CN1622821A - 剌激水生生物生长及抗病性的方法 - Google Patents
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Abstract
本发明涉及用于增加商品鱼和甲壳动物生长速度的化学合成方法。本发明的目的是提供GHRP－6以直接或间接诱导生长激素等的释放，使鱼类血液中循环生长激素水平增加。所述肽是稳定的，可溶的及是生物学活性的。所述肽能刺激鱼类和甲壳动物生长，改良幼体质量，及增加抗病原体抗性、干重、肌肉中的蛋白质浓度及RNA。
Description
发明背景
本发明涉及增加商品鱼类和甲壳动物的生长速度的化学合成方法。已经报道了Leu和Met脑啡肽的肽类似物的合成，并示出它们在动物体内刺激生长激素(GH)释放(Bowers C，Momany，G，ReynoldsG和A.Hong.1984，On the in vitro and in vivo activity of a new synthetichexapeptide that acts on the Pituitary to specifically release growthhormone.Endocrinology 114：1537-45)。
对GH释放肽(GHRP)结构-活性关系的研究导致鉴别了GHRP-6(His-D-Trp-Ala-Trp-D-Phe-Lys-NH2)，已经证明其在动物包括人体中是一种非常强力及安全的GH促分泌素(GHS)，但目前还没有在水生生物中使用这种化合物的报道。
考虑到没有刺激甲壳动物生长的信号级联迹象(下丘脑—脑垂体—靶器官)，我们证实了一种新的事实，即单独的肽GHRP-6在甲壳动物中就能发挥与在哺乳动物中相似的一种生物学功能。
淡水鱼是水生业的主要产品，但最近的十年中海藻、软体动物和甲壳动物的培养明显增多。增加对培育的生物体的遗传、繁殖、营养及生理学的了解是改良水生业生产的第一步(Gomez-Chiarri M，SmithGJ，de la Fuente J and Powers DA.1998，Gene transfer in shellfish andalgae.In de la Fuente J and Castro FO，editors.Gene transfer in aquaticorganisms.Austin，Texas：RG Landes Company and Germany：SpringerVerlag；p107-125)。
研究参与商品鱼和甲壳动物物种中生长机制的激素和肽的分子特征对改良水产业是非常重要的。
一个实施例是Silverstein等于1999年使用促性腺激素释放激素(GnRH)及多巴胺受体拮抗剂以调节和诱导鲶鱼(Ictalaruspunctatus)的繁殖(Silverstein JT.Bosworth BG.and Wolters WR.1999，Evaluation of dual injection of LHRHa and the dopamine receptorantagonist pimozide in cage spawning of channel catfish Ictalaruspunctatus.，Journal ofthe World Aquaculture Society，第30卷，No.2，6月，263-268)。这个物种在世界水产业具有极高重要性。
Hashizume等于1997年报道了使用一种合成肽增加农场动物的生产力(Hashizume T.，Sasaki M.，Tauchi S.and Masuda H.，1997，The effect of new growth Hormone-releasing peptide(KP102)on therelease of growth hormone in goats，，Animal Science and Technology，第68卷，No.3，3月，247-256)。他们证实了在山羊中注射一种新的生长激素释放合成肽诱导了生长激素。
胰岛素已经口服施用于鱼类并证明了参与鲤鱼适应不同温度的受体和激素信号产生变化(Vera MI.，Romero F.，Figueroa J.，AmthauerR.，Leon G，Villanueva and Krauskopf M.，1993，Oral administrationof insulin in water-acclimatized carp(Cyprinus carpio)induces hepaticultrastructural changes，Comp.Biochem.Physiol.Vol.106A，No.4,677-682)。
