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    Botulinum Toxin to Treat Horizontal Forehead Lines: A Refined Injection Pattern Accommodating the Lower Frontalis. Zhang Xinyu,Cai Lei,Yang Mingxia,Li Facheng,Han Xuefeng Aesthetic surgery journal BACKGROUND:When treating horizontal forehead lines with botulinum toxin type A the traditional approach requires that injection points should stay 1.5 to 2 cm above the orbital rim to avoid brow ptosis. Failure to treat the lower frontalis may potentially cause worse rhytides in the lower forehead. OBJECTIVES:The aim of this study was to present a refined injection pattern accommodating the lower frontalis and evaluate its clinical efficacy and safety. METHODS:Patients were categorized into 4 types according to the patterns of their forehead wrinkles. Moderate and severe wrinkles in the upper forehead were treated by the "safe zone" technique. Mild wrinkles and rhytides in the lower forehead were treated by the Microbotox technique. Standard photographs and measurements were taken before and after treatment. The effect on wrinkle reduction and changes in brow heights were assessed. RESULTS:In total, 330 treatments were followed up in the clinic, and 246 treatments were followed up by telephone. Among the 330 treatments, 213 were evaluated in our clinic 2 to 4 weeks later, and the patients who received these treatments were recruited for effect evaluation and brow height measurements. The posttreatment severity of forehead wrinkles was significantly reduced (P < 0.05), and brow heights remained unchanged (P > 0.05). No severe adverse events were documented. Patient satisfaction was quite high. CONCLUSIONS:The refined injection pattern is an effective and safe technique to treat horizontal forehead lines. The Microbotox technique enables treatment of the lower frontalis without changes in brow position. LEVEL OF EVIDENCE: 3: 10.1093/asj/sjz174
    Periurethral injection of sustained release basic fibroblast growth factor improves sphincteric contractility of the rat urethra denervated by botulinum-a toxin. Takahashi Satoru,Chen Qin,Ogushi Tetsuo,Fujimura Tetsuya,Kumagai Jimpei,Matsumoto Shinya,Hijikata Shigeki,Tabata Yasuhiko,Kitamura Tadaichi The Journal of urology PURPOSE:We evaluated the effects of sustained release basic fibroblast growth factor injection in rat urethra denervated by botulinum-A toxin (Wako Life Science, Osaka, Japan). MATERIALS AND METHODS:A total of 30 female Sprague-Dawley rats underwent periurethral injection of 10 U botulinum-A toxin to induce chemical denervation of the urethral sphincter. Leak point pressure in the waking state was determined and a significant decrease in leak point pressure vs that in control rats was confirmed (mean +/- SD 58.7 +/- 6.2 vs 120.7 +/- 13.0 cm H(2)O, p <0.0001). Two weeks later 0, 50 and 200 microg basic fibroblast growth factor incorporating 200 microl gelatin hydrogels in 10 rats each were injected into the urethral sphincter, enabling sustained release of basic fibroblast growth factor for 2 weeks. Four weeks later injection leak point pressure measurement and histological evaluation of the urethra were performed. RESULTS:Leak point pressure in rats with 50 and 200 microg basic fibroblast growth factor injection was significantly higher than in rats with the 0 microg injection (82.7 +/- 9.0 vs 95.1 +/- 6.2 and 119.3 +/- 8.1 cm H(2)O, p = 0.0021 and <0.0001, respectively). Maximum cross-sectional area of the urethral smooth muscle layer in the 50 and 200 microg groups significantly increased compared with that in the urethra in the 0 micro group, which was considered 100% (114.1% +/- 15.8% and 132.5% +/- 13.4%, p = 0.029 and <0.0001, respectively). Similarly the cross-sectional area of the striated sphincter in the 50 and 200 microg groups was greater than the 100% in the 0 microg group (112.3% +/- 15.6% and 124.3% +/- 14.1%, p = 0.069 and 0.0007, respectively). Vascular density in the urethral peri-atrophic zone in the 50 and 200 microg groups was significantly higher than in the 0 microg group (p = 0.027 and <0.0001, respectively). CONCLUSIONS:Sustained release basic fibroblast growth factor injection in the chemically denervated urethral sphincter facilitates regeneration of the urethral muscles and improves sphincteric contractility. Endoscopic periurethral injection of basic fibroblast growth factor incorporating gelatin hydrogels may be an attractive therapy for stress urinary incontinence. 10.1016/j.juro.2006.03.070
