组,每组18 只。实验组采用皮肤桥法建立2期压力性损伤模型,对照组不做处理。成模后HE染色观察2组大鼠皮肤组织病理 变化,免疫组化染色检测整合素αvβ3的表达情况。然后实验组大鼠分别使用自制的RGD靶向超声造影剂和空白造 影剂评估对创面的靶向效果。结果 实验组皮肤HE染色显示损伤达真皮层,对照组未见损伤。实验组新生的毛细 血管内皮细胞和表皮细胞内整合素αvβ3表达呈阳性,对照组呈阴性。实验组大鼠注射RGD靶向超声造影剂后与空 白造影剂相比靶向黏附值明显增高（P＜0.01）。结论 整合素αvβ3在大鼠2期压力性损伤中呈阳性表达,将其作为 靶向位点制备RGD靶向超声造影剂对2期压力性损伤具有良好的靶向性。     

Murine pharmacokinetics of 6-aminonicotinamide (NSC 21206), a novel biochemical modulating agent.

The pyridine nucleotide 6-aminonicotinamide (6AN) was shown recently to sensitize a number of human tumor cell lines to cisplatin in vitro. The present studies were undertaken to compare the drug concentrations and length of exposure required for this sensitization in vitro with the drug exposure that could be achieved in mice in vivo. Human K562 leukemia cells and A549 lung cancer cells were incubated with 6AN for various lengths of time, exposed to cisplatin for 1-2 hr, and assayed for Pt-DNA adducts as well as the ability to form colonies. K562 cells displayed progressive increases in Pt-DNA adducts and cisplatin sensitivity during the first 10 hr of 6AN exposure. An 18-hr 6AN exposure was likewise more effective than a 6-hr 6AN exposure in sensitizing A549 cells to cisplatin. HPLC analysis of 6AN and its metabolite, 6-amino-NAD+, permitted assessment of exposures achieved in vivo after i.v. administration of 10 mg/kg of 6AN to CD2F1 mice. 6AN reached peak serum concentrations of 80-90 microM and was cleared rapidly, with T1/2alpha and T1/2beta values of 7.4 and 31.3 min, respectively. Bioavailability was 80-100% with identical plasma pharmacokinetics after i.p. administration. At least 25% of the 6AN was excreted unchanged in the urine. The metabolite 6-amino-NAD+ was detected in perchloric acid extracts of brain, liver, kidney, and spleen, but not in serum. Efforts to prolong systemic 6AN exposure by administering multiple i.p. doses or using osmotic pumps resulted in lethal toxicity. These results demonstrated that 6AN exposures required to sensitize tumor cells to cisplatin in vitro are difficult to achieve in vivo.     

Characteristics of vasoinhibitory action of FK 453 (a pyrazolo-pyridine derivative), a new antihypertensive agent with diuretic action in isolated rabbit aorta.

The vasoinhibitory effect of FK 453 was examined in isolated rabbit aorta. FK 453 inhibited contractile responses to norepinephrine, angiotensin-I and KCl. Pretreatment of the tissue with FK 453 failed to affect the relaxing effect of verapamil on the KCl response and the inhibitory effect of prazosin on the phenylephrine response. FK 453 inhibited both the residual norepinephrine response and the subsequent Ca2+ response in a Ca(2+)-free medium containing EGTA and nifedipine. The inhibitory effect of a combined treatment with either FK 453 plus nitroglycerin or FK 453 plus theophylline, but not with FK 453 plus M & B 22,948 (2-o-propoxyphenyl-8-azapurine-6-one; May & Baker), was much greater than that of any single treatment. Pretreatment with FK 453 also potentiated relaxing effects of nitroglycerin and isoproterenol on the PGF2 alpha response. The effect of a combined treatment with FK 453 plus theophylline, but not with FK 453 plus M & B 22,948, was much greater than that of any single treatment. FK 453 also inhibited the activity of phosphodiesterase from canine aorta to convert cyclic [3H]-GMP and cyclic [3H]-AMP to 5'-GMP and 5'-AMP, respectively. These results suggest that the inhibitory action of FK 453 is not due to inhibition of voltage-operated Ca2+ channels or alpha-adrenoceptors, but due to increase in cyclic GMP level.     

Preclinical electrophysiology assays of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT(4) receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-go-related gene (HERG) tail current in a concentration-dependent manner with IC(50) values of 20.2, 41.7, and 55.0 microM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 microM, with low maximum increases in MAPD(70) (6.6%) and MAPD(90) (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.     