Patchett等于1995年在哺乳动物中测试了生长激素释放肽的合成变体。他们探查了肽MK-0677，其设计为在狗中是GH的强力口服激活剂，而在应用后对酪氨酸和促乳素水平无作用(Patchett AA.，Nargund RP.，Tata JR.，Chen MH.，Barakat KJ，Johnston DBR，ChengK.，Chan WWS，Butler B.，Hickey G.，Jacks T.，Schleim K.，Pong SS.，Chaung LYP.，Chen HY，Frazier E.，Leung KH，Chiu SHL and SmithRG.1995，Proc.Natl.Acad.Sci.USA.，第92卷，7001-7005)。
考虑到循环GH水平增加刺激乳汁产生，已经在牛中开发了生长激素释放激素的其它应用，以增加牛奶产量(Soliman EB.，HashizumeT.，Ohashi S.and Kanematsu S.，1997，Effects of Growth hormone(GH)-releasing hormone and its analogs on GH secretion from culturedadenohypophysial cells in cattle，Domestic animal endocrinology，第14(1)卷，39-46)。
目前没有在鱼类或甲壳动物中使用GHRP-6的报道。本发明报道了在鱼类和甲壳动物中使用GHRP-6而刺激生长，改良幼体质量及增加对病原体的抗性、干重、肌肉中的蛋白质浓度及RNA水平，包括一种改良培育的水生生物体的繁殖力的方法。
目前已有许多关于一些虾物种如Penaeus japonicus和Litopenaeus vanname遗传培育的初步结果，但这些不是足够的，因为没有关于这些生物体的遗传和生物化学知识(Benzie，J.A.H.，1998，Penaeid genetics and biotechnology，Aquaculture 164，23-47；Fjalestadl，K.T.，Carr.W.H.，Lotz.，J.L.，Sweeney，J.N.，1999，Geneticvariation and selection response in body weight and disease resistance inthe Pacific White Shrimp Penaeus Oannamei，Aquaculture 173，10，仅摘要部分)。非常重要的是应用生物技术学，分子生物学，遗传工程和生物化学培育虾类以改良生产力(Bachere，E.，Mialhe，E.，Noel.，D.，Boulo，V.，Morvan，A.，Rodriguez，J.(1995)，Knowledge andresearch prospects in marine mollusk and crustacean immunology，Aquaculture 132，17-32)。
本发明证实了GHRP-6单独即能在鱼类和甲壳动物中刺激生长，改良幼体质量，及增加对病原体的抗性、干重、肌肉中的蛋白质浓度及RNA水平。
发明实质
本发明的实质和新颖性是证实了单独的所述肽GHRP-6即能在鱼类和甲壳动物中刺激生长，改良幼体质量，及增加对病原体的抗性、干重、肌肉中的蛋白质浓度及RNA水平。通过口服，注射或者浸没(immersion)方式施用单独的促分泌素GHRP-6即刺激鱼类和甲壳动物生长。
发明详述
首先，在哺乳动物和鸟类中证实了具有序列His-D-Trp-Ala-Trp-D-Phe-Lys-NH2的六肽GHRP-6(生长激素释放肽)的促进GH释放的生物学活性(Bowers C，Momany，G，Reynolds Gand A.Hong，1984，On the in vitro and in vivo activity of a new synthetichexapeptide that acts on the Pituitary to specifically release growthhormone.Endocrinology 114：1537-45)。
由于硬骨鱼的GH水平每天的变化明显，每条鱼在处理之前和之后取血清样品。结果示出在腹膜内经所述六肽处理之后15分钟的时程内，血清GH水平增加。在硬骨鱼中，如在其它脊椎动物中同样，GH的生长促进作用主要通过诱导IGF而介导。应答腹膜内注射GHRP-6，第30分钟时，肝脏IGF mRNA的水平明显增加，在注射后6小时期间恢复到正常值(实施例1)。
本发明证实了单独的所述肽GHRP-6在鱼类中发挥与在哺乳动物和鸟类中相似的生物学作用，提示该作用机制是相似的。
