Intradermal concentration of hydroquinone after application of hydroquinone ointments is higher than its cytotoxic concentration

Ointments of the skin depigmentation agent hydroquinone (HQ) have been prepared by extemporaneous nonsterile compounding in our hospital. The HQ ointments were highly effective in the treatment of various types of skin pigmentations; however, various problems have emerged including chromatic aberration of the ointments, a relatively large variability of efficacy, and mild topical side effects including irritation. In this paper, the cytotoxicity of HQ was assessed in vitro using rat skin fibroblasts as the concentration with 50% survival after 24 h exposure to be 16.5 microM. The intradermal concentrations at 2 h after application of the HQ ointments was also estimated to be 358 mM and 51.7 mM in stratum corneum and viable tissue (viable epidermis+dermis), respectively, by an in vitro rat skin permeation study with rat full-thickness abdominal skin and Franz-type diffusion cells. It was demonstrated that the intradermal concentration of HQ was much higher than that eliciting cytotoxicity, suggesting that the topical side effects after application of HQ ointment were due to the cytotoxicity of HQ.     

Comparative toxicity of physiological and biochemical parameters in Euglena gracilis to short-term exposure to potassium sorbate

Ecotoxicology - Potassium sorbate is the potassium salt of sorbic acid, is a widespread and efficient antioxidant that has multiple functions in plants, traditionally associated with the reactions...     

The physiological relevance of low agonist affinity binding at opioid mu-receptors.

1. Inhibition constant (Ki) were determined for a range of opioid standards using two binding assays; [3H]-[D-Ala2, MePhe4, Gly-ol5]enkephalin ([3H]-GLYOL) binding to guinea-pig brain membranes in HEPES buffer and [3H]-naloxone binding to rat whole brain membranes in Krebs/HEPES buffer. 2. These values were compared with affinity measurements determined by antagonism of GLYOL on the rat isolated vas deferens preparation and by the receptor occlusion technique of Furchgott on the guinea-pig ileum longitudinal muscle, myenteric plexus preparation. 3. Agonists demonstrated markedly reduced binding affinity in the [3H]-naloxone binding assay where binding was conducted in the presence of sodium. 4. A strong correlation was obtained between Ki values from the [3H]-naloxone binding assay and affinity values determined in both isolated tissue preparations. Ki values obtained from [3H]-GLYOL binding did not correlate well with affinity data determined by isolated tissue techniques. 5. These findings suggest that functionally relevant receptors exhibit low agonist affinity.     

重症患者复方磺胺甲(口恶)唑血药峰浓度与不良反应的相关性研究

目的:评估重症患者使用复方磺胺甲■唑发生的不良反应与血药峰浓度(C_max)的相关性及其毒性阈值。方法:采用回顾性研究的方法,收集2016年1月至2021年12月某三甲医院重症监护室使用复方磺胺甲■唑治疗并进行治疗药物监测的患者信息,使用Naranjo评分量表评价复方磺胺甲■唑与不良反应的关联性,并分析磺胺甲■唑及甲氧苄啶C_max与不良反应发生之间的相关性。结果:本研究共获得109人次磺胺甲■唑的浓度数据及87人次甲氧苄啶的浓度数据,未发现皮疹、恶心呕吐、肝毒性及肾毒性的发生与磺胺甲■唑及甲氧苄啶C_max有相关性(P>0.05),发生血液系统毒性及高钾血症的患者其甲氧苄啶C_max显著高于未发生的患者(P<0.05),进一步通过受试者工作特征曲线分析得到高钾血症的甲氧苄啶C_max最佳阈值为8.75μg·mL^-1。结论:有必要对使用复方磺胺甲■唑的重症患者进行治疗药物监测,甲氧苄啶C_max>8.75μg·mL^-1...     

