Antibacterial Agents in Mediterranean Finfish Farming: A Synopsis of Drug Pharmacokinetics in Important Euryhaline Fish Species and Possible Environmental Implications

The literature pertaining to the use of registered antibacterial agents in Mediterranean finfish farming is reviewed, with an emphasis on the Greek fish-farming industry. This review provides a scientific resource dedicated to the design of future antibacterial dosing regimes in Mediterranean fish farming, where insufficient supporting information is currently available. This paper addresses the paucity in knowledge concerning pharmacokinetics and the efficacy and environmental impact of commonly used antibacterials needed to direct future research and promote good practices in the euryhaline fish farming industry. Several registered antibacterials are currently available for combating bacterial infections, including tetracyclines, (fluoro) quinolones, potentiated sulfa, penicillin and chloramphenicol derivatives. Based on the available data, oxytetracycline (OTC) and quinolone drugs (oxolinic acid – OA and flumequine – FLU) are the most widely used in Mediterranean aquaculture. As a result these drugs have received the most extensive studies, whereas, there is considerable paucity of reliable data on pharmacokinetic and the depletion characteristics of other drugs used, particularly potentiated sulfa, penicillin derivatives and florfenicol. We find there is incomplete data on drug efficacy and minimum inhibitory concentrations (MIC) for common antibacterials used against the major bacterial pathogens of Mediterranean fish species. Furthermore, a considerable lack of data on environmental drug concentrations around Mediterranean fish farms was also identified, highlighting the need for more extensive environmental studies to monitor contamination in environmental components i.e., water and sediment, and in non-target species (flora and fauna). Prudent selection and use of antibacterials can encourage lower dosage applications, enhance treatment efficacy, and help to minimize contamination of the environment. Selection of readily bioavailable drugs which have low environmental persistence, low aquatic toxicity and high antibacterial efficacy is advised, to reduce potential losses to the environment and associated toxic effects on target species and the development of bacterial resistance. Lack of present data made it impossible to provide thorough and accurate guidance on selection and use of antibacterials and approaches for minimizing environmental impacts for the treatment of major euryhaline aquaculture species.     

Pharmacokinetics of chlorogenic acid and rutin in larvae of Heliothis zea

Studies using [³H]chlorogenic acid and [³H]rutin demonstrated that the kinetics of uptake of these plant phenolics into the haemolymph of 5th-instar Heliothis zea (Boddie) following actue oral administration is a first-order process. The total quantity of either phenolic present in the haemolymph within 1 hr amounts to 5% or less of the total ingested dose. Based on TLC analyses, 80% or more of the radioactivity in the haemolymph occurs as the parent phenolic. Retention of [³H]-chlorogenic acid or [³H]-rutin in H. zea following chronic feeding from 1st to 3rd-instar larvae is also linearly related to dietary dose. Chlorogenic acid and rutin are both equitoxic and equivalent in bioavailability to H. zea.Loss of [³H]-rutin from the haemolymph of 5th-instar larvae following injection is biphasic. One half of the injected dose is excreted in the frass in the first 6 hr after injection; the other half is thereafter eliminated at 1/20th of the initial rate. Analyses of extracts of frass by thin-layer chromatography indicate that after either chronic or acute feeding 90% of the ingested phenolic is excreted unchanged. Possible sites and modes of action of phenolics in insects are discussed in light of these findings.     

Chronotoxicity of Sodium Valproate and Its Mechanisms in Mice: Dose-Concentration-Response Relationship

A significant circadian rhythm of acute toxicity was demonstrated in mice with intraperitoneal (i.p.) injection of sodium valproate (VPA). The role of pharmacokinetics on the rhythms of the toxicity and electroshock seizure (ES) threshold was investigated. ICR male mice, housed under a light-dark (12 :12) cycle, were injected intraperitoneally 1200 mg/kg for the acute toxicity study and 300 mg/kg for the anticonvulsant effect study. In the acute toxicity, the highest mortality was found when VPA was injected at 1700 and the lowest at 0900 or 0100. The time course of mean plasma and brain VPA concentrations after an injection of VPA was not different between mice injected at 1700 and mice injected at 0100. In the anticonvulsant effect, no significant circadian rhythm was demonstrated for both the ES threshold and the plasma VPA concentrations after i.p. Injection, although a significant rhythm has been reported for them after oral administration. The results suggest that the circadian rhythm in the mortality after an i.p. Injection of VPA may be due to the rhythm in the sensitivity of the central nervous system to the drug and that the mechanism underlying the rhythm of VPA acute toxicity is different from that of the anticonvulsant action of VPA. The route and the time of drug administration are essentially important to study the anticonvulsant effect and acute toxicity of VPA in mice.     

Chiral pharmacokinetics of rac-flurbiprofen and pharmacodynamics of anabolic bone response in the normal rat

The route of administration of the NSAID, flurbiprofen (sq vs. po) resulted in positive and negative results respectively with regard to enhanced cancellous and cortical bone accumulation in the immature rat. This pharmacokinetic study was an effort to understand the pharmacodynamic difference between the two routes of administration observed when the same dose range of drug, given as single daily doses, had been employed in both studies. Conventional chiral pharmacokinetics were evaluated in young rats. A significant difference was observed in the T_max of the active (S)-enantiomer by both administration routes (sq 4 h and po 1 h). The bioavailability, as evaluated by AUCs favored the sq route as expected. The plasma concentrations over 18 h, at steady state, for one po dose group (0.5 mg/kg/day) fell well within the therapeutic window described by the 0.1 and 0.5 mg/kg sq doses which had demonstrated anabolic bone activity. Oral dosing had exhibited no significant bone activity. We conclude that the pharmacodynamic difference between routes of administration cannot be simply explained on a pahrmacokinetic basis. Consequently, experiments detailing the pharmacodynamics and pharmacokinetics of single and multiple dose administration of aryl-propionic acids in normal and osteopenic states need further pharmacologic study. © 1994 Wiley-Liss, Inc.     