    Oculofacial contour asymmetries: Management of combined treatment with hyalurostructure and botulinum toxin injections. Berros Philippe,Tsirbas Angelo,Garcia Philippe,Farhi David,Bétis Frédéric,Galatoire Olivier Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology PURPOSE:To assess the long-term results of the treatment of oculofacial asymmetries using a combined injection schedule for injections of hyaluronic acid, with a specific micro cannula and botulinum toxin. METHOD:A retrospective study was conducted from January 2009 to January 2010. Patients were treated in the Alcazar Eye Clinic and Oculoplastic Department in Princess Grace Hospital, Monaco. We selected patients complaining of asymmetrical periorbital features who received treatment with hyalurostructure and botulinum toxin injection in one or more sessions. Nine patients were selected and presented with the following symptoms: asymmetry of eyebrow position (2 patients), superior orbital hollow (2 patients), tear trough (2 patients) and orbital volume (ocular prosthesis) (3 patients). The objective was to evaluate the efficiency of combined treatment in one or more sessions on these oculofacial asymmetries. Hyaluronic acid injections were done using hyalurostructure. Hyaluronic acid gel (Restylane Lidocaine) was used with a 25 gauge reinforced micro-cannula (pix'l +, Thiebaud). This was combined with injections of botulinum toxin (azzalure*) to areas of muscular hyperaction. Follow-up was done at 1 year by clinical examination, photography and patient satisfaction. Complications of this combined treatment have been identified. RESULTS:At 1-year follow-up, 88% of patients were satisfied or very satisfied with their results. There were no more complications secondary to both treatments in the same session. It was not noticed more hematomas and bruises than in classical injection method. The action of toxin is constant over time despite the association of hyaluronic acid injections. CONCLUSION:Combined treatments with toxin and hyaluronic acid in oculofacial asymmetries are efficient and can be proposed in the same session. These treatments must be repeated to maintain and optimize muscle contraction and volume loss. Use of hyalurostructure and botulinum toxin treatment in the same session is effective and safe. 10.3109/14764172.2012.655286
    Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation. Ausk Brandon J,Gross Ted S,Bain Steven D Clinical orthopaedics and related research BACKGROUND:Short-term muscle atrophy induced by botulinum toxin A (BTxA) has been observed to impair osteogenesis in a rat closed femur fracture model. However, it is unclear whether the underlying mechanism is a direct effect of BTxA on muscle-bone interactions or an indirect effect that is driven by skeletal unloading. Because skeletal trauma in the closed fracture model also leads to disuse atrophy, we sought to mitigate this confounding variable by examining BTxA effects on muscle-bone interactions in two complementary in vivo models in which osteogenesis is induced in the absence of skeletal unloading. The overall aim of this study was to identify a potential strategy to inhibit pathological bone formation and heterotopic ossification (HO). QUESTIONS/PURPOSES:(1) Does muscle paralysis inhibit periosteal osteogenesis induced by a transcortical defect? (2) Does muscle paralysis inhibit heterotopic bone formation stimulated by intramuscular bone morphogenetic protein (BMP) injection? METHODS:Focal osteogenesis was induced in the right hindlimb of mice through surgical initiation of a small transcortical defect in the tibia (fracture callus; n = 7/group) or intramuscular injection of BMP-2 (HO lesion; n = 6/group), both in the presence/absence of adjacent calf paralysis. High-resolution micro-CT images were obtained in all experimental groups 21 days postinduction and total volume (ie, perimeter of periosteal callus or HO lesion) and bone volume (calcified tissue within the total volume) were quantified as primary outcome measures. Finally, these outcome measures were compared to determine the effect of muscle paralysis on inhibition of local osteogenesis in both studies. RESULTS:After a transcortical defect, BTxA-treated mice showed profound inhibition of osteogenesis in the periosteal fracture callus 21 days postsurgery compared with saline-treated mice (total volume: 0.08 ± 0.06 versus 0.42 ± 0.11 mm(3), p < 0.001; bone volume: 0.07 ± 0.05 versus 0.32 ± 0.07 mm(3), p < 0.001). Similarly, BMP-2-induced HO formation was inhibited by adjacent muscle paralysis at the same time point (total volume: 1.42 ± 0.31 versus 3.42 ± 2.11 mm(3), p = 0.034; bone volume: 0.68 ± 0.18 versus 1.36 ± 0.79 mm(3), p = 0.045). CONCLUSIONS:Our data indicate that BTxA-induced neuromuscular inhibition mitigated osteogenesis associated with both a transcortical defect and BMP-2-induced HO. CLINICAL RELEVANCE:Focal neuromuscular inhibition represents a promising new approach that may lead to a new clinical intervention to mitigate trauma-induced HO, a healthcare challenge that is severely debilitating for civilian and war-wounded populations, is costly to both the patient and the healthcare system, and currently lacks effective treatments. 10.1007/s11999-015-4271-4