Silver nanoparticle toxicity is related to coating materials and disruption of sodium concentration regulation

Silver nanoparticles (AgNPs) have been increasingly commercialized and their release into the environment is imminent. Toxicity of AgNP has been studied with a wide spectrum of organisms, yet the mechanism of toxicity remains largely unknown. This study systematically compared toxicity of 10 AgNPs of different particle diameters and coatings to Japanese medaka (Oryzias latipes) larvae to understand how characteristics of AgNP relate to toxicity. Dissolution of AgNPs was largely dependent on particle size, but their aggregation behavior and toxicity were more dependent on coating materials. 96?h lethal concentration 50% (LC50) values correlated with AgNP aggregate size rather than size of individual nanoparticles. Of the AgNPs studied, the dissolved Ag concentration in the test suspensions did not account for all of the observed toxicity, indicating the role of NP-specific characteristics in resultant toxicity. Exposure to AgNP led to decrease of sodium concentration in the tissue and increased expression of Na⁺/K^+?ATPase. Gene expression patterns also suggested that toxicity was related to disruption of sodium regulation and not to oxidative stress.     

Pulmonary toxicity of an atmospheric particulate sample is due to the soluble fraction.

Adverse health effects have been associated with the inhalation of a variety of atmospheric particles. The potential toxicity of a recently collected urban air particulate sample (EHC-93, mean diameter < 1 microm) was assessed after instilling 1 mg to mouse lung. A soluble fraction (15% of total) and an insoluble fraction of the original dust were also instilled at 1 and 0.15 mg doses and the lung reaction was followed for up to 8 weeks. The complete dust sample induced an inflammatory response in the first week with increased cell numbers and protein levels in lavage fluid. There was also ultrastructural evidence of epithelial necrosis followed by increased thymidine labeling during repair. The insoluble fraction induced only mild inflammation with no evidence of cell injury or repair at either dose. The soluble fraction produced similar early inflammatory changes but also produced the greatest lung injury. Type 1 cell necrosis was observed, followed by increased tritiated thymidine uptake mainly by Type 2 epithelial cells. This was found after 0.15 mg soluble fraction and was greatly increased in the 1.0 mg group, which subsequently developed fibrosis. The results indicate that while all particle samples induce some inflammation, the lung toxicity produced by the total dust sample EHC-93 can be accounted for by the reaction to its 15% soluble component. This suggests that the pulmonary response and cell injury following exposure to this urban dust is related to soluble material, probably metal ions, rather than to the number or composition of the insoluble particles.     

Acidosis-induced relaxation of human internal mammary artery is due to activation of ATP-sensitive potassium channels

Metabolic acidosis is associated with various clinical situations including diabetes mellitus and renal diseases. The aim of this study was to investigate the effects of acidosis on the resting as well as precontracted human left internal mammary artery. The vessels were obtained from the patients undergoing coronary artery bypass grafting surgery at The Aga Khan University Hospital, Karachi. Left internal mammary artery was cut into rings and isometric tension recording experiments were performed. Decrease in pH of the bathing solution from 7.4 to 6.8 had no effect on the resting tension of left internal mammary artery, whereas, acidic pH markedly relaxed the contractions to 24.8 mM KCl and 300 nM phenylephrine. Interestingly, when the KCl- or phenylephrine-contracted rings were treated with 3 microM glibenclamide; an inhibitor of ATP-sensitive potassium (K(ATP)) channels, the relaxant effect of acidosis was abolished. Similarly, acidosis failed to cause relaxation of 100 nM endothelin-1-induced contraction in Ca2+-free bathing solution or in the presence of a voltage-dependent Ca2+ channel inhibitor, verapamil (10 microM), whereas, endothelin-1-induced contraction was attenuated by acidosis in Ca2+-containing normal solution. From all these data, it is concluded that under the acidic pH conditions, opening of K(ATP) channels occurs; resulting in the hyperpolarization, decrease in Ca2+ influx via voltage-dependent Ca2+ channels and subsequent relaxation of human left internal mammary artery.     

Enhancement of benzodiazepine receptor binding by L-lysine is chloride-dependent and due to increase in binding affinity

L-Lysine enhanced specific [3H]flunitrazepam binding dose dependently on extensively washed bovine brain membrane in vitro. This enhancement was stimulated by chloride ions dose dependently. Scatchard analysis indicated this enhancement by L-lysine to be due to increase in binding affinity (KD) with no change in receptor density (Bmax). Since enhancement of [3H]flunitrazepam binding by L-lysine was partially inhibited by picrotoxinin, L-lysine may act on a distinct picrotoxinin-sensitive site which was distinct from the gamma-aminobutyric acid receptor site. This binding site, however, appears to have some features resembling that of the central nervous system-depressant barbiturates.     

