A型肉毒杆菌毒素对鼠前列腺增生模型的影响
摘要
目的:探讨A型肉毒杆菌毒素(BTX-A)对鼠前列腺增生模型的影响。
方法：64只雄性Wistar大鼠，随机分为模型组(52只)、假手术组(12只)。模型组行去势手术1周后，予皮下注射丙酸睾酮4mg/d.kg造模，连续1周。假手术组同期予皮下注射等量橄榄油,连续1周。随机处死4只模型鼠，取出其前列腺，光镜下观察证实造模成功。将其余48只模型鼠随机分为高、中、低剂量组、阴性对照组，每组均为12只，分别予上述各组前列腺内注射15u/0.1ml BTX-A，10u/0.1ml BTX-A、5u/0.1ml BTX-A、0.1ml生理盐水。继续予皮下注射丙酸睾酮4mg/d.kg造模,连续四周；假手术组继续予皮下注射等量橄榄油,连续四周。各组实验鼠分别于注射2周、4周后分2批(每次6只)处死，取出前列腺、膀胱、心脏、肾脏、肝脏，光镜下观察其形态学变化，计算各实验组前列腺重量、前列腺指数(PI)。病理图像分析系统半定量检测各组腺体面积、间质面积。免疫组化检测bax、fas、bcl-2蛋白表达情况。所有数据用SPSS软件包进行分析。
结果：
与阴性对照组相比，给药2周时高、中、低剂量组前列腺重量、PI、
腺体面积、bcl-2表达下降(P<0.05)；bax、fas表达增加(P<0.05)；间质面积相对增加(P<0.05)。
与阴性对照组相比，给药4周时高、中剂量组前列腺重量、PI、腺体
面积、bcl-2表达下降(P<0.05)，bax、fas表达增加(P<0.05),间质面积相对增加(P<0.05)。低剂量组腺体面积减少(P<0.05)，低剂量组和阴性对照组间质面积相比，差异无统计意义(P>.05)。
给药2、4周时假手术组各项指标比较，差异无统计意义(P>0.05)。
结论：BTX-A导致增生鼠前列腺腺体体积缩小，有望成为临床治疗前列腺增生的新方法。
Abstract Objective: To investigate effects of botulinum toxin A on rat model of benign prostate hypertrophy.
Methods: 64 male Wistar rats were divided into sham operation group(n=12) and model group(n=52). After castrated,52 rats of model group were injected subcutaneously testosterone propionate 4mg/kg.d to induce BPH;12 rats of sham operation group were injected subcutaneously the same dose of olive oil .After 1 week, the 4 model rats were randomly killed.The structure of prostates were observed by light microscopy.It proved that rat model was successful.The other 48 model rats were randomly divided into high dose group、medium dose group、low dose group、negative control group.The high、 medium、low dose group received respectively 15u/0.1ml 、10u/0.1ml 、5u/0.1ml BTX-A injected into the prostate；negative control group undergent 0.1ml NS injection into the prostate at the same position. After injections, the high、medium、low dose group、negative control group rats were injected subcutaneously testosterone propionate 4mg/kg.d for four weeks; sham operation group was injected subcutaneously the same dose of olive oil .The partly rats of the groups were killed randomly at 2、4 weeks. The prostates、bladders、hearts、kidneys、livers and hearts were removed.The structural changes of prostates、bladders、hearts、kidneys、livers and hearts were observed by light microscopy.The prostate weigh、prostate index(PI) were calculated.Morphometric changes of glandul areas、interstitial areas were semi-quantified by image analysis system.The expression of bax、fas、bcl-2 protein were analysed by means of immunohistochemical technique.All data were analysed by SPSS.
Results:
At two weeks,compared with negative control group, prostate weigh、PI、glandular areas、bcl-2 protein of high、medium、low dose group were significantly decreased(P<0.05),the expression of bax、fas protein significantly increased
(P<0.05), interstitial areas relatively increased(P<0.05).
At four weeks,compard with negative control group,prostate weighs、PI、glandular areas、bcl-2 protein of high、medium dose group were significantly decreased (P<0.05),the expression of bax、fas protein significantly increased(P<0.05), interstitial areas relatively increased(P<0.05),glandular areas of low dose group remarkablely differences(P<0.05).There were insignificantly differences between low group and negative control group in interstitial areas (P>0.05).