分析了GHRP-6在体内控制淡水幼罗非鱼(tilapia)机体生长的作用。与对照组相比，使用不同的施用方式用GHRP-6处理明显刺激生长，通过在用三种不同施用方式处理三周后生长速度的增加而确定，所述施用方式是：a)腹膜内注射，b)口服及c)浸没(实施例2)。
在1g罗非鱼幼体中表明通过浸没应用的所述六肽GHRP-6在增加病原体抗性及肌肉质量中有作用(实施例3)。结果示出用GHRP-6处理的罗非鱼组重量及蛋白质浓度增加而病原体侵染的强度和范围及肌肉中水含量降低。这个结果提示所述六肽在蛋白质合成中的阳性作用。
在南美白对虾(Litopenaeus Schmitt)中分析GHRP-6表明通过不同的施用方式单独施用即能改良甲壳动物的生长速度，所述施用方式是a)腹膜内注射，b)口服及c)浸没(实施例4)。
将所述六肽在南美白对虾中分析表明其单独在不同的幼体阶段通过应用4-浸没室应用即能改良生长速度。在幼体培养周期最后阶段幼体的性质通过所述肽得以改良。所述幼体示出重量，大小，腮分支数，喙骨修饰，肌肉中蛋白质浓度和RNA水平明显增加。这显然是代谢活性增加。
幼体性质改良通过成体虾产生增加的生物量及所述动物的重量和大小更一致而得以维持。通过肌内注射，GHRP-6能促进成体虾南美白对虾的生长速度。在注射GHRP-6 15天后，处理组动物示出比对照组增加100％-150％(实施例5)。
在南美白对虾中以在食物中或以包在Artemia salina中的形式口服施用促分泌素GHRP-6，改良了生长速度，与对照组相比增加30％-40％(实施例6)。
附图简述
图1：罗非鱼IGF mRNA水平及用GHRP-6肽注射的幼罗非鱼血清GH水平。每组三只动物经腹膜内注射。在注射后15分钟、30分钟、1小时和6小时取肝脏和血清样品。在处理之前从每个动物取一份血清样品。*明显不同于对照组(p＜0.001 ANOVA，Duncan test)。
图2：在幼罗非鱼中注射GHRP-6三周后对体重和生长速度的作用。将每组7只罗非鱼均腹膜内注射0.1μg肽/gbw，一周两次，对照组接受盐水载体。*明显不同于对照组(p＜0.029，Student’test)。条杆(bar)表示标准误差。三角形表示平均生长速度。
图3：为幼罗非鱼口腔插管服用未包囊化的GHRP-6三周后对体重和生长速度的作用。将每组5只罗非鱼用0.1μg肽/gwb处理，一周两次，对照组接受盐水载体。*明显不同于对照组(p＝0.015，Multiple Range test)。条杆表示标准误差。三角形表示平均生长速度。
图4：为幼罗非鱼口服包囊化的GHRP-6三周后对体重和生长速度的作用。将每组5只罗非鱼用0.1μg肽/gwb处理，对照组接受盐水载体。*明显不同于对照组(p＝0.007，Multiple Range test)。条杆表示标准误差。三角形表示平均生长速度。
图5：GHRP-6在用GHRP-6浸没处理的南美白对虾中的生长促进活性。
A：在用GHRP-6处理的三个组及对照组中重量增加的毫克数。B：用GHRP-6处理的三个组及对照组中大小增加的毫米数。C：用GHRP-6处理的三个组及对照组中腮分支的绝对频数分布(absolutefrequency distribution)。D：用GHRP-6处理的三个组及对照组中喙骨的绝对频数分布。I：组1：0.001mg/L；II：组2：0.01mg/L；III：组3：0.1mg/L和对照组：1mg BSA/L。***p＜0.001。条杆表示标准误差(±DS)。随后通过DUNCAN test的ANOVA用于统计学计算重量和大小的差异。Kolmogorov-Smmimov用于喙骨及腮分支。
图6：用GHRP-6处理的组及对照组的虾的干重。***t-test p＜0.001。条杆表示标准误差。
图7：用GHRP-6处理的组及对照组的虾的RNA，蛋白质和DNA之间的关系。***t-test p＜0.001。条杆表示标准误差。
图8：在GHRP-6浸没处理的生产条件下的南美白对虾幼虾的生长速度。实验进行6周。***t-test p＜0.001。条杆表示标准误差。
实施例
实施例1：证实GHRP-6在鱼类中的生物学活性
将15只平均重量为71±28g的罗非鱼用于该实验。以0.1μg/gbw注射六肽GHRP-6。在处理之前及注射后15分钟、30分钟、1小时及6小时取肝脏和血液样品(每组3只动物)。收集血清和肝脏样品并贮存在-70℃直至用于总RNA分离及Northern印迹分析。在所有动物处理之前均取血清样品。