    A comparison study of prabotulinumtoxinA vs onabotulinumtoxinA in myostatin-deficient mice with muscle hypertrophy. Bak Dong-Ho,Choi Mi Ji,Lee Esther,Kwon Tae-Rin,Kim Jong Hwan,Nam Sang-Hyun,Kim Kyoung-Yun,Ahn Seung Won,Mun Seog-Kyun,Na Jungtae,Kim Beom Joon Basic & clinical pharmacology & toxicology Botulinum toxin A (BoNT-A) is used clinically for various muscle disorders and acts by preventing the release of the neurotransmitter acetylcholine into the synapse space. Here, we compared the efficacy of prabotulinumtoxinA (PRA) and onabotulinumtoxinA (ONA) for the reduction in hypertrophy in myostatin-deficient (Mstn ) mice. Two different BoNT-A products (2.5, 10 and 25 U/kg) were injected to paralyse the hindlimb for 2 months, after which sciatic nerve conduction study, 3D micro-CT, haematoxylin and eosin (H&E) and dystrophin staining were conducted. Administration of BoNT-A products induced denervation-mediated atrophy and alleviated muscle hypertrophy generated in Mstn mice. The present study revealed that each BoNT-A regulates skeletal muscle size, myofibre number and myofibre diameter in Mstn mice. The potential applicability of BoNT-A for the treatment of rare muscle hypertrophic diseases was demonstrated. Compared with ONA, PRA had a comparable ability to act in the local area. 10.1111/bcpt.13151
    The mechanism of botulinum A on Raynaud syndrome. Zhou Yanwen,Liu Ying,Hao Yunhua,Feng Ya,Pan Lizhen,Liu Wuchao,Li Bing,Xiao Libin,Jin Lingjing,Nie Zhiyu Drug design, development and therapy Background:Botulinum neurotoxin type A (BoNT/A) is emerging as a treatment modality for Raynaud's phenomenon (RP). However, the mechanism of the role of BoNT/A in antagonizing the constriction of arteriola in RP remains unclear. Materials and methods:We tested the constriction of arteriole diameter and the distribution of adrenergic receptors on the rat cremaster modle. Moreover, we measured the secretion of norepinephrine (NE), protein level changes and related receptors on cultured rat superior cervical ganglia neurons(SCGNs), a model of sympathetic neuron. Results:Based on our results, the inhibition of arteriole vasoconstriction was increased with increasing doses of BoNT/A. BoNT/A, prazosin, and BQ123 treatment can result in significant inhibition of arteriole vasoconstriction with the same electrical stimulation. The inhibition effect of prazosin was equivalent to BoNT/A, while BQ123 has a synergistic effect with BoNT/A. After treating SCGNs using BoNT/A for 30 min, the decrease in fluorescence intensity of FM1-43 slowed down which was correlated with the doses of BoNT/A. Furthermore, release of NE in the supernatant was significantly decreased as measured by enzyme-linked immunosorbent assay, 24 h after a high dose of BoNT/A (25 µ/mL). Cleaved-SNAP-25 was detected by Western blotting 24 h following BoNT/A (50 µ/mL) treatment. Moreover, receptor SV2C, GM1, and FGFR3 were detected on sympathetic neurons, similarly to cholinergic neurons. Conclusion:Our study showed that BoNT/A could significantly inhibit electrical stimulation-induced arteriole vasoconstriction through the sympathetic pathway. The mechanism was similar to the cholinergic one, in which the vesicle release of sympathetic neurons could be inhibited by cleavage of SNAP-25. The end result was blocked vesicle fusion with the presynaptic membrane after BoNT/A treatment, inhibiting the release of the NE. 10.2147/DDDT.S161113
    Cellular and Matrix Response of the Mandibular Condylar Cartilage to Botulinum Toxin. Dutra Eliane H,O' Brien Mara H,Lima Alexandro,Kalajzic Zana,Tadinada Aditya,Nanda Ravindra,Yadav Sumit PloS one OBJECTIVES:To evaluate the cellular and matrix effects of botulinum toxin type A (Botox) on mandibular condylar cartilage (MCC) and subchondral bone. MATERIALS AND METHODS:Botox (0.3 unit) was injected into the right masseter of 5-week-old transgenic mice (Col10a1-RFPcherry) at day 1. Left side masseter was used as intra-animal control. The following bone labels were intraperitoneally injected: calcein at day 7, alizarin red at day 14 and calcein at day 21. In addition, EdU was injected 48 and 24 hours before sacrifice. Mice were sacrificed 30 days after Botox injection. Experimental and control side mandibles were dissected and examined by x-ray imaging and micro-CT. Subsequently, MCC along with the subchondral bone was sectioned and stained with tartrate resistant acid phosphatase (TRAP), EdU, TUNEL, alkaline phosphatase, toluidine blue and safranin O. In addition, we performed immunohistochemistry for pSMAD and VEGF. RESULTS:Bone volume fraction, tissue density and trabecular thickness were significantly decreased on the right side of the subchondral bone and mineralized cartilage (Botox was injected) when compared to the left side. There was no significant difference in the mandibular length and condylar head length; however, the condylar width was significantly decreased after Botox injection. Our histology showed decreased numbers of Col10a1 expressing cells, decreased cell proliferation and increased cell apoptosis in the subchondral bone and mandibular condylar cartilage, decreased TRAP activity and mineralization of Botox injected side cartilage and subchondral bone. Furthermore, we observed reduced proteoglycan and glycosaminoglycan distribution and decreased expression of pSMAD 1/5/8 and VEGF in the MCC of the Botox injected side in comparison to control side. CONCLUSION:Injection of Botox in masseter muscle leads to decreased mineralization and matrix deposition, reduced chondrocyte proliferation and differentiation and increased cell apoptosis in the MCC and subchondral bone. 10.1371/journal.pone.0164599