There was insignificantly differences between each index of two weeks and four weeks in sham operation group.
Conclusions: BTX-A can induce glandular atrophy of the rat model of BPH. Applications of BTX-A therapy could be candidated for the new treatment of BPH.
方法：64只雄性Wistar大鼠，随机分为模型组(52只)、假手术组(12只)。模型组行去势手术1周后，予皮下注射丙酸睾酮4mg/d.kg造模，连续1周。假手术组同期予皮下注射等量橄榄油,连续1周。随机处死4只模型鼠，取出其前列腺，光镜下观察证实造模成功。将其余48只模型鼠随机分为高、中、低剂量组、阴性对照组，每组均为12只，分别予上述各组前列腺内注射15u/0.1ml BTX-A，10u/0.1ml BTX-A、5u/0.1ml BTX-A、0.1ml生理盐水。继续予皮下注射丙酸睾酮4mg/d.kg造模,连续四周；假手术组继续予皮下注射等量橄榄油,连续四周。各组实验鼠分别于注射2周、4周后分2批(每次6只)处死，取出前列腺、膀胱、心脏、肾脏、肝脏，光镜下观察其形态学变化，计算各实验组前列腺重量、前列腺指数(PI)。病理图像分析系统半定量检测各组腺体面积、间质面积。免疫组化检测bax、fas、bcl-2蛋白表达情况。所有数据用SPSS软件包进行分析。
结果：
与阴性对照组相比，给药2周时高、中、低剂量组前列腺重量、PI、
腺体面积、bcl-2表达下降(P<0.05)；bax、fas表达增加(P<0.05)；间质面积相对增加(P<0.05)。
与阴性对照组相比，给药4周时高、中剂量组前列腺重量、PI、腺体
面积、bcl-2表达下降(P<0.05)，bax、fas表达增加(P<0.05),间质面积相对增加(P<0.05)。低剂量组腺体面积减少(P<0.05)，低剂量组和阴性对照组间质面积相比，差异无统计意义(P>.05)。
给药2、4周时假手术组各项指标比较，差异无统计意义(P>0.05)。
结论：BTX-A导致增生鼠前列腺腺体体积缩小，有望成为临床治疗前列腺增生的新方法。
Abstract Objective: To investigate effects of botulinum toxin A on rat model of benign prostate hypertrophy.
Methods: 64 male Wistar rats were divided into sham operation group(n=12) and model group(n=52). After castrated,52 rats of model group were injected subcutaneously testosterone propionate 4mg/kg.d to induce BPH;12 rats of sham operation group were injected subcutaneously the same dose of olive oil .After 1 week, the 4 model rats were randomly killed.The structure of prostates were observed by light microscopy.It proved that rat model was successful.The other 48 model rats were randomly divided into high dose group、medium dose group、low dose group、negative control group.The high、 medium、low dose group received respectively 15u/0.1ml 、10u/0.1ml 、5u/0.1ml BTX-A injected into the prostate；negative control group undergent 0.1ml NS injection into the prostate at the same position. After injections, the high、medium、low dose group、negative control group rats were injected subcutaneously testosterone propionate 4mg/kg.d for four weeks; sham operation group was injected subcutaneously the same dose of olive oil .The partly rats of the groups were killed randomly at 2、4 weeks. The prostates、bladders、hearts、kidneys、livers and hearts were removed.The structural changes of prostates、bladders、hearts、kidneys、livers and hearts were observed by light microscopy.The prostate weigh、prostate index(PI) were calculated.Morphometric changes of glandul areas、interstitial areas were semi-quantified by image analysis system.The expression of bax、fas、bcl-2 protein were analysed by means of immunohistochemical technique.All data were analysed by SPSS.
Results:
At two weeks,compared with negative control group, prostate weigh、PI、glandular areas、bcl-2 protein of high、medium、low dose group were significantly decreased(P<0.05),the expression of bax、fas protein significantly increased
(P<0.05), interstitial areas relatively increased(P<0.05).