Northern印迹分析用于测定所述肽注射的罗非鱼中相对的IGFmRNA水平。如Chomczynski和Sacchi所述从肝脏样品中纯化总RNA(Chomczynski P.，Sacchi N.，Single step method of RNA isolation byacid guanidium thiocyanate-phenol-chloroform extraction.Anal Biochem1987，162：156-59)。将20μg RNA在1％甲醛琼脂糖凝胶上分级分离并移至尼龙膜上(Hybond N，Amersham UK)，与罗非鱼IGF-IcDNA探针杂交，随后与人甘油醛-3-磷酸脱氢酶cDNA再杂交(GAPDH，由Dr.Bryan Williams惠赠，Cleveland Foundation，OH，USA)以将信号标准化。用Hewlett Packard Scanjet Plus扫描仪经扫描凝胶的数字图像处理而量化杂交信号。将图像用Bandleader计算机程序处理。结果以RNA任意单位表示。
血清GH水平通过ELISA使用罗非鱼的两个单克隆抗体加以确定(Munoz等，待发表)。
由于硬骨鱼GH水平一天中变化非常明显，因此在处理之前和处理之后针对每条鱼均取血清样品。图1示出在腹膜内经所述六肽处理后15分钟的时程内血清GH水平增加。在硬骨鱼中，与在其它脊椎动物中一样，GH的生长促进作用主要通过诱导IGF而介导。应答腹膜内注射GHRP-6，在30分钟时肝脏IGF mRNA水平明显增加，在注射后6小时期间恢复正常水平(图1)。
实施例2：在幼罗非鱼(Oreochromis sp)中GHRP-6的生长促进活性
2.1腹膜内注射
将Aquadique Aquaculture Station(Havana，Cuba)提供的幼杂种罗非鱼(Oreochromis aureus)在500升容器中驯化，所述容器中具有25℃的再循环淡水，恒定光周期(14小时光照及10小时黑暗)，并喂食商业制备的饲料(CENPALAB，Havana，Cuba)。每日施用二次占体重5％的日常定量饲料直至用于实验。
将GHRP-6(BACHEM，Switzerland)在PBS中稀释，并在三周期间每周注射两次0.1μg/g鱼体重(gbw)。将所述肽施用于一组8条平均体重为61±14.3g的雄性罗非鱼中，并将7条平均体重为61.41±29.67g的雄性罗非鱼注射PBS作为对照。
每周测定体重克数。在所有实验中，将动物均用微芯片标记(Stoelting Co.Wood Dale，美国)。
通过在腹膜内注射0.1μg/gbw处理三周后生长速度的增加确定了腹膜内施用GHRP-6进行处理明显刺激生长(p＜0.05)(图2)。
2.2：口服施用
评价口腔插管服用所述肽(图3)及包囊化的所述肽(图4)的其它肽释放途径，与各自对照组相比在这两种处理中生长速度在统计学上明显增加，在后者情况中，在处理结束时体重存在统计学差异。这两种口腔插管处理之间的对比示出用包囊化肽处理组体重增加较高(p＜0.05)。
将GHRP-6肽在磷酸盐缓冲盐水(PBS)中稀释并通过一个塑料管施用于平均体重为87.22±14.1g的一组7条雄性罗非鱼的咽腔中。平均体重为89.22±7.66g的对照组施用PBS(7条，均为雄性罗非鱼)。在三周期间用0.1μg/gbw一周处理两次。每周测定体重克数(图3)。
为将所述肽包囊化，如Knorr等于1988年所述使用脱乙酰壳多糖和藻酸包囊化的肽获得所述胶囊。所述六肽GHRP-6通过一个塑料管施用于平均体重为89.09±8.38g的7条雄性罗非鱼的咽腔。将无所述肽的聚合物珠施用于平均体重为89.86±13.54的7条雄性罗非鱼作为对照。以0.14μg/gbw每周处理两次(图4)。
实施例3：通过浸没GHRP-6在幼罗非鱼(Oreochromis sp)中的生长促进活性
将平均重量为1.5g的罗非鱼(Oreochromis aureus)通过用两种不同剂量的GHRP-6(10μg/100ml和100μg/100ml)浸没进行处理。相似的对照组用生理盐水溶液处理。
在该实验中，测定体重(表1)，生物化学血液参数(表2)，腮中寄生虫数(Trichodinicos(表3)y Helmintos mongeneos(表4))及肌肉中湿度及蛋白质浓度。
选择平均体重为1g的每组15条动物(3×)进行分析。在9个40升容器中进行该实验。一周应用一次，共45天。
实验组及剂量如下所示：
I组：10μg/100ml(处理1)
II组：100μg/100ml(处理2)
III组：对照组(生理盐水溶液)
表1：在用GHRP-6通过浸没处理的罗非鱼的不同组群中测定的平均重量
| 处理组 | n | 平均重量(g)±DS | 组间对比 | 统计学差异 |
| I组10μg/100ml | 25 | 4.56±1.07 | I-II | 0.01454 |
| II组100μg/100ml | 25 | 4.54±1.38 | II-III | 1.07177* |
