1、WORD格式A Good Practice Guide to the Administration of Substances and Removal of Blood,Including Routes andVolumes專業(yè)資料整理WORD格式良好的實(shí)驗(yàn)動(dòng)物給藥和采血(包括途徑和體積)標(biāo)準(zhǔn)指南專業(yè)資料整理WORD格式12345專業(yè)資料整理WORD格式Karl-Heinz Diehl, Robin Hull, David Morton, Rudolf Pfister , Yvon Rabemampianina ,專業(yè)資料整理WORD格式678David Smith ,*, Jean-Marc

2、 Vidaland Cor van de Vorstenbosch1Aventis, PO Box 1140, D35001 Marburg, Germany德國(guó)馬爾堡市35001 區(qū) 1140 信箱安萬特公司2N I B S C, Blanch Lane, South Miimms, Potters Bar, Hertfordshire EN6 3QG英國(guó)赫特福德郡EN6 3QG 波特斯巴鎮(zhèn)South Miimms 布蘭奇道英國(guó)國(guó)家生物制品檢定所3英國(guó)伯明翰市B15 2TT 艾吉馬斯頓伯明翰大學(xué)醫(yī)學(xué)院4Novartis Pharma AG, CH-4002 Basel, Switzerlan

3、d瑞士巴塞爾CH-4002 諾華制藥公司5Centre de Recherche Pfizer, Etablissement dAmboise, Z1 Poce -sur-Cisse-BP 159 37401 Amboise Cedex, France法國(guó) Amboise Cedex Z1 Poce -sur-Cisse-BP 159 37401 Etablissement dAmboise 輝瑞研究中心6英國(guó)萊斯特郡LE11 5RH 拉夫堡市貝克韋爾路Charnwood 阿斯利康研究中心7Aventis, 102 Route de Noisy, 95235 Romainville Ce de

4、x, France 法國(guó) Romainville Ce dex 95235 Noisy 路 102 號(hào)安萬特公司8N V Organon, PO Box 20, 5340 BH Oss, Netherlands荷蘭 BH Oss5340 20 號(hào)信箱歐加農(nóng)公司Key words: blood volumes; blood removal; administration substances; laboratory animals; refinement.關(guān)鍵詞：血容量；采血；給藥；實(shí)驗(yàn)動(dòng)物；簡(jiǎn)化This article is the result of an initiative betwee

5、n the European Federation of Pharmaceutical Industries Associations (EFPIA) and the European Centre for the Validation of Alternative Methods (ECV AM).Its objectives are to provide the researcher in the safety evaluation laboratory with an up-to-date, easyto-use set of data sheets to aid in the stud

6、y design process whilst at the same time affording maximum welfare considerations to the experimental animals.該文章為歐盟制藥工業(yè)協(xié)會(huì)(EFPIA) 和歐洲替代動(dòng)物實(shí)驗(yàn)方法驗(yàn)證中心(ECVAM) 之間的初步結(jié)果。 其目的在于為平安性評(píng)價(jià)實(shí)驗(yàn)室的研究者提供最新的易于使用的數(shù)據(jù)庫(kù)以幫助研究設(shè)計(jì)過程，同時(shí)最大可能地考慮到實(shí)驗(yàn)動(dòng)物的福利。Although this article is targeted at researchers in the European Pharmaceutical

7、 Industry, it is considered that the principles underpinning the data sets and refinement proposals are equally applicable to all those who use these techniques on animals in their research, whether in research institutes,universities or other sectors of industry. The implications of this article ma

8、y lead to discussion with regulators, such as those responsible for pharmacopoeial專業(yè)資料整理WORD格式testing.盡管該文章針對(duì)的是歐洲制藥工業(yè)界的研究者，但支撐該數(shù)據(jù)庫(kù)的根本原理及改進(jìn)建議同樣適用于所有在他們的研究中使用這些動(dòng)物實(shí)驗(yàn)技術(shù)的人，不管是研究所、大學(xué)或其它行業(yè)中的研究者。There are numerous publications dealing with the administrationof test substances and the removal of bloodsamples

9、, and many laboratories also have their own ,in -house guidelines that have been developed by custom and practice over many years. Within European Union Directive 86/609EEC1 we have an obligation to refineexperiments to cause the minimum amount of stress. We hope that this article will provide backg

