Pharmacokinetics of lopromide Liposomes in Rabbits

Purpose. The dose-proportionality of pharmacokinetics of an iodinated contrast medium, iopromide, encapsulated into liposomes was investigated. Methods. Following single intravenous administration of 150 mg iodine/kg (potential diagnostic dose) and a five-fold higher dose in rabbits the pattern of elimination was studied until 7 d and the blood concentrations were monitored up to 72 h after administration. The iodine concentration in the liver was calculated on the basis of the blood concentration and related to the concentration measured in the rabbit liver. Results. The dose-normalized blood concentration-time profiles of the encapsulated iodine were not superimposable. Contrary to the low dose a steady-state concentration of 2.8 mg iodine/mL was observed in blood for 60 min after the high dose administration indicating a saturation of the liposomal liver uptake. For both doses the elimination of iodine occurred predominantly via the kidneys and was complete 7 d after administration. The dose-normalized amounts of iodine excreted with the urine were similar for both dose groups. From the blood data it was calculated that doses up to about 300 mg iodine/kg should result in a dose-proportional increase of liposomal liver uptake before saturation occurs. This was confirmed by the measured iodine liver concentrations after increasing the doses stepwise from 150 to 750 mg iodine/kg. Conclusions. In rabbits for the dose range 150 to 750 mg iodine/kg iopromide liposomes reveal dose-dependent pharmacokinetics due to a saturation in liver uptake which occurs for doses of 300 mg iodine/kg corresponding to 300 mg lipid/kg onwards.     

Multi‐Component Synthesis of Dihydropyrimidines by Iodine Catalyst at Ambient Temperature and in‐vitro Antimycobacterial Activity

An efficient and simple three‐component domino synthesis of some new dihydropyrimidines (DHPMs) from aromatic aldehydes, 1,3‐dicarbonyl compounds and N‐(3‐chloro‐4‐fluorophenyl)urea using molecular iodine as catalyst is described. The 1‐substituted dihydropyrimidines were isolated in good to excellent yields (78‐90%) within a short reaction time (4‐6 h) at ambient temperature. The biological evaluation revealed that the newly synthesized compounds ( 4a ‐ i and 5a ‐ i ) exhibited moderate antimycobacterial activity against Mycobacterium tuberculosis H₃₇ RV.     

Characterization of a Synthetic Anionic Vector for Oligonucleotide Delivery Using in Vivo Whole Body Dynamic Imaging

Purpose. To compare the pharmacokinetics and bioavailability of an oligonucleotide delivered in a free form or using cationic or anionic synthetic carrier systems. Methods. Whole body dynamic quantitative imaging and metabolism of a HIV antisense oligonucleotide intravenously administered either free or incorporated into synthetic carriers were compared in baboons, using non invasive positron emission tomography and an enzyme-based competitive hybridization assay, respectively. Results. In its free form, the oligonucleotide showed high liver and kidney concentration, rapid plasmatic degradation and elimination from the body. Use of a cationic vector slightly protected the oligonucleotide against degradation and enhanced uptake by the reticulo-endothelial system. In contrast, the anionic vector dramatically enhanced the uptake in several organs, including the lungs, spleen and brain, with a prolonged accumulation of radioactivity in the brain. Using this vector, intact oligonucleotide was detected in plasma for up to two hours after injection, and the T_1/2 and distribution volume increased by 4- and 7-fold, respectively. No evidence of toxicity was found after a single dose administration. Conclusions. The anionic vector improves significantly the bioavailability and the pharmacokinetics of the oligonucleotide, and is a promising delivery system for in vivo administration of therapeutic nucleic acids.     