| III组盐水溶液 | 25 | 3.47±1.52 | III-I | 1.08632* |
*显著差异，多秩检验(multiple rank test)
表2：在用GHRP-6通过浸没处理的罗非鱼的不同组群中血细胞比容值
| 处理组 | n | 平均重量(g)±SD | 组群间对比 | 统计学差异 |
| I组10μg/100ml | 15 | 27.46±4.53 | I-II | (2.4)* |
| II组100μg/100ml | 15 | 25.06±5.25 | II-III | (1.0)* |
| III组盐水溶液 | 15 | 26.46±4.08 | III-I | (1.4)* |
*无显著差异，多秩检验
表3：在通过GHRP-6浸没处理的罗非鱼中原生动物车轮虫(Trichodina sp)的侵润强度(I)和范围(extension，E)
| 处理组 | n | Ia | E(％)b | 组间对比 | 统计学差异 |
| I组10μg/100ml | 25 | 7.73 | 100 | I-II | (4.42) |
| II组100μg/100ml | 25 | 2.80 | 84.6 | II-III | (5.84)* |
| III组盐水溶液 | 25 | 8.76 | 92.30 | III-I | (1.42) |
Ia：侵润强度
Eb：侵润范围
*显著差异，多秩检验
表4：在通过GHRP-6浸没处理的罗非鱼中每条鱼腮中Helmintosmonogeneos的侵润强度(I)和范围(E)
| 处理组 | n | Ia | E(％)b | 组群间对比 | 统计学差异 |
| I组10μg/100ml | 25 | 0.39 | 34.7 | I-II | (0.304) |
| II组100μg/100ml | 25 | 0.66 | 50 | II-III | (0.521) |
| III组盐水溶液 | 25 | 1.07 | 46 | III-I | (0.826)* |
Ia：侵润强度
Eb：侵润范围
*显著差异，多秩检验
表5：通过GHRP-6浸没处理后罗非鱼肌肉中湿度平均值
| 处理组 | n | 平均湿度±SD(％) | 组间对比 | 统计学差异 |
| I组10μg/100ml | 24 | 82.96±3.63 | I-II | (0.791) |
| II组100μg/100ml | 24 | 83.5±3.31 | II-III | (2.666)* |
| III组盐水溶液 | 24 | 86.42±3.23 | III-I | (3.458) |
*显著差异，多秩检验
表6：通过GHRP-6浸没处理后罗非鱼中蛋白质浓度平均值
| 处理组 | n | 平均湿度±SD(％) | 组间对比 | 统计学差异 |
| I组10μg/100ml | 23 | 6.10 | I-II | (1.160)* |
| II组100μg/100ml | 23 | 4.94 | II-III | (1.38)* |
| III组盐水溶液 | 23 | 3.55 | III-I | (2.64)* |
*显著差异，多秩检验
实施例4：在通过GHRP-6浸没处理的南美白对虾(Litopenaeusschmitti)中GHRP-6的生长促进活性
将三种不同剂量的GHRP-6通过浸没用于虾幼体组中。每三天应用一次。每组应用四次，对照组接受牛血清白蛋白(BSA)。所述处理为如下每1个小时在含有一定浓度的GHRP-6/升海水中进行：
组1：0.001mg/L
组2：0.01mg/L
组3：0.1mg/L
组4：1mgBSA/L
用0.1mg/L GHRP-6处理组改良虾幼体的质量，示出平均重量增加153％，平均大小增加26％，腮分支数和喙骨数均增加。在所有情况中，所述差异均是有统计学意义的(图5)。
全部处理的动物示出肌肉中较低的水含量及RNA/DNA、蛋白质/DNA之间的比值增加提示GHRP-6对幼体肌肉中代谢的激活作用(图6和7)。
这些结果对甲壳动物幼体培育质量非常重要。
在生产条件下，GHRP-6处理组与非处理组相比幼体的存活率增加20％。在同样的分析中，重量增加115％，大小增加37％。另一方面，所述六肽处理组中动物的一致性较高，重量和大小的变化系数较低(图8)。
实施例5：在肌内注射GHRP-6处理的成体南美白对虾中GHRP-6的生长促进活性
在大约15g的成体虾的第二和第三腹部节段之间注射50μlGHRP-6。每三天注射一次，剂量为1μgGHRP-6/g虾重。对照组接受相同浓度的BSA注射。每组15只动物。测定的变量是所述肽处理组重量和大小。在GHRP-6处理组动物中观测到显著差异(p＜0.001)，增加100％-150％。