低浓度碘对比剂在肾脏MSCT增强扫描中的可行性研究

目的：对比分析270、350 mg I/ml两种浓度碘对比剂在肾脏多层面CT(MSCT)增强扫描中的强化作用以探讨低浓度碘对比剂在肾脏增强扫描中的可行性。方法收集90例2012年9月~2014年5月本院疑似肾脏病变患者,随机分成A、B组,各45例,分别给予肾脏平扫和多期MSCT增强扫描,A组选用270 mg I/ml碘对比剂,B组选用350 mg I/ml碘对比剂,注射后18 s、30 s、80 s、3~5 min测量各期增强扫描腹主动脉、双肾动脉、双肾静脉、双肾皮质、双肾髓质、双肾盂的CT强化值并观察各组患者不良反应的发生情况。结果 B组患者发热等不良反应发生率高于A组患者;B组患者腹主动脉、右肾动脉、左肾动脉、右肾静脉、左肾静脉、右肾皮质、左肾皮质、右肾髓质、左肾髓质、右肾盂、左肾盂CT强化值均高于A组患者,但差异均无统计学意义(P<0.05)。结论在相同注射速率条件下多层螺旋肾脏血管成像使用低浓度对比剂可以获得满意的图像,同时可以减轻对比剂的不良反应。     

Electrophysiologic effects of ambasilide (LU 47110), a novel class III antiarrhythmic agent, on the properties of isolated rabbit and canine cardiac muscle.

Electrophysiologic effects of ambasilide in canine isolated cardiac muscle driven at 1 Hz and in rabbit sinoatrial (SA) node preparations were determined by standard microelectrode technique. Ambasilide (10(-7)-10(-5) M) produced concentration-dependent increases in action potential duration measured at -80 mV (APD-80) repolarization time in canine ventricular muscle and in Purkinje fibers. APD measured at -20 mV (APD-20) was also increased in ventricular muscle, but it shortened with 10(-5) M in Purkinje fibers; at this concentration, there was a negligible change in the amplitude and the maximum upstroke velocity (Vmax) of action potentials and in the resting membrane potential. With the stimulation frequency between 30/min and 120/min, ambasilide (10(-5) M) produced a parallel increase in APD-80 as well as in APD-20 of ventricular muscle. In Purkinje fibers, the prolonging effect of ambasilide on APD-80 was more pronounced at lower stimulation frequency, whereas APD-20 shortened at all stimulation frequencies. Ambasilide at 10(-5) M also produced a prolongation of the effective refractory period (ERP) in Purkinje fibers. The drug produced no significant change in the frequency-dependent relationship between ERP and APD-80. A small but significant frequency-dependent inhibition of Vmax was noted in both ventricular muscle and Purkinje fibers. When the stimulus cycle length was reduced from 1,000 to 300 ms, Vmax in ventricular muscle decreased by 8.4 +/- 3.4% in control solution but by 22.6 +/- 5.6% after 10(-5) M ambasilide (n = 8, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantification of phosphatidylserine, phosphatidic acid and free fatty acids in an ultrasound contrast agent by normal-phase high-performance liquid chromatography with evaporative light scattering detection

Sonazoid is a new contrast agent for ultrasound imaging. The product is an aqueous suspension of perfluorobutane microbubbles coated with phospholipids obtained from hydrogenated egg phosphatidylserine (H-EPS). A normal-phase high-performance liquid chromatographic (HPLC) method with evaporative light scattering detection was developed for quantification of free fatty acids, phosphatidylserine and phosphatidic acid in H-EPS and Sonazoid. Separation of the lipids was carried out on an HPLC diol column and a gradient of chloroform and methanol with 0.2% formic acid titrated to pH 7.5 with ammonia. The calibration standards contained stearic acid, distearoyl-phosphatidic acid (DSPA) and distearoyl-phosphatidylserine (DSPS) in the concentration range of 0.016-1.0mg/ml (0.4-25microg injected). The method was validated with a limit of quantification of the three lipids set to 0.4microg (approximately 20-60microM). The best fit of the three calibration curves were obtained when the logarithmic transformed theoretical lipid concentration was plotted against the logarithmic transformed area under the peak and fitted to a second order polynomial equation. Stearic acid, DSPA and DSPS were analysed with an intermediate precision ranging from 4.4% to 5.3% R.S.D. and they were extracted from an aqueous suspension with a recovery ranging from 103.3% to 113.3%. The sum of total phospholipid concentration determined in H-EPS ranged from 96.4% to 103.2% of the theoretical values. The lipids in the ultrasound product were quantitated with a repeatability ranging from 6.2% to 11.7% R.S.D.     