At four weeks,compard with negative control group,prostate weighs、PI、glandular areas、bcl-2 protein of high、medium dose group were significantly decreased (P<0.05),the expression of bax、fas protein significantly increased(P<0.05), interstitial areas relatively increased(P<0.05),glandular areas of low dose group remarkablely differences(P<0.05).There were insignificantly differences between low group and negative control group in interstitial areas (P>0.05).
There was insignificantly differences between each index of two weeks and four weeks in sham operation group.
Conclusions: BTX-A can induce glandular atrophy of the rat model of BPH. Applications of BTX-A therapy could be candidated for the new treatment of BPH.
引文
Walsh PC.Treatment of benign prostatic hyperplasia.N Engl Med,1996,335:586-587.
BarryMJ,Roehr bornCG. Benign prostatic hyperplasia BMJ,2001,
323:1042–1046.
中华人民共和国卫生部药政局新药(西药)临床前研究指导原则汇编(M),1993,101-103.
裴发光、林福地、李金雨等.前列腺增生组织中细胞凋亡调控基因的表达.临床泌尿外科杂志,2000, Vol.15 No.07.
刘盾等.前列腺病变组织中细胞凋亡与bcl-2、bax、PCNA表达.临床与实验病理学杂志,2003,Vol.19 No.2.
王鸿雁、张贤生、王固新等.凋亡相关基因bcl-2、bax蛋白在前列腺良、恶性病变中的表达及意义.西安医科大学学报，2000,Vol.21 No.04.
Barry MJ,Roehrborn CG. Benign prostatic hyperplasia. BMJ,2001, 323:
1042–1046.
Oesterling JE.Benign prostatic hyperplasia: medicaland minimally invasive treatment options. N Engl J Med,1995,332:99–109.
Clifford GM, Farmer RD.Medical therapy for benignprostatic hyperplasia:a review of the literature. Eur Urol,2000,38: 2–19, 2000.
de la Rosette JJ, Alivizatos G, Madersbacher S, et al.EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol,2001,40: 256–263.
Boyle P, Robertson C, Manski R, et al.Meta-analysis ofrandomized trials of terazosin in the treatment of benign prostatic hyperplasia.Urology,2001,58: 717–722.
Narayan P, and Lepor H.Long-term, open-label, phaseIII multicenter study of tamsulosin in benign prostatic hyperplasia. Urology, 2001,57: 466–470.
Lepor H;Role of long-acting selective alpha-1 blockersin the
treatment of benign prostatic hyperplasia. Urol ClinNorth Am,1990,17: 651–659.
McConnell JD,Brukewitz R,Walsh P,et al;for the Finasteride Long-Term Efficacy and Safety Study Group:The effect of finasteride on the risk of acute urinary retention and need for surgcical treatment among men with benign prostatic hyperplasia: N Engl J Med ,1998,338:557-563.
Van Ermengen E. Ueber.einen neuen anaeroben Bacillus and seine Beziehungen zum Botulisms Ztsch Hyg Infect,1987,26:1-56.
Jahn R, Niemann H. Molecular mecanism of loxtridial neurotoxin. Ann.N.Y.Acad.Sci.1994,15:245.
Mitchell F.Brin, MD Botulinum Toxin: Chemistry, Pharmacology, Toxicity, and Immunology. Muscle and Nerve,1997,Supplement 6.
Scott AB.Botulinum toxin injection of eye muscles to correct strablismus.Trans Am Ophthalmol Soc,1981,79:734-770.
Kolbasnik J，Waterfall WE , Fachine B.Long-term efficacy of botulinum toxin in classical achalasia:a prospective study. Am j Gastrointerol,1999,94:3434-3439.
Schnider P,Binder M,Kitter H,et al.A randomized ,double-blind，placebo-controlled trial of botulinum A toxin for severe axillary hyperhidrosis.Brit J Dermatol,1999,140:677-680.
Pasricha PJ,Ravich WJ,Hendrix TR,et al.Intrasphiteric botulinum toxin for the treatment of achalasia.N Engl J Med,1995, 332: 774
-778.
Kim Ks ,Kim SS,Yoon JH,et al.The effect of botulinum toxin type A injection for instrinic rhinitis J laryngol Otol,1998,112: 248-251.
Schurch B, Stohrer M, Kramer G,et al. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results.J Urol 2000 Sep,164(3 Pt 1):692-697.