将所述动物维持在池塘中的网中(0.8cm)。池塘水温为25℃及自然光周期。
实施例6：用包含在食物中的GHRP-6处理的南美白对虾中GHRP-6的生长促进活性
在后幼体南美白对虾的食物中包含1％的GHRP-6。所述肽通过Knorr报道的方法包囊化(Knorr D.和M.Daly(1988)，Mechanics anddiffusional changes observed in multi-layer chitosan/alginate coacervatecapsules.Process Biochemistry，48-50)。对照组喂食含有1％BSA的食物。在实验开始及结束时测定平均重量和大小。实验持续时间为30天。
在后幼体虾的食物中包含GHRP-6与对照组相比生长速度改良30％-40％。显著差异(p＜0.001)。
6.1丰年虾(Artemia salina)包囊化
将GHRP-6在Artemia中包囊化以喂食给后幼体南美白对虾和Litopenaeus vanamei。为进行包囊化，将所述肽以10mg/L浓度加入丰年虾中1小时，收集Artemia并在盐水溶液中洗涤。每天四次喂食所述后幼体虾，持续一个月。对照组接受以同样浓度在Artemia中包囊化的BSA。
在丰年虾中包囊化的GHRP-6改良虾幼体的重量和大小，增加30％-40％。与对照组相比有显著差异(p＜0.001)。
序列表
<110>遗传和生物技术工程中心
<120>刺激水生生物生长及抗病性的方法
<130>organismos acauticos
<140>
<141>
<150>CU 2002-0020
<151>2002-01-24
<160>1
<170>PatentIn Ver.2.1
<210>1
<211>6
<212>PRT
<213>Secuencia Artificial
<220>
<221>PEPTIDE
<222>(1)..(6)
<223>GHRP6
<220>
<223>Descripción de la Secuencia Artificial：GHRP-6
<400>1
His D-Trp Ala Trp D-Phe Lys
1 5
Claims (15)
1.一种刺激鱼类和甲壳动物生长及抗病性的方法，其特征在于使用具有以下序列的肽GHRP-6：His-D-Trp-Ala-Trp-D-Phe-Lys-NH2。
2.权利要求1的方法，所述方法的特征在于在配制的饲料中使用GHRP-6以刺激鱼类和甲壳动物生长及抗病性，浓度为0.01-50μg肽/g动物湿重。
3.权利要求1的方法，所述方法的特征在于定期注射使用GHRP-6以刺激鱼类和甲壳动物生长及抗病性，浓度为0.01-50μg肽/g动物湿重。
4.权利要求1的方法，所述方法的特征在于通过浸没在淡水和海水中使用GHRP-6刺激鱼类和甲壳动物生长及抗病性，浓度为10-500μg肽/升，间隔1到7天。
5.权利要求1的方法，所述方法的特征在于在饲料中以包囊化形式使用GHRP-6以刺激鱼类和甲壳动物生长及抗病性，浓度为0.05-10μg肽/g动物湿重，间隔1到7天。
6.权利要求1-5的方法，所述方法的特征在于其在罗非鱼(Oreochromis sp.)中应用。
7.权利要求1-5的方法，所述方法的特征在于其在鲑鱼(Salmonsp.)中应用。
8.权利要求1-5的方法，所述方法的特征在于其在南美白对虾(Litopenaeus schmitti)，Litopenaeus vanamei中应用。
9.权利要求8的方法，所述方法的特征在于其在对虾(Penaeussp.)中应用。
10.权利要求1-9的方法，所述方法的特征在于其用于预防和治疗寄生虫感染及其它疾病。
11.权利要求10的方法，所述方法的特征在于其用于预防和治疗由Trichodina sp.和Helmintos monogeneos所致寄生虫感染。
12.权利要求10的方法，所述方法的特征在于其用于预防和治疗海虱所致寄生虫感染。
13.权利要求10的方法，所述方法的特征在于其用于预防和治疗外寄生物所致的寄生虫感染。
14.一种刺激鱼类和甲壳动物生长及抗病性的兽医学配方，所述配方的特征在于使用具有以下序列的肽GHRP-6：His-D-Trp-Ala-Trp-D-Phe-Lys-NH2。
15.权利要求14的应用，所述应用的特征在于其以注射、口服或浸没施用方式应用。