    Botox-induced muscle paralysis alters intracortical porosity and osteocyte lacunar density in skeletally mature rats. Gatti Vittorio,Ghobryal Bishoy,Gelbs Michelle J,Gerber Michael B,Doty Stephen B,Cardoso Luis,Fritton Susannah P Journal of orthopaedic research : official publication of the Orthopaedic Research Society Reduced mechanical loading can lead to disuse osteoporosis, resulting in bone fragility. Disuse models report macroscopic bone loss due to muscle inactivity and immobilization, yet only recently has there been quantification of the effects of disuse on the vascular pores and osteocyte network, which are believed to play an important role in mechanotransduction via interstitial fluid flow. The goal of this study was to perform a high-resolution analysis of the effects of muscle inactivity on intracortical porosity and osteocyte lacunar density in skeletally mature rats. Muscle paralysis was induced in 20-week-old female Sprague Dawley rats by injection of botulinum neurotoxin. Rats were injected in the right hindlimb muscles with either Botox (BTX, n = 8) or saline solution (CTRL, n = 8), with a third group used as baseline controls (n = 8). Four weeks after injection, Botox caused a ∼60% reduction in hindlimb muscle mass. High-resolution micro-CT analysis showed that Botox-induced muscle paralysis increased vascular canal porosity and reduced osteocyte lacunar density within the tibial metaphysis cortex. Cortical thickness and other areal properties were diminished in the proximal tibial metaphysis, whereas no differences were found in the mid-diaphysis. Within the BTX group, the injected limbs showed a lower cancellous bone volume fraction relative to the contralateral limb. These results indicate that diminished muscle activity alters the vascular canal porosity and osteocyte lacunar density in cortical bone, which could alter interstitial fluid flow, affecting molecular transport and the transmission of mechanical signals to osteocytes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. 10.1002/jor.24276
    Botulism in infants: a cause of sudden death? Marx J L Science (New York, N.Y.) 10.1126/science.684407
    Botulism and sudden infant death. Lancet (London, England)
    Botulism in a pregnant woman. Robin L,Herman D,Redett R The New England journal of medicine 10.1056/NEJM199609123351117
    A new role for botulinum? Lancet (London, England)
    Chronic constipation. Brisinda Giuseppe,Cadeddu Federica,Maria Giorgio The New England journal of medicine 10.1056/NEJM200403183501219
    Clinical problem-solving. The eyes have it. Vasa Miten,Baudendistel Thomas E,Ohikhuare Christine E,Grace Elizabeth M,Yan Wilson,Josephson S Andrew,Tierney Lawrence M The New England journal of medicine 10.1056/NEJMcps1105394
    Botulinum toxin A in orthopaedic surgery. Gasser T,Fritsch K,Arnold G,Oertel W Lancet (London, England) 10.1016/0140-6736(91)91485-d
    Botulinum toxin for spasticity after stroke. Buitrago Manuel M,Koolwijk Irene The New England journal of medicine
    Botulinum toxin for spasticity after stroke. Dobkin Bruce H The New England journal of medicine
    Stroke, spasticity, and botulinum toxin. Rowland Lewis P The New England journal of medicine 10.1056/NEJMp020071
    Therapeutic options in oesophageal dysphagia. Tack Jan,Zaninotto Giovanni Nature reviews. Gastroenterology & hepatology High-resolution manometry enables the categorization of patients with oesophageal dysphagia caused by oesophageal motility disorders into diagnostic categories according to the Chicago Classification. This Review provides an overview of the literature concerning treatment options for patients with dysphagia associated with achalasia, hypercontractile disorders and hypocontractility disorders of the oesophagus. In achalasia, pharmacotherapy and botulinum toxin are less effective than pneumatic dilation or surgical Heller myotomy, which had comparable efficacy in the largest controlled trial to date. Peroral endoscopic myotomy is a novel therapeutic modality that is currently being evaluated in controlled trials versus pneumatic dilation or surgical myotomy. A variety of medical treatments have been evaluated in hypermotility disorders, but only botulinum toxin injection yielded favourable results in a single controlled trial. Few studies have addressed the treatment of dysphagia in patients with oesophageal hypomotility. A variety of prokinetic agents have been studied, but there is no evidence of clinically relevant efficacy from controlled trials. 10.1038/nrgastro.2015.45
    Botulinum toxin A in the early treatment of sixth nerve palsy-induced diplopia in type 2 diabetes. Broniarczyk-Loba Anna,Czupryniak Leszek,Nowakowska Olimpia,Loba Jerzy Diabetes care 10.2337/diacare.27.3.846
    Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Gracies Jean-Michel,Brashear Allison,Jech Robert,McAllister Peter,Banach Marta,Valkovic Peter,Walker Heather,Marciniak Christina,Deltombe Thierry,Skoromets Alexander,Khatkova Svetlana,Edgley Steven,Gul Fatma,Catus France,De Fer Beatrice Bois,Vilain Claire,Picaut Philippe, The Lancet. Neurology BACKGROUND:Resistance from antagonistic muscle groups might be a crucial factor reducing function in chronic hemiparesis. The resistance due to spastic co-contraction might be reduced by botulinum toxin injections. We assessed the effects of abobotulinumtoxinA injection in the upper limb muscles on muscle tone, spasticity, active movement, and function. METHODS:In this randomised, placebo-controlled, double-blind study, we enrolled adults (aged 18-80 years) at least 6 months after stroke or brain trauma from 34 neurology or rehabilitation clinics in Europe and the USA. Eligible participants were randomly allocated in a 1:1:1 ratio with a computer-generated list to receive a single injection session of abobotulinumtoxinA 500 U or 1000 U or placebo into the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]), and into at least two additional muscle groups from the elbow, wrist, or finger flexors or shoulder extensors. Patients and investigators were masked to treatment allocation. The primary endpoint was the change in muscle tone (Modified Ashworth Scale [MAS]) in the PTMG from baseline to 4 weeks. Secondary endpoints were Physician Global Assessment (PGA) at week 4 and change from baseline to 4 weeks in the perceived function (Disability Assessment Scale [DAS]) in the principal target of treatment, selected by the patient together with physician from four functional domains (dressing, hygiene, limb position, and pain). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01313299. FINDINGS:243 patients were randomly allocated to placebo (n=81), abobotulinumtoxinA 500 U (n=81), or abobotulinumtoxinA 1000 U (n=81). Mean change in MAS score from baseline at week 4 in the PTMG was -0·3 (SD 0·6) in the placebo group (n=79), -1·2 (1·0) in the abobotulinumtoxinA 500 U group (n=80; difference -0·9, 95% CI -1·2 to -0·6; p<0·0001 vs placebo), and -1·4 (1·1) in the abobotulinumtoxinA 1000 U group (n=79; -1·1, -1·4 to -0·8; p<0·0001 vs placebo). Mean PGA score at week 4 was 0·6 (SD 1·0) in the placebo group (n=78), 1·4 (1·1) in the abobotulinumtoxinA 500 U group (n=80; p=0·0003 vs placebo), and 1·8 (1·1) in the abobotulinumtoxinA 1000 U group (n=78; p<0·0001 vs placebo). Mean change from baseline at week 4 in DAS score for the principal target of treatment was -0·5 (0·7) in the placebo group (n=79), -0·7 (0·8) in the abobotulinumtoxinA 500 U group (n=80; p=0·2560 vs placebo), and -0·7 (0·7) in the abobotulinumtoxinA 1000 U group (n=78; p=0·0772 vs placebo). Three serious adverse events occurred in each group and none were treatment related; two resulted in death (from pulmonary oedema in the placebo group and a pre-existing unspecified cardiovascular disorder in the abobotulinumtoxinA 500 U group). Adverse events that were thought to be treatment related occurred in two (2%), six (7%), and seven (9%) patients in the placebo, abobotulinumtoxinA 500 U, and abobotulinumtoxinA 1000 U groups, respectively. The most common treatment-related adverse event was mild muscle weakness. All adverse events were mild or moderate. INTERPRETATION:AbobotulinumtoxinA at doses of 500 U or 1000 U injected into upper limb muscles provided tone reduction and clinical benefit in hemiparesis. Future research into the treatment of spastic paresis with botulinum toxin should use active movement and function as primary outcome measures. FUNDING:Ipsen. 10.1016/S1474-4422(15)00216-1
    Botulinum toxin treatment for oropharyngeal dysphagia associated with diabetic neuropathy. Restivo Domenico A,Marchese-Ragona Rosario,Lauria Giuseppe,Squatrito Sebastiano,Gullo Damiano,Vigneri Riccardo Diabetes care OBJECTIVE:No specific treatment for oropharyngeal dysphagia related to diabetic neuropathy has been described to date. Chemical myotomy of the cricopharyngeus (CP) muscle by botulinum neurotoxin type A (BoNT/A) has been effective in reducing or abolishing dysphagia associated with upper esophageal sphincter (UES) hyperactivity of different etiologies. In the present study, we evaluated the efficacy of BoNT/A injections into the CP muscle in diabetic patients with severe oropharyngeal dysphagia associated with diabetic autonomic and/or somatic peripheral neuropathy. RESEARCH DESIGN AND METHODS:Twelve type 2 diabetic patients with severe dysphagia for both solid and liquid foods associated with autonomic and/or peripheral somatic neuropathy were investigated. Swallowing function was evaluated by clinical examination, videofluoroscopy, and simultaneous needle electromyography (EMG) of the CP and pharyngeal inferior constrictor (IC) muscles. Clinical evaluation using a four-level dysphagia severity score was performed every other day for the 1st week and thereafter every other week until week 24. Videofluoroscopy and EMG follow-up were carried out at week 1, 4, 12, 16, 18, and 24 after BoNT/A injection. BoNT/A was injected percutaneously into the CP muscle under EMG control. RESULTS:BoNT/A induced the complete recovery of dysphagia in 10 patients and had a significant (P = 0.0001, ANOVA) improvement in 2 patients within 4 +/- 1.1 days (range 3-7). Clinical improvement was confirmed by videofluoroscopy and EMG. CONCLUSIONS:Our findings suggest a potential benefit from BoNT/A treatment in dysphagia associated with diabetic neuropathy. Randomized controlled trials are needed to confirm this observation. 10.2337/dc05-2486
    Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide-induced cystitis in rats. Chuang Yao-Chi,Yoshimura Naoki,Huang Chao-Cheng,Wu Moya,Chiang Po-Hui,Chancellor Michael B European urology BACKGROUND:Cyclooxygenase 2 (COX-2) elevation and subsequent prostaglandin E(2) (PGE(2)) production play a major role in bladder inflammation and hyperactivity. EP4 receptor, a subtype of PGE(2) receptors, mediates tissue inflammation and hypersensitivity. OBJECTIVE:To investigate the effect of intravesical botulinum toxin A (BoNT-A) on COX-2 and EP4 expression in cyclophosphamide (CYP)-induced cystitis in rats. DESIGN, SETTING, AND PARTICIPANTS:Experimental (N=40) and control animals (N=20) were injected with CYP (75 mg/kg intraperitoneally) or saline on days 1, 4, and 7. BoNT-A (1 ml, 20 unit/ml) or saline were administered into the bladder and retained for 1 h on day 2. INTERVENTION:Waking cystometrograms (CMGs) were performed. Bladder and L6 and S1 spinal cord were harvested on day 8. MEASUREMENTS:CMG parameters, histology, and COX-2 and EP4 expression by immunostaining or western blotting were measured. RESULTS AND LIMITATIONS:CYP induced increased bladder inflammatory reaction, bladder hyperactivity, and COX-2 and EP4 expression in the bladder and spinal cord. The CYP effects were suppressed by BoNT-A treatment. BoNT-A treatment decreased inflammatory reaction (56.5% decrease), COX-2 expression (77.8%, 61.7%, and 54.8% decrease for bladder, L6, and S1 spinal cord, respectively), EP4 expression (56.8%, 26.9%, and 84.2% decrease for bladder, L6, and S1 spinal cord, respectively), and suppressed bladder hyperactivity (intercontraction interval, 107% increase and contraction amplitude, 43% decrease). CONCLUSIONS:CYP injection activated COX2 and EP4 expression in the bladder and spinal cord and induced bladder inflammation and hyperactivity, which effects were suppressed by BoNT-A treatment. These findings suggest a potential benefit of EP4-targeted pharmacotherapy and BoNT-A treatment for bladder inflammatory conditions. 10.1016/j.eururo.2008.05.007
    Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. Brashear Allison,Gordon Mark F,Elovic Elie,Kassicieh V Daniel,Marciniak Christina,Do Mai,Lee Chia-Ho,Jenkins Stephen,Turkel Catherine, The New England journal of medicine BACKGROUND:Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injections of botulinum toxin type A reduce disability in persons with spasticity of the wrist and fingers after a stroke. METHODS:We performed a randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of one-time injections of botulinum toxin A (200 to 240 units) in 126 subjects with increased flexor tone in the wrist and fingers after a stroke. The primary outcome measure was self-reported disability in four areas: personal hygiene, dressing, pain, and limb position (on a four-point scale ranging from no disability to severe disability) at six weeks; at base line, each subject selected one of these areas in which there was moderate-to-severe disability as the principal target of treatment. RESULTS:Subjects who received botulinum toxin A had greater improvement in flexor tone in the wrist and fingers at all follow-up visits through 12 weeks than did subjects who received placebo (P<0.001 for all comparisons). Subjects treated with botulinum toxin A had greater improvement in the principal target of treatment at weeks 4, 6, 8, and 12 (P<0.001, P<0.001, P=0.03, and P=0.02, respectively); at week 6, 40 of the 64 subjects in the botulinum-toxin group (62 percent), as compared with 17 of the 62 in the placebo group (27 percent), reported improvement of at least one point on the Disability Assessment Scale in the principal target of treatment (P<0.001). There were no major adverse events associated with injection of botulinum toxin A. CONCLUSIONS:Intramuscular injections of botulinum toxin A reduce spasticity of the wrist and finger muscles and associated disability in patients who have had a stroke. 10.1056/NEJMoa011892
    The treatment of diabetic gastroparesis with botulinum toxin injection of the pylorus. Lacy Brian E,Crowell Michael D,Schettler-Duncan Ann,Mathis Carole,Pasricha Pankaj J Diabetes care OBJECTIVE:Gastroparesis is a disorder of delayed gastric emptying that is often chronic in nature. Up to 50% of type 1 diabetic subjects have symptoms of gastroparesis, which include nausea, vomiting, and early satiety. Elevated pyloric pressures may be responsible for delayed gastric emptying in diabetic subjects. Botulinum toxin inhibits the release of acetylcholine and produces transient paralysis when injected into smooth muscle. The aim of this study was to determine whether injection of the pylorus with botulinum toxin in patients with diabetic gastroparesis improves symptoms of gastroparesis, alters gastric emptying scan time, and/or changes weight and insulin use. RESEARCH DESIGN AND METHODS:This was an open-label trial with age- and sex-matched control subjects from a tertiary care referral center for patients