10、round data useful to those responsible for protocol design and review.有關(guān)供試品給予和采血的出版物眾多，且許多實(shí)驗(yàn)室在多年的經(jīng)歷和實(shí)踐根底之上亦開展了它們自己的內(nèi)部指南。在歐盟化裝品標(biāo)準(zhǔn)86/609EEC 中，我們有義務(wù)簡(jiǎn)化實(shí)驗(yàn)以最小化動(dòng)物的緊X程度。我們希望該文能夠?qū)δ切┴?fù)責(zé)方案設(shè)計(jì)和審核的研究者提供有用的背景數(shù)據(jù)。This guide is based on peer-reviewed publications whenever possible, but where this is not possible we ha

11、ve used ,in-house data and the experience of those on the working party (as well as helpful comments submitted by the industry) for a final opinion. The guide also addresses the continuing need to refine the techniques associated with the administration of substances and the withdrawal of blood, and

12、 suggests ways of doing so. Data-sharing between laboratories should be encouraged to avoid duplication of animal work, as well as sharing practical skills concerning animal welfare and scientific problems caused by ,overdosing in some way or another. The recommendations in this guide refer to the ,

13、normal animal, and special consideration is needed, for instance, during pregnancy and lactation.Interpretation of studies may be confounded when large volumes are administered or excessive sampling employed, particularly if anaesthetics are used. Copyright 2001 John Wiley & Sons, Ltd.該文章基于歷年所有可能收集到

14、的同行評(píng)議出版物，但我們未能夠收集到的內(nèi)部數(shù)據(jù)和那些工作組的經(jīng)專業(yè)資料整理WORD格式驗(yàn) (以及行業(yè)提交的有用的注釋)除外。該指南亦強(qiáng)調(diào)了持續(xù)性簡(jiǎn)化與給藥和采血有關(guān)的技術(shù)的必要性，并且建專業(yè)資料整理WORD格式議該如何去進(jìn)展這方面的工作。應(yīng)該鼓勵(lì)實(shí)驗(yàn)室間的數(shù)據(jù)共享以防止重復(fù)性動(dòng)物研究，以及共享在某些方法專業(yè)資料整理WORD格式或其它情況下的“藥物過量 所引起的與動(dòng)物福利有關(guān)的實(shí)際技術(shù)和科學(xué)問題。有必要對(duì)該指南中涉及到的“正專業(yè)資料整理WORD格式常動(dòng)物 要求進(jìn)展特殊考慮，如妊娠和哺乳期間的動(dòng)物。當(dāng)給藥體積較大或過度采樣時(shí)對(duì)研究結(jié)果的詮釋可能會(huì)令人感到困惑，特別是使用麻醉動(dòng)物時(shí)。GOOD PRA

15、CTICE GUIDE FOR ADMINISTRATION OF SUBSTANCES 良好的給藥標(biāo)準(zhǔn)指南Introduction引言Dosing of experimental animals is necessary for a variety of scientific investigations and to meet regulatory demands. The pharmaceutical industry, in particular,has investigated the levels of dosing compatible with animal welfare a

16、nd valid science.2 In the preclinical stage of the safety evaluation of new drugs it is normal practice to use multiples of the ,effective dosein order to attempt to establish the necessary safety m argins. Where chemicals are of low toxicity or are only poorly soluble in acceptable formulations, a

17、large volume may be required to be given to專業(yè)資料整理WORD格式individual animals to satisfy both scientific and regulatory requirements.The intended clinical use may also have an impact on the acceptability of larger than usual dose volumes, e.g. imaging agents or plasma expanders for intravenous applicati

18、on.各種科學(xué)研究都需要對(duì)實(shí)驗(yàn)動(dòng)物給藥以符合藥品注冊(cè)要求。特別是在制藥工業(yè)領(lǐng)域已研究了與動(dòng)物福利以及科學(xué)性相一致的給藥水平。在新藥的臨床前平安性評(píng)價(jià)階段使用多種“有效劑量 以盡量確定必要的平安性X圍是一種常規(guī)慣例。在使用低毒或溶解性極差的化學(xué)藥品以一種可承受的制劑形式進(jìn)展研究時(shí)，動(dòng)物的個(gè)體給藥體積可能較大以滿足科學(xué)性和注冊(cè)的要求。擬用臨床劑量可能會(huì)使得給藥體積較大，超過了動(dòng)物可承受的正常給藥體積，如靜脈內(nèi)注射用的造影劑或血漿增容藥物。The objectives of the Technical Sub group of EFPIA/ECVAM were as follows:(i) to p

19、rovide a guide on administration volumes for use in common laboratory species used in toxicity studies required by regulatory authorities;(ii) to provide consensus dosage levels for routine use that represent good practice in terms of animal welfare and practicality;(iii) to produce a guide to dosag