Differences in the Distribution of Iodine and Iodide in the Sprague-Dawley Rat

Differences in the Distribution of Iodine and Iodide in theSprague-Dawley Rat. THRALL, K. D., AND BULL, R. J. (1990). FundamAppl. Toxicol. 15, 75–81. Use of iodine as a drinkingwater disinfectant for extended space flight raises concernsabout potential chronic effects on health. A key question iswhether the chemical form of iodine might play a role. To addressthis question the influence chemical form has on the uptakeand distribution of radioiodine was studied in fed and fastedrats. Following oral administration of ¹²⁵I₂ or ¹²⁵I^–,blood ¹²⁵I levels were maximal at 2 hr and reached similar concentrationsin fed animals receiving ¹²⁵I^– and fasted animals receivingeither ¹²⁵I₂ or ¹²⁵I^– However, when ¹²⁵I₂ was administeredto fed animals the initial levels of ¹²⁵I into blood were significantlylower than after the other treatments. The half-life of eliminationof ¹²⁵I from the blood appeared independent of the form of iodineadministered. The initial distribution of ¹²⁵I to the thyroiddepended sharply on chemical form, being greater when iodiderather than iodine was administered, whether animals were fedor fasted. In fed animals administered I₂, this may largelybe explained by the increased retention of ¹²⁵I in the stomachcontents. In fasted animals, both stomach content and bloodlevels of I^– were similar whether I₂ or I^– was administered.Since thyroid uptake of iodine is specific for I^–, thissuggests that the form of iodine in the blood was differentin animals administered I₂. This notion was further supportedby the finding that pretreatment of animals with varying concentrationsof I^– in drinking water was four times as effective insuppressing the uptake of a test dose of ¹²⁵I^– than pretreatmentwith equivalent concentrations of I₂.     

低碘对大鼠脑组织抗氧化能力的影响

目的 :研究低碘对大鼠脑组织抗氧化能力的影响。方法 :20只清洁级Wistar大鼠随机分为低碘组 (LI)、适碘组 (NI) ,6个月后测定24h尿碘含量、甲状腺质量、脑组织匀浆中超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GSH -Px)活性及丙二醛 (MDA)含量。结果 :LI组甲状腺质量、24h尿碘含量明显低于NI组 (P<0.01) ;与NI组相比LI组GSH -Px降低 ,而MDA升高 (P<0.01) ,2组间SOD差别无统计学意义。结论 :低碘6个月的大鼠脑组织抗氧化能力降低 ,无法保护脑组织免受自由基的损伤     

温度敏感原位凝胶中药物的扩散行为温度敏感原位凝胶中药物的扩散行为

环境敏感凝胶对外界物理或化学条件的微小变化发生响应的性质在药物控制释放领域得到广泛应用.原位凝胶(in situ gel)是指高分子材料的溶液因温度[1,2]、离子强度[3]或pH[4]的改变而在用药部位发生相转变,形成的半固体制剂.由于完美地融合了液体与凝胶制剂的优点,该药物传递系统近年来已逐步发展成为环境敏感凝胶最受瞩目的分支.     

Block-copolymer of Polyethylene Glycol and Polylysine as a Carrier of Organic Iodine: Design of Long-circulating Particulate Contrast Medium for X-ray Computed Tomography

Abstract

In order to obtain small, polymer-stabilized particulate carriers for organic iodine to serve as a contrast agent for X-ray computed tomography (CT) an attempt was made to design a carrier based on polymeric micelles. Here we describe the synthesis of an iodine-containing amphiphilic block-copolymer which can micellize in aqueous solutions. The two blocks of the copolymer consisted of methoxypoly(ethyleneglycol) and poly[?,N-(triiodobenzoyi)-L-lysine]. Upon dispersion in water, the block copolymer formed particles with average diameter 80 nm and iodine content up to 44.7%. The particles start to dissociate to the individual polymeric chains in the concentration range of 0.05-0.5 μM in water at 23°C. Upon intravenous injection at 250 mg of iodine/kg (570 mg of the agent/kg) in rabbits the medium demonstrated exceptional 24 hr half-life in the blood substantiating corona/core structure of the particles with PEG chains protecting the iodine-containing core. The possible use of these particulates as contrast medium for X-ray computed tomography is discussed.     

Systemic iodine absorption associated with the use of preoperative ophthalmic antiseptics containing iodine

Abstract

Background: Polyvinylpyrrolidone-Iodine (PVP-I) is routinely used as preoperative antiseptic during ophthalmic surgery. Iodine absorption from iodine-containing antiseptics can lead to the development of thyroid disorders. Therefore, a quantitative measurement of iodine absorption from these antiseptics was performed in patients undergoing elective cataract surgery.

Methods: This study enrolled 241 patients to evaluate systemic iodine absorption after exposure to conjunctival and/or periorbital 1.25% and 10% PVP-I compared to an iodine-free antiseptic.