Increase in plasma potassium concentration following indomethacin administration: absence of a role for membrane Na-K ATPase

To elucidate whether indomethacin-induced hyperkalaemia is due to an inhibition of Na-K ATPase in the membranes, indomethacin (25 mg t.d.s.) was administered to 7 normal subjects for 7 days. This resulted in an increase in plasma potassium concentrations in all 7 subjects: median (range) for the entire group increased from 4.19 (3.98-4.79) mmol/l to 4.29 (4.13-4.87) mmol/l. Leucocytes prepared from these subjects prior to and after indomethacin were tested for 86Rb influx and [3H]-ouabain binding (an index of Na-K ATPase sites). Neither 86Rb influx (total, ouabain sensitive and ouabain insensitive) nor [3H]-ouabain binding changed significantly following indomethacin. We conclude that (a) indomethacin-induced hyperkalaemia is not due to alterations in potassium influx into cells and (b) the modulation of Na-K ATPase sites/activity is in leucocytes not dependent upon prostaglandins.     

The relative sensitivity and sensitivity patterns of short-term toxicity tests applied to industrial wastewaters

Ten short-term toxicity tests were run for ten different industrial wastewaters. The tests included standardized toxicity tests with bacteria, microalgae, higher plants, invertebrates, and fish. An algal test battery of 13 microalgae was also run in microplates. The results were compared with regard to the tests' relative sensitivity and the similarity in sensitivity patterns between different tests. The test with highest sensitivity was the algal test battery. This was due to the fact that the algal species in the battery had complementary sensitivity patterns. The sensitivity patterns of the zoological tests had a high degree of similarity and they were less sensitive than the microbial tests. The relative sensitivity of a test is, however, dependent on the end point for the tests, and it is pointed out that this must be matched with how the test is interpreted. © by John Wiley & Sons, Inc.     

Changes in renal clearance of furosemide due to changes in renal blood flow and plasma albumin concentration

Summary We have shown that, within therapeutic plasma concentrations, the unbound fraction of furosemide changes in direct proportion to the reciprocal of the plasma albumin concentration (correlation coefficient 0.99). Changes in the albumin concentration were produced by ultrafiltration of human plasma using a haemofiltration filter. Thus, we propose that, when studying changes in the pharmacokinetics of a highly protein bound drug, calculated changes in the unbound fraction offer an alternative to actual measurement of the unbound concentration, which is often difficult.Nine healthy volunteers receiving a continuous furosemide infusion were studied in normovolaemia and after dehydration (–1.4 kg), with and without pretreatment with an angiotensin converting enzyme inhibitor (captopril) or an a₁-adrenoceptor blocking agent (prazosin). Significantly larger changes in the renal clearance of furosemide were found that could be explained by changes in the unbound fraction. Following dehydration, the unbound fraction of furosemide was decreased by about 5%, while its renal clearance fell by 27%, 33% and 13% after pretreatment with placebo, captopril and prazosin, respectively. The secretory clearance of the unbound furosemide changed substantially and in parallel with changes in the renal blood flow. It is suggested that changes in the renal clearance and excretion of furosemide and its t_1/2 are much more dependent on changes in renal blood flow than on changes in its unbound fraction.     

重度低钾麻痹症心电监护下高浓度静脉补钾治疗临床观察

目的观察心电监护下静脉补充高浓度钾对重度低钾麻痹的疗效。方法对90例重度低钾麻痹患者采用高浓度(500～800mmol/L)氯化钾溶液以25～40mmol/h的速度,在心电监护下用微泵快速静脉输入。结果90例患者均在5～12h内血钾升至3.5mmol/L,心律失常消失,四肢肌力恢复。5例发生静脉炎,所有病例均未出现严重心律失常。结论心电监护下高浓度静脉补钾治疗重度低钾麻痹疗效好,疗程短,安全可靠。     