Schurch B, Stohrer M, et al.Botulinum-A toxin to treat detrusor hyperreflexia in spinal injured patients abstract Neurourol Urology 2001,20:521-522.
Del Popolo A.Botulinum-A toxin in the treatment of detrusor hyperreflexia. Neurourol Urodyn,2001,20:522-524.
Schulte-Baukloh H, Michael T, Sturzebecher B, Knispel HH.Botulinum-a toxin detrusor injection as a novel approach in the treatment of bladder spasticity in children with neurogenic bladder.Eur Urol,2003 Jul,44(1):139-43.
Radziszewski P, Dobronski P,Borkowski,A. Treatment of non-neurogenic storage and voiding disorders with chemical denervation caused by botulinum-A toxin :a pilot study abstract. Neurourol Urology, 2001,20:410-412.
Schurch B, Hauri D, Rodic B, Curt A, Mey et at;Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients.J Urol, 1996 Mar,155(3):1023-9.
Wheeler JS Jr, Walter JS, Chintam RS,et al: Botulinum toxin injections for voiding dysfunction following SCI.Spinal Cord Med, 1998 Jul,21(3):227-9.
Gallien P, Robineau S, Verin M,et al:Treatment of detrusor sphincter dyssynergia by transperineal injection of botulinum toxin. Arch Phys Med Rehabil,1998 Jun,79(6):715-7.
Denis et al:Introduction.Prostate,1989,suppl,2:1.
Mcneal,J.Pathology of benign prostatic hypertrophy:insight into etiology.Urol.Clin.North Am,1990,17:477.
Farns worth WE.Prostate stroma: physiology. Prostate，1999,38: 60–72.
Ruggieri MR, Colton MD, Wang P, et al.Human prostatemuscarinic receptor subtypes. J Pharmacol Exp Ther,1995,274:976–982.
Purintion,Fletchcher,Bardley. Gross and light microscopic features
of the pelvic plexus in the rat.Anat Rec,1973,175:697.
Hulsebosch,C.E,Colggeshall,R.E.An analysis of the axon populations in the nerves to the pelvic plexus viscera in the rat.J.Comp.Neurol,1982,211:1.
Lujan M, Paez A, Llanes L,et al.Role of autonomic innervation in rat prostatic structure maintenance: a morphometric analysis.J Urol,1998 Nov,160(5):1919-23.
Lujan Galan M, Paez Borda A,et al. Macroscopic and histologic analysis of the rat prostate after denervation.Arch Esp Urol,1998 Apr,51(3):219-25.
Lepor H, Kuhar MJ.Characterization and localizationof the muscarinic cholinergic receptor in human prostatictissue. J Urol,1984,132: 397.
Bruschini H, Schmidt RA, Tanago EA.Neurologiccontrol of prostatic secretion in the dog. Invest Urol,1978,15: 288.
Kubo T, Fukuda K, Mikami A, et al.Cloning, sequencing andexpression of complementary DNA encoding the muscarinicacetylcholine receptor. Nature,1986,323: 411.
Bonner TI,Buckley NJ, Young AC，et al Iden-ti?cation of a family of muscarinic acetylcholine receptor genes.Science,1987,237: 527.
Obara K, Arai K, Miyajima N,et al.Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells. Urol Res,2000 Jun,28(3):196-200.
Rayford W,Noble MJ,Austenfeld MA et al.Muscarinic cholinergic receptors promote growth of human prostate cancer cells.Prostate,1997 Feb 15,30(3):160-6.
Coffied JA,Considine RV,Simpson LL.The and medchanism of action of Botulinum neurotoxin.In Jankovic,J Hallet M(eds):”Therapy with Botulinum Toxin.”New York:Marcel Dekker.1994:3-13.
Mackenzie I,Burnstock G,Dolly JO.The effects of purified Botulinum neurotoxin type A on cholinergic,adrenergic and non-adrenergic,
atropine-resistant autonomi neuromuscular transmitter. Neuroscience, 1982,997-1006.
Rhodes PR,Krogh RH,Bruskewitz RC.Impact of drug therapy on benign prostatic hyperplasis specific quality of life. Urology, 1999, 53: 1090-1098.