微波凝固及醋酸注射治疗兔肝VX_2肿瘤的实验对照研究

目的　探讨微波凝固及醋酸注射治疗肝肿瘤的效果 ,并将二者进行对照研究。方法　将 18只 2 0个 VX2 兔肝癌结节随机分为两组 :微波治疗组与醋酸治疗组。微波治疗组 :肿瘤直视下将微波针斜形尽量插入肿瘤中心 ,微波辐射每次 6 0 W× 12 0 s。醋酸治疗组 :超声检测瘤灶 ,沿已选择好的路径用抽有 70 %醋酸的注射器针头经皮经肝穿刺肿瘤 ,待荧光屏上观察到针尖位于肿块中心时 ,随即在 2 0～ 30 s内匀速注入适量醋酸。每个瘤灶注射 1次 ,注射剂量为 1～ 1.5 m L ,平均 1.2 5 m L ;每 1.0 cm瘤灶直径注射量平均为 0 .8m L。治疗后 10～ 15 m in后行能量多普勒声学造影 (levovist)评价其疗效。随机抽取各阶段标本行常规病理光镜检查。结果　醋酸瘤内注射 2 4h后 8个结节肿瘤细胞发生完全凝固性坏死 ,2个结节肿瘤原发灶大部分发生变性及凝固性坏死 ,边缘有少量肿瘤残存。微波治疗 2 4h后 ,10个肿瘤结节均呈不完全坏死 ,2周后 9个肿瘤结节显示为完全坏死。结论　醋酸治疗后即刻、2 4h肿瘤坏死程度明显强于微波治疗组。但醋酸弥散性强 ,疼痛剧烈 ,凝固范围不固定 ;微波热场分布均匀 ,凝固范围稳定可靠     

Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors

Summary Background ZD6126 is a novel vascular-targeting agent that disrupts the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor necrosis. This Phase I clinical study was conducted to evaluate the dose and administration schedule of ZD6126. Methods Adult patients with solid tumors refractory to existing treatments received a 10-min, single-dose intravenous infusion of ZD6126 every 14 or 21 days. Subsequent dose escalation was performed, based on the incidence of adverse events (AEs) within the first cycle of drug administration. Blood samples were obtained for pharmacokinetic analysis, and the effects of ZD6126 on tumor vasculature were visualized using DCE-MRI technology. Results Forty-four patients received ZD6126 (5−112 mg/m² in the 21-day schedule, n = 35; 40−80 mg/m² in the 14-day schedule, n = 9). Common AEs were similar in both groups and included abdominal pain, nausea and vomiting, which appeared to be dose related. The incidence of abdominal pain at 112 mg/m² in the 21-day study prevented further dose escalation. Pharmacokinetic studies confirmed that ZD6126 is rapidly hydrolyzed to ZD6126 phenol. There was no difference in the pharmacokinetics of ZD6126 phenol upon repeat administration or between the two dosing regimens. DCE-MRI evaluation has demonstrated the antivascular effects of ZD6126. Conclusions This study identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m² was well tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 out of 44) of patients, ZD6126 was associated with cardiac events categorized as dose limiting toxicities (one patient with asymptomatic decreased left ventricular ejection fraction (LVEF), two with increased troponin concentrations, one with myocardial ischemia, and one with ECG signs of myocardial ischemia). Previous presentations of study: Preliminary data from this study were presented at: 2001 AACR-NCI-EORTC (poster); 2002 American Society of Clinical Oncology (poster).     

Pharmacological and pharmacokinetic properties of azithromycin (Zithromac), a novel 15-membered ring macrolide antibacterial agent]

Azithromycin (Zithromac), a 15-membered ring macrolide antibacterial agent, was approved to be manufactured in Japan in March 2000. It showed good in vitro and/or in vivo antibacterial activities against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Peptostreptococcus micros, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Chlamydia pneumoniae. Its activity against H. influenzae was particularly more potent than that of currently used macrolide antibacterial agents. After oral administration to patients, azithromycin was readily absorbed and became widely distributed throughout the body, achieving higher concentrations in tissues and phagocytic cells than in serum or plasma. Its distribution into phagocytes was as high as more than 10 times that of erythromycin, and azithromycin was readily released from phagocytes in the presence of S. aureus. In experimentally infected mice, the concentration of azithromycin was higher in infected tissues than in uninfected tissues, which indicated that azithromycin was selectively delivered to infected tissues by migrating phagocytes. These pharmacological and pharmacokinetic properties were reflected in good clinical results for the treatment of respiratory infections and other infections with once daily dosing for 3 days.