Results: All patients who received the 10% PVP-I regardless of the application site showed a 1.2–1.5-fold increase in urinary iodine excretion after 24?h (p?=?0.01). In 17 out of 110 (15.5%) patients in whom 10% PVP-I was used, the critical threshold of urinary iodine excretion as defined by WHO (>300?µg/L) was exceeded. In contrast, no significant ioduria was observed with the use of 1.25% PVP-I except in patients after 48?h (p?=?0.01) and with a concurrent conjunctival and periorbital application. The proportion of the excreted iodine in urine ranged from 0.24% to 1.77%. No correlation was found between the total applied concentration of iodine and the amount excreted in urine.

Conclusion: Based on our findings, we believe that the use of 10% PVP-I as preoperative ophthalmic antiseptic should undergo further clinical evaluation in regard to its impact on thyroid function. Conjunctival or periorbital application of 1.25% PVP-I does not result in significant ioduria.     

58例非离子型碘造影剂不良反应报告分析

目的：调查非离子型碘造影剂的不良反应,探讨其安全性。方法：收集院内2009～2012年医师、护士、药师自发呈报的所有非离子型碘造影剂ADR报告并进行统计分析。结果：共收到ADR报告58份,其中轻度反应28例,中度反应26例,重度反应4例,无死亡病例,过敏反应构成比最高,出现时间均在30 min内。结论：我院使用非离子型碘造影剂较安全,得益于用药前预防和准备,用药时密切观察,出现不良反应时及时正确救治。     

Preparation and evaluation of [125I]troxacitabine: L‐nucleoside model of a potential agent for tumor diagnosis and radiotherapy

In this study, the optimization of troxacitabine labeling with iodine‐125 and its biological evaluation were described. Troxacitabine was labeled via direct electrophilic substitution using chloramine‐T as oxidizing agent. The optimum amounts of reactants were: 50 µ g troxacitabine, 75 µ g Chloramine‐T and ～19 kBq carrier free Na¹²⁵I. The labeled troxacitabine was stable for more than 24 h. Results of the in‐vivo evaluation revealed that the new tracer, [¹²⁵I]troxacitabine, tends to localize in tissues with high proliferation rate with preferential accumulation in cancerous tissues. Imaging should be carried at 3 h postinjection. The in vitro cell growth inhibition assay showed that the effect of [¹²⁵I]troxacitabine was stronger than the effect of cold troxacitabine, which strongly suggested that its cytotoxicity was mainly due to radiotoxicity rather than chemotherapeutic activity. The binding assay revealed that [¹²⁵I]troxacitabine uptake by the Ehrlich and the ARAC8C cells was high and that it bounded well to DNA. Copyright © 2010 John Wiley & Sons, Ltd.     

Labeling,biodistribution and evaluation of [125I] gemcitabine: a potential agent for tumor diagnosis and radiotherapy

In this study, the optimization of gemcitabine labeling with iodine‐125 and its biological evaluation are described. Gemcitabine was labeled via direct electrophilic substitution using chloramine‐T as an oxidizing agent. The optimum amounts of reactants were 75 µg gemcitabine, 75 µg chloramine‐T and 18 MBq carrier‐free Na¹²⁵I. The labeled gemcitabine was stable for more than 20 h. Results of the in vivo evaluation revealed that the new tracer, [¹²⁵I] gemcitabine, tends to localize in tissues with high proliferation rate with preferential accumulation in cancerous tissues. Imaging should be carried at 2‐h postinjection. The in vitro cell growth inhibition assay showed that the effect of [¹²⁵I] gemcitabine was stronger than the effect of tenfold cold gemcitabine, which strongly suggested that its cytotoxicity was mainly due to radiotoxicity rather than chemotherapeutic activity. The binding assay revealed that [¹²⁵I] gemcitabine uptake by the Ehrlich cells was high and that it bound well to DNA where the decay of the radionuclide introduced lethal irreversible double‐strand breaks. Copyright © 2009 John Wiley & Sons, Ltd.     

Navigating tuberculosis drug discovery with target-based screening

Introduction: Mycobacterium tuberculosis kills more people than any other bacterial pathogen. New drugs are required to shorten the treatment time and provide a viable therapy for drug-resistant and latent forms of tuberculosis. The tuberculosis field has advanced considerably since the publication of the M. tuberculosis genome sequence. Today, researchers can build a high definition map of the pathogen's traits and behavior and select individual targets for chemical disruption.