20、e levels representing the upper limit of common practice, which leaves scope to make the case for special investigations.EFPIA/ECVAM 技術(shù)小組的目標(biāo)如下：(i) 提供一個(gè)藥品注冊(cè)當(dāng)局所要求的毒性研究中常規(guī)使用的實(shí)驗(yàn)動(dòng)物的給藥體積的指南；(ii) 根據(jù)動(dòng)物福利和實(shí)用性提供一個(gè)在良好標(biāo)準(zhǔn)條件下常規(guī)使用的一致性劑量水平；(iii) 提供一個(gè)代表常規(guī)標(biāo)準(zhǔn)上限的劑量水平，以為特殊研究留下一定的劑量擴(kuò)展余地。Administration volumes給藥體積Table 1

21、presents administration volumes for the commonly employed routes in the most frequently used species. They are consensus figures based on published literature and internal guidelines. The marmoset and minipig are now considered within this category because they are being used increasingly in Europe.

22、表 1 表示最常使用的種屬的一般給藥途徑下的給藥體積。它們是根據(jù)發(fā)表的文獻(xiàn)和內(nèi)部指南綜合得到的結(jié)果?，F(xiàn)在認(rèn)為絨猴和小型豬在此類常用動(dòng)物之列，因?yàn)樗鼈冊(cè)跉W洲的使用日漸增加。Two sets of values are shown in each column:values on the left are intended as a guide to ,good practice dose volumes for single or multiple dosing;values on the right, where given, are the possible maximal values.

23、If maximal values are exceeded, animal welfare or scientific implications may result and reference to the responsible veterinary surgeon should be made. In some instances values are there to accommodate pharmacopoeial requirements.每一列顯示了兩組數(shù)據(jù)，左側(cè)數(shù)據(jù)擬用來指導(dǎo)在單次或?qū)掖谓o藥的“良好標(biāo)準(zhǔn)中的給藥體積；所給出的右側(cè)數(shù)據(jù)為可能的最大給藥值。如果超過了最大值就會(huì)

24、涉及到動(dòng)物福利或科學(xué)性，應(yīng)當(dāng)參考負(fù)責(zé)獸醫(yī)的外科醫(yī)生的意見。在某些實(shí)際運(yùn)用中，這些數(shù)據(jù)應(yīng)符合藥典要求。Some of these suggested maximum values have been obtained from recent literature,3,4 but appear high when compared with ,good practice values. The need for careful attention to animal welfare and the formulation of專業(yè)資料整理WORD格式material used at high do

25、se volumes are emphasized,particularly if repeat dosing is intended. Study duration could be restricted and scientific validity compromised by physiological reaction to high dose volumes. It is therefore essential from an ethical standpoint that these issues are fully considered, e.g. by inspectorat

26、e or ethical committee, before protocols are finalized and work commences. It is also strongly recommended for ethical as well as scientific reasons that physicochemical compatibility studies ( in vitro ) and smallscale pilot studies (small groups of animals) are carried out on any new formulation b

27、efore committing to larger scale studies. Dose volumes should be the minimum compatible with compound formulation and accuracy of administration.從近來發(fā)表的文獻(xiàn)中已經(jīng)得到了這些建議的最大值中的某些數(shù)據(jù)，但當(dāng)與“良好標(biāo)準(zhǔn)數(shù)據(jù)相比時(shí)顯得較高。強(qiáng)調(diào)了較高給藥體積時(shí)對(duì)動(dòng)物福利和使用的原料制劑進(jìn)展仔細(xì)關(guān)注的必要性，特別是擬進(jìn)展重復(fù)給藥時(shí)。研究的持續(xù)時(shí)間和科學(xué)有效性應(yīng)該讓步于由于給藥體積過高所出現(xiàn)的生理反響。因此在方案定稿以及著手研究之前通過比方監(jiān)察員或倫理委員

28、會(huì)充分地考慮到了這些出版物中的倫理觀要素。亦就倫理及科學(xué)依據(jù)強(qiáng)烈要求對(duì)任何新劑型進(jìn)展物理化學(xué)相容性研究(體外 )和小型的先導(dǎo)性研究( 少量動(dòng)物組 ) 以免在大型研究中出現(xiàn)失誤。給藥體積應(yīng)該最大限度地與化合物劑型和給藥準(zhǔn)確性相一致。Administrative routes給藥途徑Oral route.On occasions, it may be necessary to restrict the animals food intake before dosing. This factormay affect absorption. Large dose volumes (40 ml kg 1