with gastroparesis. Eight type 1 diabetic subjects (six women and two men; mean age 41 years; mean years with diabetes 25.3) who had failed standard therapy were enrolled. Intervention consisted of injection of the pylorus with 200 units of botulinum toxin during upper endoscopy. Symptoms, antropyloric manometry, gastric emptying scan times, weight, and insulin use were all recorded before intervention and during a 12-week follow-up period. RESULTS:Seven of the eight patients completed the full 12-week follow-up period. No complications were noted. Mean symptom scores declined from 27 to 12.1 (P < 0.01), whereas the SF-36 physical functioning domain also improved (P < 0.05). Four patients noted an increase in insulin use of >5 units/day. Six of the seven patients gained weight (P = 0.05). Gastric emptying scan time improved in four patients. CONCLUSIONS:Botulinum toxin injection of the pylorus is safe and improves symptoms in patients with diabetic gastroparesis. These results warrant further investigation with a large, double-blind, placebo-controlled trial. 10.2337/diacare.27.10.2341
    Intraprostatic botulinum toxin type a injection in patients unfit for surgery presenting with refractory urinary retention and benign prostatic enlargement. Effect on prostate volume and micturition resumption. Silva João,Silva Carlos,Saraiva Luis,Silva André,Pinto Rui,Dinis Paulo,Cruz Francisco European urology OBJECTIVES:To evaluate the effect of intraprostatic injection of botulinum toxin A (BoNTA) on prostate volume and refractory urinary retention in patients with benign prostatic enlargement. METHODS:Twenty-one men with benign prostatic enlargement on chronic indwelling catheter for at least 3 mo who were not candidates for surgery because of poor general condition received 200 U BoNTA in the transition zone by transrectal approach under ultrasound guidance. Patients were reevaluated at 1 and 3 mo posttreatment. RESULTS:Patients had a mean age of 80+/-2 yr. Injections were done without anaesthetic support as an outpatient procedure. No significant local effects occurred. Baseline prostate volume of 70+/-10 ml decreased to 57+/-10 ml (p<0.0006) at 1 mo and to 47+/-7 ml (p=0.03 against 1 mo) at 3 mo. At 1 mo, 16 patients (76%) could resume voiding with a mean Qmax of 9.0+/-1.2 ml/s. At 3 mo, 17 patients (81%) voided with a mean Qmax of 10.3+/-1.4 ml/s. Residual urine was 80+/-19 ml and 92+/-24 ml at the two time points, respectively. Mean serum total PSA decreased from 6.0+/-1.1 ng/ml at baseline to 5.0+/-0.9 ng/ml at 3 mo (p=0.04). CONCLUSIONS:BoNTA injection into the prostate swiftly reduces prostate volume and may be a promising treatment for refractory urinary retention in patients with benign prostatic enlargement who are unfit for surgery. Future studies will determine the duration of BoNTA effect. 10.1016/j.eururo.2007.08.050
    Botulinum toxin A detrusor injections in patients with neurogenic detrusor overactivity significantly decrease the incidence of symptomatic urinary tract infections. Gamé Xavier,Castel-Lacanal Evelyne,Bentaleb Youssef,Thiry-Escudié Isabelle,De Boissezon Xavier,Malavaud Bernard,Marque Philippe,Rischmann Pascal European urology OBJECTIVES:To study the effect of botulinum toxin A (BoNTA) injections into the detrusor muscle on the incidence of symptomatic urinary infections in patients with neurogenic detrusor overactivity. METHODS:Between February 2004 and June 2005, 30 patients (18 men, 12 women), mean age 39.4+/-12.1 yr, with neurogenic detrusor overactivity received an injection of 300 U Botox (Allergan Inc., Irvine, CA, USA) into the detrusor. Fifteen patients had multiple sclerosis, 14 had spinal cord injury, and 1 had myelitis. Twenty-two patients had urinary incontinence. Patients were either resistant to anticholinergic medications, had discontinued treatment because of adverse effects, or had contraindications to anticholinergic drugs. Before and 6 wk after injection, each patient kept a bladder diary and underwent urodynamic investigation, retrograde and voiding cystourethrography, and urine culture. All symptomatic urinary infections (pyelonephritis, orchitis, prostatitis) occurring in the 6 mo before and the 6 mo after injection were recorded. RESULTS:Before injection, the mean number of symptomatic urinary infections over 6 mo was 1.75+/-1.87. After injection, the mean was 0.2+/-0.41 (p=0.003), and only 3 patients presented symptomatic urinary infections. These patients were those who showed less improvement in their urodynamic parameters after injection (volume of the first uninhibited contraction, maximum bladder pressure, and maximum cystometric capacity, respectively; p=0.0037, p=0.0002, p=0.0027, ANOVA). CONCLUSIONS:BoNTA injections into the detrusor muscle significantly decreased the incidence of symptomatic urinary infections. This effect seems to be related to improvement in urodynamic parameters, reflecting improved reservoir capacity at low pressure. 10.1016/j.eururo.2007.08.039
    Editorial comment on: Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide-induced cystitis in rats. Vignozzi Linda,Morelli Annamaria European urology 10.1016/j.eururo.2008.05.008