Areas covered: This review examines the discovery of current clinical and candidate tuberculosis drugs. It outlines recent developments in the selection of molecular targets for the discovery of new anti-mycobacterial agents. It appraises techniques that incorporate target knowledge into the screening protocol. These techniques include in silico, in vitro enzyme-based, differential antisense sensitivity and gene expression screening systems. The review also looks ahead to further techniques that may be applied in tuberculosis drug discovery.

Expert opinion: The adoption of an ‘either/or’ approach to targeted or random tuberculosis drug screening is not expected. The historical success of random screening in providing the tuberculosis drugs currently in clinical use is likely to ensure that non-targeted protocols retain an important role in drug screening. However, a number of M. tuberculosis inhibitors in lead optimization and preclinical development have been discovered using targeted methods. Realization of the first clinically-approved tuberculosis drugs derived from targeted screening and continued refinements in targeted screening technologies are likely to increase the adoption of targeted approaches in the future.     

泻白散及其主药体外抗氧化活性研究

目的 建立泻白散和方中3味主药甘草、地骨皮、桑白皮的体外抗氧化活性测定方法,并对31批药材和10批泻白散煎液的抗氧化活性进行测定。方法 采用紫外可见分光光度法检测一定浓度的药材提取液引起DPPH溶液吸光度（A）值降低,考察波长为517 nm,分别探索3味药材抗氧化活性成分的提取条件;并进行不同溶剂的吸收考察、专属性考察、DPPH线性考察、药材提取液线性考察、精密度试验、重复性试验、耐用性考察等方法学验证;以清除DPPH自由基的半抑制浓度（IC₅₀）作为评价指标,对泻白散和方中3味药材的体外抗氧化活性进行考察。结果 地骨皮、甘草、桑白皮和泻白散提取液的IC₅₀均值为0.31、1.24、1.49和0.91 g/L,泻白散提取工艺对方中药物抗氧化活性的保留均值为56%。结论 建立的抗氧化活性测定方法可用于泻白散及方中主药的抗氧化活性测定,为多维度评价中药和中药材质量提供新思路。     

New Strategy for the cultivation of microalgae using microencapsulation

The four species of microalgae (Dunaliella bardawil, Chlorella minutissima, Pavlova lutheri and Haematococcus pluvialis) were immobilized in Ca-alginate capsules as a basic study for the development of the economic cultivation process. Under the batch culture of aerobic conditions, the thickness of the capsule membrane and CO₂ supply did not affect the growth of the immobilized microalgae, Dunaliella bardawil. Cell concentration of immobilized microalgae in the capsule was higher than those of immobilized microalgae in beads and free cells. The cell concentrations of microencapsulated Dunaliella bardawil and Haematococcus pluvialis were five times greater than that of free cells. Based on these results, microencapsulation for the culture of microalgae was an effective method for the high-density cultivation. In comparison to the immobilized cultivation on the bioreactor type, it was more effective for the cultivation in the bubble column bioreactor than that in the stirrer tank bioreactor.     

The influence of free fatty acids on valproic acid plasma protein binding during fasting in normal humans

Summary The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p<0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p<0.01) than in fasting samples (10–50%,p<0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p<0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.     

Effect of variations in acute and chronic iodine intake on the accumulation and metabolism of [35S]methimazole by the rat thyroid gland: Differences from [35S]propylthiouracil

Studies were performed to ascertain the effect of various levels of chronic iodine intake and varying doses of iodide [0.002–100 μmoles KI/100 g body weight (BW)] given acutely on the rat thyroid metabolism of [³⁵S]methimazole ([³⁵S]MMI, 8.76 μmoles/kg BW). Variations in both acute and chronic iodine intake were associated with as much as four-fold changes in thyroid levels of total ³⁵S and unchanged [³⁵S]MMI. Chronic low iodine intake resulted in a considerable reduction in the thyroid uptake of [³⁵S]MMI (40% decrease) from high or normal chronic iodine intake. Unlike [³⁵S]PTU studies, the effect of increasing acute iodide dosage produced a biphasic response in the thyroid uptake of [³⁵S]MMI only in low chronic iodine intake. In these animals 0.1 μmoles KI/100 g BW produced the maximum uptake of [³⁵S]MMI (300% increase) but had no effect on high or normal chronic iodine intake. In these latter groups of rats, thyroidal total ³⁵S increased to plateau levels with increasing acute iodide dosage in the range of 0.1–1 μmoles/100 g BW which were unaffected by increased iodide up to 100 μmoles/100 g BW. In low chronic iodine intake rats also, the thyroid ³⁵S level seen at 1 μmole/100 g was unaffected by increased iodide dosage up to 100 μmoles/100 g. The steady thyroid ³⁵S levels seen in this acute iodide dose range in low, normal and high chronic iodine rats were 100, 70 and 110% respectively greater than their control values. Unlike [³⁵S]PTU studies, in general, an increase in thyroid total ³⁵S achieved by varying acute or chronic iodine intake was found to be associated with a large increase in the percentage thyroid ³⁵S occurring as free inorganic sulphate with a consequent effect on thyroid unchanged [³⁵S]MMI. In chronic low iodine intake animals treated with acute radioidide, in agreement with [³⁵S]PTU studies, no direct correlation was found between thyroid uptake or oxidation of [³⁵S]MMI and thyroidal total iodine, the accumulation or organification of acute [¹²⁵I]iodide, the occurrence of the Wolff-Chaikoff effect or saturation of thyroid iodide transport.     