29、) have been shown to overload the stomach capacity and pass immediately into the small bowel.5Larger volumes may also reflux into the oesophagus.The duration of fasting will depend upon the feeding pattern of the species, the starting time for food restriction,the physiology of the species, the leng

30、th of time of dosing, diet and the light cycle.6 It is recommended that for accuracy of dosing and to avoid dosing accidents liquids are administered by gavage.經(jīng)口給藥途徑：某些情況下在給藥前有必要限制動(dòng)物的攝食。該因素可能會(huì)影響藥物吸收。較大的給藥體積 (40ml/kg) 說明超過了胃容量負(fù)荷并快速通過胃進(jìn)入小腸。較大的給藥體積亦可以造成食管返流。禁食時(shí)間取決于動(dòng)物種屬的飼養(yǎng)方式、禁食的起始時(shí)間、種屬的生理學(xué)特征、給藥時(shí)間的長(zhǎng)短、食物

31、和光照周期。當(dāng)藥液通過灌胃給予時(shí)，要求給藥必須準(zhǔn)確以防止給藥意外。Parenteral routes. For substances administered parenterally,the dose volume used, stability of the formulationbefore and after administration, pH, viscosity,osmolality, buffering capacity, sterility and biocompatibility of the formulation are factors to consider. Thi

32、s is particularly important for multiple dose studies. These factors are reviewed in some detail by Claassen.7 The smallest needle size should be used, taking into account the dose volume, viscosity of injection material, speed of injection and species.胃腸外給藥途徑：對(duì)于經(jīng)胃腸外給予的藥物而言，應(yīng)考慮所采用的制劑的給藥體積、給藥前和給藥后制劑的

33、穩(wěn)定性、 pH 、粘度、等滲性、 緩沖能力、 無菌及生物相容性因素。這對(duì)于屢次給藥研究尤其重要。Claassen總結(jié)了這些因素中的某些細(xì)節(jié)。應(yīng)使用最小型號(hào)的針頭、考慮給藥體積、注射物粘度、注射速度和動(dòng)物種屬。Subcutaneous.This route is frequently used. The rate and extent of absorption depend on the formulation.皮下給藥： 該途徑經(jīng)常使用。吸收的速度和程度取決于制劑。專業(yè)資料整理WORD格式Intraperitoneal. This route is used infrequently for

34、 multiple dose studies because of possiblecomplications.There is a possibility of injecting into the intestinal tract and irritant materials may cause peritonitis.Drug absorption from the peritoneal cavity after the administration of the compound as a suspension is dependent on the properties of the

35、 drug particles and the vehicle, and the drug may be absorbed into both systemic and portal circulations.腹腔內(nèi)給藥：屢次給藥研究時(shí)較少用到該途徑，因?yàn)榭赡軙?huì)出現(xiàn)并發(fā)癥。該途徑存在著注射入腸道的可能，而且刺激性物質(zhì)可能引起腹膜炎?；衔镆曰鞈乙盒问浇o予后在腹腔的吸收取決于藥物粒子及賦型劑的特征，藥物可能被吸收進(jìn)展全身或局部循環(huán)。Intramuscular. Intramuscular injections may be painful because muscle fibres are ne

36、cessarily placed undertension by the injected material. Sites need to be chosen to minimize the possibility of nerve damage.Sites should be rotated for multiple dose studies. A distinction needs to be made between aqueous and oily formulations when speedof absorption is important (oily formulations

37、are likely to remain as a depot for. 24 h). With multiple dose studies there is a need to consider the occurrence of inflammation and its sequelae.肌肉內(nèi)注射：肌肉內(nèi)注射可能會(huì)引起疼痛，因?yàn)樽⑸鋾r(shí)必須使肌纖維處于緊X狀態(tài)。必須對(duì)注射部位進(jìn)行選擇以盡量減少神經(jīng)損傷的可能性。屢次給藥研究不應(yīng)在同一個(gè)部位反復(fù)注射。當(dāng)吸收速度很重要時(shí)，必須在水性和油性制劑之間加以選擇(油性制劑在注射部位的殘留很可能超過24小時(shí)。 ) 。進(jìn)展多劑量研究時(shí)，有必要考慮到出現(xiàn)炎癥