Disposition kinetics of ML-1035 sulfoxide enantiomers and the prochiral sulfide in rats

ML-1035, 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl]benzamide, is a sulfoxide compound and a racemic gastroprokinetic agent with a chiral center at the sulfur atom. We have investigated the disposition kinetics of (R)-ML-1035 sulfoxide (R) and (S)-ML-1035 sulfoxide (S) after the single enantiomers and the racemic mixture were administered to rats in separate experiments. There was no noticeable chiral inversion after either enantiomer dose. Both enantiomers were rapidly absorbed. After dosing with enantiomers or with the racemate, the resulting plasma concentration-time curve of R was closely parallel to that of S in both intravenous and oral experiments, suggesting that the two enantiomers have approximately the same disposition kinetics. After intravenous enantiomer doses, only S underwent conversion to sulfide, suggesting that sulfidation in the liver is enantioselective. However, the enantioselective sulfidation after intravenous dosing did not introduce a difference in the global plasma disposition profiles between R and S, since the reduction reaction is a minor metabolic process. Other metabolic reactions such as sulfonation and mono-N-desethylations were not enantioselective. After oral administration, conversion to sulfide was observed for both enantioners, implicating the existence of a nonhepatic pathway in sulfidation. Administration of a prochiral sulfide dose was associated with an enantioselective sulfoxidation, in which the R/S concentration ratios increased as a function of time. In addition, enantiomeric interaction causing changes in pharmacokinetic parameters was observed after the oral racemate dose, while the interaction is negligible after an intravenous racemate dose, indicating a route dependency in enantiomeric interaction. © 1993 Wiley-Liss, Inc.     

Tissue distribution of bupivacaine enantiomers in sheep

rac-Bupivacaine HCl was infused intravenously to constant arterial blood drug concentrations in sheep using a regimen of 4 mg/min for 15 min followed by 1 mg/min to 24 h. At 24 h, arterial blood was sampled, the animal was killed with a bolus of KCl solution, then rapidly dissected and samples were obtained from heart, brain, lung, kidney, liver, muscle, fat, gut, and rumen. Tissue:blood distribution coefficients for (+)-(R)-bupivacaine exceeded those of (?)-(S)-bupivacaine (P < 0.05) for heart, brain, lung, fat, gut, and rumen by an overall mean of 43%. Blood:plasma distribution coefficients of (?)-(S)-bupivacaine exceeded those of (+)-(R)-bupivacaine by a mean of 29% and this offset the tissue:blood distribution coefficients so that the previously significant enantioselective differences disappeared. It is concluded that although enantioselectivity of bupivacame distribution is shown by the measured tissue:blood distribution coefficients, it is not shown when tissue:plasma water distribution coefficients are calculated, suggesting that there is no intrinsic difference between the bupivacaine enantiomers in tissue affinity. Sheep given fatal intravenous bolus doses of rac-bupivacaine had significantly greater concentrations of (+)-(R)-bupivacaine than (?)-(S)-bupivacaine in brain (P = 0.028) and ventricle (P = 0.036); these could augment the greater myocardial toxicity of this enantiomer found in vitro. © 1993 Wiley-Liss, Inc.     

绿原酸的药理学研究进展

绿原酸(chlorogenic acid,CGA)存在于多种植物之中,具有广泛的药理作用。近年来,对绿原酸的研究发展较快,目前研究表明绿原酸口服吸收率低,在血浆中主要以代谢产物的形式存在,主要经过肾脏排泄,具有抗氧化、抗肿瘤、抗菌、抗病毒、免疫调节、降糖等多种作用。对CGA的深入研究,将为我们科学制药与合理用药提供重要的理论依据。     

定量检测 IL-2-HSA 融合蛋白双抗体夹心 ELISA 法的建立

目的:通过抗体配对方法,建立能高特异、高灵敏地定量检测食蟹猴体内 IL-2-HSA 融合蛋白浓度的双抗体夹心 ELISA 法.方法:以 IL-2单克隆抗体为包被抗体、IL-2-HSA 融合蛋白为夹心抗、生物素标记的 HSA 为检测抗体,一抗和二抗的工作浓度分别为8μg/mL 和1∶5000,HRP 标记的亲和素为1∶200.结果:IL-2-HSA 融合蛋白标准品的曲线范围为3.9~250 ng/mL,最低检测限为3.9 ng/mL,与 IL-2、HSA、GLP-1/HSA 和 CD20单抗均无交叉反应,方法的回收率为98.9%~101.5%,批内和批间准确度分别为96.1%~98.3%和93.9%~105.4%.结论:本方法符合新生物制品临床前药代动力学研究指导则的要求,可用 IL-2-HSA 融合蛋白在临床前药代动力学试验的定量检测.