正交试验优选浓碘酊处方

目的优选浓碘酊的最佳处方.方法采用L9（34）正交设计,以碘和碘化钾含量变化为考察指标,考察碘与碘化钾比例、乙醇浓度两个因素对浓碘酊稳定性的影响.结果最优处方为碘与碘化钾比例1：0.6,乙醇浓度76%.结论按优化处方制备的制剂稳定性较好.     

Formation of Charge-Transfer Complexes of Penicillins with Iodine

Benzylpenicillin, benzathine benzylpenicillin, procaine benzylpenicillin, anhydrous ampicillin and sodium ampicillin form charge-transfer complexes with iodine in 1,2-dichloroethane, which were examined by UV, FIR, ¹H-NMR, ¹³C-NMR, and ¹⁵N-NMR spectroscopy.     

Comparison of free iodine as a function of the dilution of two commercial povidone-iodine formulations

Binding studies by means of equilibrium dialysis on two different Povidone-lodine-solutions reveal that the amount of available iodine and free iodine is very different as such and after dilution. The free iodine concentration in the Braunol concentrate was found to be ca. 22 mg/L and in the iso-Betadine concentrate only ca. 2.1 mg/L, despite the total amount of available iodine in iso-Betadine being higher than that of Braunol. As the bactericidal level of free iodine is characterised by concentrations >5 ppm, Braunol can be employed as a disinfectant as such, iso-Betadine has to be diluted before use. In both concentrates more than 99% of available iodine is present as reservoir for free iodine. Concerning the results as a function of dilution, it was demonstrated that, for both solutions, free iodine reaches a maximum after a 50-fold dilution (ca. 31 mg/L and ca. 51 mg/L for iso-Betadine and Braunol respectively). After dilution, a more constant level of free iodine was observed in the Braunol than in the iso-Betadine solution, and this is attributed to the present molar ratio of I(2)/I- and the addition of iodate in the former. The pH for both solutions approximates that of the skin, as such and after dilution. In summary, it can be stated that Braunol is superior to iso-Betadine as to the release of free iodine in both the undiluted as well as in the diluted form.     

Preparation,characterization and tissue distribution of brucine stealth liposomes with different lipid composition

Objective: To improve the therapeutic index of brucine, the novel stealth liposomes (SLS-n), composed of naturally unsaturated and hydrogenated soy phosphatidylcholines, with significant difference of phase transition temperature, were developed to encapsulate brucine.

Methods: Brucine-loaded stealth liposomes with different lipid compositions were prepared and characterized for their entrapment efficiency (EE), particle size, zeta potential and in vitro drug release profile. Tissue distribution after intravenous administration of different brucine formulations was further compared in tumor-bearing mice.

Results: Compared with the conventional stealth liposomes composed of SPC (SLS-s) or HSPC (SLS-h), EE and zeta potential of SLS-n were increased slightly, and the size was decreased slightly. The results of drug release showed that SLS-n were more stable than SLS-s. After intravenous administration, tumor AUC in SLS-s, SLS-n and SLS-h treated animals were 1.33, 1.72 and 2.59-fold higher than in mice treated with the same dose of free brucine, respectively. Compared with brucine solution, administration of SLS-s and SLS-n could significantly decrease brucine concentration in brain, but administration of SLS-h resulting in significantly increased (2.75-fold) concentration in 10?min.

Conclusion: Since brucine has severe central nervous system toxicity, our study indicated that SLS-n could considerably improve the therapeutic index of brucine.