38、及其后遺癥。Intravenous administration. For this route, distinctions are made between bolus injection, slow intravenousinjection and intravenous infusion. The values in Table 1 relate to bolus injection and slow intravenous injection.靜脈內(nèi)給藥： 對(duì)于該途徑，必須區(qū)分團(tuán)注、緩慢靜脈內(nèi)注射和靜脈內(nèi)輸液。表1中的數(shù)據(jù)與團(tuán)注和緩慢靜脈內(nèi)注射有關(guān)。(i) Bolus injectio

39、n. In most studies using the intravenous route the test substance is given over a short period of approximately 1 min. Such relatively rapid injections require the test substance to be compatible with blood and not too viscous.When large volumes are required to be given,the injection material should

40、 be warmed to body temperature. The rate of injection is an important factor in intravenous administration and it is suggested that, forrodents, the rate should not exceed 3 ml min-1. No detectable changes in haematocrit or heart rate were observed indogs following rapid intravenous injection of 6ml

41、 kg-1 saline,but 20ml kg -1 was associated with 15% haemodilutionand a transient tachycardia (up 46% over 1 min). 8(i) 團(tuán)注：在大多數(shù)采用靜脈內(nèi)給藥途徑的研究中，受試物在大約1 min 內(nèi)快速給予。如此相對(duì)迅速的注射要求受試物與血液之間具有相容性且粘度不能太高。當(dāng)需要給予較大的體積時(shí)，注射原料必須加熱至與體溫一樣。在靜脈內(nèi)給藥中注射速度是一個(gè)重要因素，建議對(duì)于嚙齒類動(dòng)物而言，注射速度不應(yīng)超過3ml/min 。犬經(jīng)靜脈內(nèi)快速注射 6ml /kg 生理鹽溶液后未發(fā)現(xiàn)紅細(xì)胞壓積或心率

42、變化，但快速注射 20ml /kg后血液被稀釋了 15%且出現(xiàn)一過性心動(dòng)過速 (一分鐘內(nèi)心率增加達(dá)46%)。(ii)Slow intravenous injection. Because of the expected clinical application of the compound, or because oflimitingfactors such as solubility or irritancy, it may be necessary to consider administering substances by slow專業(yè)資料整理WORD格式intravenous in

43、jection.Typically, different techniques would be applied for slow injection to minimize the possibilityof extravascular injection of material. For slow intravenous injection over the course of 510 min a standard or butterfly needle might be used, or better still an intravenous cannula may be taped i

44、n place in a superficial vein (short專業(yè)資料整理WORD格式term), or surgically placed some time prior to use (longer term or multiple injections).(ii) 緩慢靜脈內(nèi)注射： 因?yàn)榛衔镱A(yù)期的臨床適應(yīng)癥或限制性因素如溶解性或刺激性，因此可能有必要考專業(yè)資料整理WORD格式慮通過緩慢靜脈內(nèi)注射給藥。特別需加以說明的是緩慢靜脈內(nèi)注射會(huì)應(yīng)用不同的技巧以盡可能地防止原料被注射入血管外組織。對(duì)于注射過程為510min 的緩慢靜脈內(nèi)注射而言，可能需要采用標(biāo)準(zhǔn)的或蝶形針，或淺靜脈內(nèi)注射

45、 (適用于短期靜脈內(nèi)注射)時(shí)使用靜脈內(nèi)套管并用膠帶固定更佳，或在使用前通過外科手術(shù)放置注射針(適用于更長(zhǎng)時(shí)間的注射或?qū)掖巫⑸?。It has been shown that rats may be given daily intravenous injections of isotonic saline at dosages up to 80 ml kg-1 at 1 ml min 1 for 4 days without significant signs of distress or pulmonary lesions. 9 However, pulmonary lesions incre

46、ased in incidence and severity when the duration of treatment increased to 30 days and the injection was administered at either 0.25, 0.5 or 1.0 ml min -1 .10 There may well have been adverse effects at an earlier time point but the pathology had not had time to develop.已有證據(jù)說明大鼠每日可以1ml/min 的速度靜脈內(nèi)注射等

47、滲鹽溶液劑量達(dá)80ml/kg ，共 4天，沒有明顯不適病癥或肺部損傷。但是，當(dāng)注射時(shí)間增加至30天時(shí)，給藥速度為0.25、 0.5或 1.0ml/min 的大鼠肺部損傷的發(fā)生率和嚴(yán)重程度均增加。在用藥早期可能出現(xiàn)不良反響，但是在這么短的時(shí)間內(nèi)不會(huì)有病理變化出現(xiàn)。(iii) Continuous infusion. For similar reasons of solubility or clinical indication it may be necessary to consider continuous infusion, but careful consideration is nee