Bartsch G, Frick J, Roegg I, et al.Electron microscopic stereological analysisof the normal human prostate and of benign prostatic hyper-plasia. J Uro,l979,122: 481.
Barrack,ER,Berry SJ.DNA synthesis in the canine prostate:effects of androgen and estrogen treatment.Prostate,1987,10:45-49.
Kyprianou N,TuH,Jacobs,SC.Apoptotic versus proliferative activities in human benign prostatic hyperplasia. Hum Pathol, 1996, 27: 668-675.
邓方明,顾方六,夏同礼等.人良性前列腺增生细胞增殖和凋亡状态的研究.中华外科杂志,1996,34∶620-622.
Maria G, Brisinda G, Civello IM, et al; Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study:Urology, 2003 Aug,62(2):259-64.
BarryMJ,Roehr bornCG. Benign prostatic hyperplasia BMJ,2001,
323:1042–1046.
中华人民共和国卫生部药政局新药(西药)临床前研究指导原则汇编(M),1993,101-103.
裴发光、林福地、李金雨等.前列腺增生组织中细胞凋亡调控基因的表达.临床泌尿外科杂志,2000, Vol.15 No.07.
刘盾等.前列腺病变组织中细胞凋亡与bcl-2、bax、PCNA表达.临床与实验病理学杂志,2003,Vol.19 No.2.
王鸿雁、张贤生、王固新等.凋亡相关基因bcl-2、bax蛋白在前列腺良、恶性病变中的表达及意义.西安医科大学学报，2000,Vol.21 No.04.
Barry MJ,Roehrborn CG. Benign prostatic hyperplasia. BMJ,2001, 323:
1042–1046.
Oesterling JE.Benign prostatic hyperplasia: medicaland minimally invasive treatment options. N Engl J Med,1995,332:99–109.
Clifford GM, Farmer RD.Medical therapy for benignprostatic hyperplasia:a review of the literature. Eur Urol,2000,38: 2–19, 2000.
de la Rosette JJ, Alivizatos G, Madersbacher S, et al.EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol,2001,40: 256–263.
Boyle P, Robertson C, Manski R, et al.Meta-analysis ofrandomized trials of terazosin in the treatment of benign prostatic hyperplasia.Urology,2001,58: 717–722.
Narayan P, and Lepor H.Long-term, open-label, phaseIII multicenter study of tamsulosin in benign prostatic hyperplasia. Urology, 2001,57: 466–470.
Lepor H;Role of long-acting selective alpha-1 blockersin the
treatment of benign prostatic hyperplasia. Urol ClinNorth Am,1990,17: 651–659.
McConnell JD,Brukewitz R,Walsh P,et al;for the Finasteride Long-Term Efficacy and Safety Study Group:The effect of finasteride on the risk of acute urinary retention and need for surgcical treatment among men with benign prostatic hyperplasia: N Engl J Med ,1998,338:557-563.
Van Ermengen E. Ueber.einen neuen anaeroben Bacillus and seine Beziehungen zum Botulisms Ztsch Hyg Infect,1987,26:1-56.
Jahn R, Niemann H. Molecular mecanism of loxtridial neurotoxin. Ann.N.Y.Acad.Sci.1994,15:245.
Mitchell F.Brin, MD Botulinum Toxin: Chemistry, Pharmacology, Toxicity, and Immunology. Muscle and Nerve,1997,Supplement 6.
Scott AB.Botulinum toxin injection of eye muscles to correct strablismus.Trans Am Ophthalmol Soc,1981,79:734-770.
Kolbasnik J，Waterfall WE , Fachine B.Long-term efficacy of botulinum toxin in classical achalasia:a prospective study. Am j Gastrointerol,1999,94:3434-3439.
Schnider P,Binder M,Kitter H,et al.A randomized ,double-blind，placebo-controlled trial of botulinum A toxin for severe axillary hyperhidrosis.Brit J Dermatol,1999,140:677-680.
Pasricha PJ,Ravich WJ,Hendrix TR,et al.Intrasphiteric botulinum toxin for the treatment of achalasia.N Engl J Med,1995, 332: 774
-778.