HPLC法测定人血浆中盐酸二甲双胍的浓度及其在药动学研究中的应用

目的:建立了人血浆中盐酸二甲双胍浓度的反相离子对高效液相色谱测定法,研究复方盐酸二甲双胍片在中国男性健康志愿者体内盐酸二甲双胍的药动学行为,评价其生物利用度和生物等效性.方法:血浆样品经高氯酸沉淀蛋白,二氯甲烷脱脂后直接进样.流动相为甲醇-0.015mol·L-1磷酸二氢钾溶液(含0.001mol·L-1十二烷基磺酸钠,0.02mol·L-1氢氧化钾调节pH 5.2)(40:60),检测波长232nm,流速1mL·min-1.采用双交叉随机实验设计,20例受试者交叉口服复方盐酸二甲双胍试验片2片(每片含盐酸二甲双胍250mg和格列本脲1.25mg)或对照制剂盐酸二甲双胍片(每片含盐酸二甲双胍500mg)与格列本脲片(每片含格列本脲2.5mg)各1片,服药后0.5～24h内间隔取血.结果:HPLC测定盐酸二甲双胍在20～2 000μg·L-1范围内线性关系良好(r=0.999 8),最低定量限20μg·L-1,日内及日间精密度均小于10%.口服试验和对照制剂后,盐酸二甲双胍的t1/2,Tmax,Cmax分别为(3.84±0.61)h和(4.26±0.96)h,(2.0±0.7)h和(2.1±0.9)h,(1402.4±349.2)μg·L-1和(1 329.7±315.4)μg·L-1.以等剂量的盐酸二甲双胍与格列本脲片为对照,由AUC0～24计算,复方盐酸二甲双胍片中盐酸二甲双胍的相对生物利用度为(101.1±28.5)%.结论:本方法专属性强,灵敏度高.药动学试验结果表明试验复方片与联合使用的对照片盐酸二甲双胍生物等效.     

抗癫痫药物血药浓度监测的作用及价值

目的：通过血药浓度监测了解常用抗癫痫药在儿科临床应用中血药浓度与药物疗效及不良反应的关系，以防止或减少药物不良反应的发生。方法：采用FPIA法则定228例癫痫患儿单一使用抗癫痫药物(AED)的血药浓度，并对药物剂量、疗效和药物不良反应的关系进行分析．所有患几经过一年以上随访。结果：228例中192例(84．2％)在有效血药浓度范围内，癫痫发作控制有效183例(80.3％)，发生不良反应55例(24．1％)。结论：剂量过大和特异体质是抗癫痫药发生不良反应的主要原因；不同类型的AED所导致的不良反应有明显差异：选择抗癫痫药物类型不当和药物剂量过低是造成治疗效果不满意的重要因素。     

高效液相色谱法测定不同时间人血浆中帕拉米韦的浓度及临床观察

目的 测定帕拉米韦给药后不同时间人血浆中的药物浓度,观察病人用药后安全性及疗效,为临床使用帕拉米韦提供依据.方法 高效液相色谱(HPLC)法测定帕拉米韦的血药浓度,以5 mmol/L磷酸二氢钾溶液(0.1％三乙胺)-乙腈为流动相,磷酸调pH 5.0;检测波长210 nm;流速1.0 mL/min;用药后对病人进行安全性...     

Effect of gradual rise in plasma calcium concentration on the impairment of atrioventricular nodal conduction due to verapamil

The possible reversal by calcium of the inhibitory action of verapamil on the atrioventricular (AV) node was investigated in anesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitory electrode and the AV node effective refractory period measured by the extrastimulus method. Calcium infusion was effective against the impairment of AV nodal conduction induced by verapamil, provided it remained moderate: the gradual rise in the plasma calcium concentration counteracted the effects of an infusion of verapamil on conduction time and effective refractory period in the AV node, as long as it did not exceed 5 mmol/L. However, beyond this level, calcium appeared less and less capable of reversing the effects of verapamil. Thus, the protective action of calcium had a bell-shaped dose-response curve, with the optimum at 5 mmol/L. This biphasic influence is consistent with the opposite opinions previously given concerning the antagonism between calcium and calcium blockers, depending on whether hypercalcemia brought into play was mild or major. In any case, the prominent role played by calcium in the slow inward current in the AV node accounts for the antagonism, observed in vivo, between calcium and verapamil. The pacemaker activity of the sinoatrial (SA) node was less influenced by both calcium blocker and calcium.     