48、ded if infusions are prolonged.The volume and rate of administration will depend on the substance being given and take account of fluid therapy practice. As a guide, the volume administered on a single occasion will be ,10% of the circulating blood volume over 2 h.Information on circulating blood vo

49、lumes is available in Table 3. Minimal effective restraint of animals with least stress is a key factor to consider for prolonged infusions.(iii) 連續(xù)輸液：出于溶解性或臨床適應(yīng)癥這一類似原因，有必要考慮連續(xù)輸液，如果長(zhǎng)時(shí)間輸液那么必須進(jìn)展周詳?shù)目紤]。給藥體積和速度取決于所給物質(zhì)并應(yīng)考慮液體治療標(biāo)準(zhǔn)。作為一個(gè)指南，單次給藥情況下的給藥體積占循環(huán)血容積的 10% 時(shí)，給藥時(shí)間應(yīng)不低于 2小時(shí)。有關(guān)循環(huán)血容積的信息見表 3。長(zhǎng)時(shí)間輸液應(yīng)考慮如何盡量減少動(dòng)物

50、的不適，這是一個(gè)關(guān)鍵因素。The total duration of an infusion is also a factor.Table 2 presents recommended dose rates and volumes for discontinuous (4h per day) and continuous (24h) infusion. (Further data are required to complete this table.)輸液的總持續(xù)時(shí)間亦是一個(gè)應(yīng)該考慮的因素。表 2給出了推薦的連續(xù)性(4小時(shí) /天 )和持續(xù)性 (24小時(shí) )輸液的給藥速度和體積(需要進(jìn)一步的數(shù)

51、據(jù)來完善此表)。Volumes and rates for the rabbit are based on data derived from embryotoxicity studies, which showed no effects on the foetus but perivascular granular leucocyte cuffing and proliferative endocarditis in damsreceiving 2ml kg -1 h-1.11 Infusion rates in rats are typically in the range 1 4 ml

52、kg -1 h-1 ,1214 but ideally should not exceed 2 ml kg -1 h-1 in embryotoxicity studies. Values for the mouse,15 dog and macaque16 and minipig專業(yè)資料整理WORD格式(unpublished data) are based on repeated dose studies of 1 month in duration.家兔的給藥體積和速度基于來源于胚胎毒性研究的數(shù)據(jù)，該研究說明對(duì)胎兒沒有影響，但當(dāng)給藥劑量2專業(yè)資料整理WORD格式ml/kg/h 時(shí)，母體出

53、現(xiàn)血管周粒細(xì)胞成袖口狀聚集以及增殖性心內(nèi)膜炎。大鼠的典型輸液速度在14 ml/kg/ h ，專業(yè)資料整理WORD格式但在胚胎毒性研究中的理想速度應(yīng)不超過2ml/kg/h 。對(duì)于小鼠、犬和恒河猴以及小型豬(未公開數(shù)據(jù))的數(shù)據(jù)基專業(yè)資料整理WORD格式于為期 1個(gè)月的重復(fù)給藥研究。專業(yè)資料整理WORD格式Other limits, indicating the importance of the vehicle formulation at high dose volumes, are highlighted in four publications. 1720 These data indica

54、te that there are large differences in tolerated volume by i.v. infusion, dependent upon the vehicle used. The long-term effects on other physiological systems have not been investigated.在四篇出版物中突出了其它表示高給藥體積時(shí)的賦型劑劑型的重要性的有限數(shù)據(jù)。這些數(shù)據(jù)說明對(duì)于靜脈內(nèi)輸液的可耐受體積方面存在著巨大差異，取決于所使用的賦型劑。尚未研究對(duì)其它生理系統(tǒng)的長(zhǎng)期影響。Intradermal. This si

55、te is typically used for assessment of immune, inflammatory or sensitization21,22response. Material may be formulated with an adjuvant. Volumes of 0.05 0.1 ml can be used, dependent upon the thickness of the skin.皮內(nèi)給藥： 該部位給藥主要用于評(píng)估免疫、炎癥或過敏反響。原料可以用佐劑配制。給藥體積為0.050.1ml，取決于皮膚厚度。Vehicles for administratio

56、n用于給藥的賦型劑Vehicle selection is an important consideration in all animal investigations. Vehicles themselves should offer optimal exposure but should not influence the results obtained for the compound under investigation, and as such they should ideally be biologically inert, have no effect on the biophysical properties of the compound and have no toxic effects on the animals. If a component of the vehicle has biological effects, the dose should be limited such that these effects are minimized or not produced. Simple vehicles used to adm