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| CU2002002020020020A CU23016A1 (es) | 2002-01-24 | 2002-01-24 | Método para la estimulación del crecimiento y resimétodo para la estimulación del crecimiento y resistencia a enfermedades en organismos acuáticos y fstencia a enfermedades en organismos acuáticos y formulación veterinaria ormulación veterinaria |
| CU2002/0020 | 2002-01-24 | ||
| PCT/CU2003/000002 WO2003080102A1 (es) | 2002-01-24 | 2003-01-22 | Metodo para la estimulacion del crecimiento y resistencia a enfermedades en orgamismos acuaticos |
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| CU23634A1 (es) * | 2007-05-31 | 2011-02-24 | Ct Ingenieria Genetica Biotech | Secuencias de ácido nucleico y aminoácidos, y vacuna para el control de infestaciones por ectoparásitos en peces |
| TWI398219B (zh) * | 2009-12-10 | 2013-06-11 | Univ Nat Pingtung Sci & Tech | 一種藻酸鈉用於提升對蝦屬生殖能力之用途 |
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| US4411890A (en) * | 1981-04-14 | 1983-10-25 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4880778A (en) * | 1986-05-12 | 1989-11-14 | Eastman Kodak Company | Combinations having synergistic growth hormone releasing activity and methods for use thereof |
| US5486505A (en) * | 1990-07-24 | 1996-01-23 | Polygen Holding Corporation | Polypeptide compounds having growth hormone releasing activity |
| EP0650597A4 (en) * | 1992-06-29 | 1996-12-18 | Univ South Florida | DIAGNOSTIC PROCEDURE FOR EVALUATING THE ETIOLOGY OF STATURAL INSUFFICIENCY. |
| WO1997006803A1 (en) * | 1995-08-21 | 1997-02-27 | Eli Lilly And Company | 2-acylaminopropanamides as growth hormone secretagogues |
| US5767124A (en) * | 1995-10-27 | 1998-06-16 | Merck & Co., Inc. | Polymorphic forms of a growth hormone secretagogue |
| US5972895A (en) * | 1996-12-11 | 1999-10-26 | A. Glenn Braswell | Composition and method for increasing growth hormone levels |
| DE19828924C1 (de) * | 1998-06-29 | 1999-06-02 | Siemens Ag | Schaltungsanordnung zum Steuern eines Fahrwerks- oder Antriebssystems in einem Kraftfahrzeug |
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| EP1477181B1 (en) | 2006-12-06 |
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