The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

In a safety study, Cape Griffon vultures (Gyps coprotheres) were dosed with ketoprofen at single doses of ~1 mg/kg (n = 5) and 5 mg/kg (n = 11). No toxicity was reported in the 1 mg/kg group, with the AUC_inf, V_z and Cl being 10.42 μg/ml h, 0.37 l/kg and 0.10 l/h kg, respectively. Toxicity occurred in the 5 mg/kg group, with 7 of the 11 birds dying. Clinical signs of toxicity included depression, loss of appetite and apparent coma. Animals died within 48 h of dosing. The AUC_inf, V_z and Cl in the birds that survived were 52.26 μg/ml h, 0.45 l/kg and 0.10 l/h kg, respectively. The AUC_inf, V_z and Cl in the birds those died were 207.90 μg/ml h, 0.26 l/kg and 0.02 l/h kg, respectively. Based on the increase in the AUC_inf and C_max in the birds that died, we surmise that toxicity resulted from saturation of the metabolic process. While the exact metabolic pathway remains unknown in these vultures, we believe that toxicity may be due to pharmacogenomic differences in the cytochrome P450 pathway.     

Immunological and physiological effects of chronic exposure of Peromyscus leucopus to Aroclor 1254 at a concentration similar to that found at contaminated sites

Polychlorinated biphenyls (PCBs) are environmental contaminants known to cause adverse health effects to biological systems. Limited data are available on their effects on the immune system of wildlife species. Previously, we found that 4 and 6-week-old white-footed mice (Peromyscus leucopus) born from dams injected with a single dose (300 mg/kg) of Aroclor 1254, had altered immunological, hematological, and biochemical responses. Here, we examined the effect of transplacental, lactational and postnatal exposure to Aroclor 1254, at a concentration similar to that found at contaminated sites, on various physiological parameters of 22-week-old white-footed mice. Liver weight and liver somatic index of PCB treated animals were significantly higher, the combined weights of the adrenal glands were significantly lower and EROD and BROD enzyme activity was significantly higher compared to control values. The number of thymocytes of the treated mice was significantly lower than that of the controls; however, thymocytes of treated mice had a higher proliferative response to the mitogen Con A. These alterations were correlated with the PCBs body burdens. Some toxic effects of chronic exposure to PCBs, at levels comparable to exposure found in contaminated sites in the USA, are still evident in adult P. leucopus.     

The effects of adrenoceptor agonists and antagonists on plasma potassium concentration in anaesthetized guinea-pigs, rabbits and rats.

An intravenous K+-sensitive electrode has been used to monitor plasma [K+] changes induced by alpha- and beta-adrenoceptor agonists in anaesthetized guinea-pigs, rabbits and rats. The effects of phentolamine and propranolol on these responses were studied. In the guinea-pig both alpha- and beta-adrenoceptor agonists produced a biphasic response consisting of an initial rapid increase in [K+] which was followed, within 1 min, by a fall below baseline. The antagonist studies indicated that in this species both phases of the response could be elicited by either alpha- or beta-adrenoceptor activation. In the rabbit the responses were both slower and smaller than those seen in the guinea-pig and required larger agonist doses. In addition it was found that the increase in plasma [K+] was alpha-adrenoceptor-mediated while the subsequent fall was seen only with beta-adrenoceptor activation. In the rat triphasic changes in plasma [K+] were seen consisting of an initial decrease which was alpha-adrenoceptor-mediated, followed by an increase and then a second fall which was elicited by beta-adrenoceptor stimulation. The increase in plasma [K+] was only slightly reduced by either alpha- or beta-adrenoceptor antagonists. Apamin, a toxin from bee venom which blocks Ca2+-activated K+-channels, was found to block the hyperkalaemic phase of the response in the guinea-pig and rabbit but had no effect in the rat. It is concluded that there are marked species differences in the effects of adrenoceptor agonists on plasma [K+] in vivo.