Kim Ks ,Kim SS,Yoon JH,et al.The effect of botulinum toxin type A injection for instrinic rhinitis J laryngol Otol,1998,112: 248-251.
Schurch B, Stohrer M, Kramer G,et al. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results.J Urol 2000 Sep,164(3 Pt 1):692-697.
Schurch B, Stohrer M, et al.Botulinum-A toxin to treat detrusor hyperreflexia in spinal injured patients abstract Neurourol Urology 2001,20:521-522.
Del Popolo A.Botulinum-A toxin in the treatment of detrusor hyperreflexia. Neurourol Urodyn,2001,20:522-524.
Schulte-Baukloh H, Michael T, Sturzebecher B, Knispel HH.Botulinum-a toxin detrusor injection as a novel approach in the treatment of bladder spasticity in children with neurogenic bladder.Eur Urol,2003 Jul,44(1):139-43.
Radziszewski P, Dobronski P,Borkowski,A. Treatment of non-neurogenic storage and voiding disorders with chemical denervation caused by botulinum-A toxin :a pilot study abstract. Neurourol Urology, 2001,20:410-412.
Schurch B, Hauri D, Rodic B, Curt A, Mey et at;Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients.J Urol, 1996 Mar,155(3):1023-9.
Wheeler JS Jr, Walter JS, Chintam RS,et al: Botulinum toxin injections for voiding dysfunction following SCI.Spinal Cord Med, 1998 Jul,21(3):227-9.
Gallien P, Robineau S, Verin M,et al:Treatment of detrusor sphincter dyssynergia by transperineal injection of botulinum toxin. Arch Phys Med Rehabil,1998 Jun,79(6):715-7.
Denis et al:Introduction.Prostate,1989,suppl,2:1.
Mcneal,J.Pathology of benign prostatic hypertrophy:insight into etiology.Urol.Clin.North Am,1990,17:477.
Farns worth WE.Prostate stroma: physiology. Prostate，1999,38: 60–72.
Ruggieri MR, Colton MD, Wang P, et al.Human prostatemuscarinic receptor subtypes. J Pharmacol Exp Ther,1995,274:976–982.
Purintion,Fletchcher,Bardley. Gross and light microscopic features
of the pelvic plexus in the rat.Anat Rec,1973,175:697.
Hulsebosch,C.E,Colggeshall,R.E.An analysis of the axon populations in the nerves to the pelvic plexus viscera in the rat.J.Comp.Neurol,1982,211:1.
Lujan M, Paez A, Llanes L,et al.Role of autonomic innervation in rat prostatic structure maintenance: a morphometric analysis.J Urol,1998 Nov,160(5):1919-23.
Lujan Galan M, Paez Borda A,et al. Macroscopic and histologic analysis of the rat prostate after denervation.Arch Esp Urol,1998 Apr,51(3):219-25.
Lepor H, Kuhar MJ.Characterization and localizationof the muscarinic cholinergic receptor in human prostatictissue. J Urol,1984,132: 397.
Bruschini H, Schmidt RA, Tanago EA.Neurologiccontrol of prostatic secretion in the dog. Invest Urol,1978,15: 288.
Kubo T, Fukuda K, Mikami A, et al.Cloning, sequencing andexpression of complementary DNA encoding the muscarinicacetylcholine receptor. Nature,1986,323: 411.
Bonner TI,Buckley NJ, Young AC，et al Iden-ti?cation of a family of muscarinic acetylcholine receptor genes.Science,1987,237: 527.
Obara K, Arai K, Miyajima N,et al.Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells. Urol Res,2000 Jun,28(3):196-200.
Rayford W,Noble MJ,Austenfeld MA et al.Muscarinic cholinergic receptors promote growth of human prostate cancer cells.Prostate,1997 Feb 15,30(3):160-6.
Coffied JA,Considine RV,Simpson LL.The and medchanism of action of Botulinum neurotoxin.In Jankovic,J Hallet M(eds):”Therapy with Botulinum Toxin.”New York:Marcel Dekker.1994:3-13.
Mackenzie I,Burnstock G,Dolly JO.The effects of purified Botulinum neurotoxin type A on cholinergic,adrenergic and non-adrenergic,
atropine-resistant autonomi neuromuscular transmitter. Neuroscience, 1982,997-1006.
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