    Editorial comment on: Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide-induced cystitis in rats. Giannantoni Antonella European urology 10.1016/j.eururo.2008.05.009
    Editorial comment on: neurogenic detrusor overactivity treated with english botulinum toxin a: 8-year experience of one single centre. Wyndaele Jean-Jacques European urology 10.1016/j.eururo.2007.09.035
    Botulinum toxin as a new therapy option for voiding disorders: current state of the art. Leippold Thomas,Reitz André,Schurch Brigitte European urology Botulinum toxin is a presynaptic neuromuscular blocking agent inducing selective and reversible muscle weakness up to several months when injected intramuscularly in minute quantities. Different medical disciplines have discovered the toxin to treat mainly muscular hypercontraction. In urology, indications for botulinum-A toxin have been neurogenic detrusor overactivity, detrusor-sphincter dyssynergia, motor and sensory urge and, more recently, chronic prostatic pain. The available literature was reviewed using Medline Services. The keywords "botulinum-A toxin", "detrusor-sphincter dyssynergia", "neurogenic bladder", "spinal cord injury", "denervation", "chronic prostatic pain", "chronic urinary retention" were used to obtain references. A toxin injection is effective to treat detrusor-sphincter dyssynergia when injected either transurethrally or transperineally. After treatment, external urethral sphincter pressure, voiding pressure and post-void residual volume decreased. The effect lasts between 2 to 9 months depending on the number of injections. Best indications seem to be multiple sclerosis and incomplete spinal cord injury patients suffering from neurogenic detrusor overactivity and detrusor-sphincter dyssynergia. According to the previous results, the use of botulinum-A toxin injections into the external urethral sphincter has been extended to a variety of bladder obstructions and to decrease outlet resistance in patients with acontractile detrusor. In cases of successful treatment, spontaneous voiding re-occurs and catheterization can be resumed. Injections of the toxin into the external urethral sphincter also seem to have a beneficial effect on chronic prostatic pain, presumably by reducing hypertonicity and hyperactivity of the external urethral sphincter. Injections of botulinum-A toxin into the detrusor muscle has first been tested to treat neurogenic detrusor activity in spinal cord injured patients and in myelomeningocele children. Long lasting (mean 9 months) detrusor relaxation occurs after injection of usually 300 units of Botox). Continence is restored in about 95% of the patients and anticholinergic drugs can be markedly reduced or even stopped. Excellent results of botulinum-A toxin injections into the detrusor in neurogenic detrusor overactivity have lead to an expansion of this treatment to incontinence due to idiopathic detrusor overactivity. Although preliminary results are promising, adequate dosage of the toxin required for this indication is not yet known. In conclusion, it appears that botulinum toxin injection into either the external urethral sphincter or the detrusor offers new promising treatment options for many different urological dysfunctions. However, large controlled trials are absolutely required to establish the role of botulinum-A toxin injections in the fields of urology and neurourology on evidence based medicine.
    Neurogenic detrusor overactivity treated with english botulinum toxin a: 8-year experience of one single centre. Del Popolo Giulio,Filocamo Maria Teresa,Li Marzi Vincenzo,Macchiarella Angelo,Cecconi Filippo,Lombardi Giuseppe,Nicita Giulio European urology OBJECTIVE:Determine long-term effect of English botulinum neurotoxin type A (BoNTA; Dysport) for refractory neurogenic detrusor overactivity (NDO) for possible reduction of BoNTA efficacy after repeated injections. METHODS:Between 1999 and 2005, 199 patients with spinal cord lesions with refractory NDO were treated with Dysport. All patients underwent a clinical examination, urinalysis, and videourodynamic study at baseline and at 3, 6, and 12 mo after each treatment, as well as a visual analogue scale (VAS) assessment and a bladder diary checked for 1 wk before each visit. We used 1000, 750, 500 IU BoNTA at the beginning of our experience, and thereafter we mainly used 750 IU. Outcome measures included frequency of urge urinary incontinence (Incontinence Episode Frequency [IEF] test); urodynamic parameters including maximum cystometric bladder capacity (MCBC), reflex volume (RV), bladder compliance (BC); number of pads/condoms; antimuscarinic drug consumption; short- and long-term side-effects; and quality of life measured with VAS. RESULTS:No statistically significant differences were found in efficacy duration with the three Dysport doses (p=0.5274). The difference between the intervals of injections was not statistically significant (p=0.2659). MCBC, RV, and BC improved significantly after treatment compared with baseline values (p<0.001) and there were no statistically significant differences after each retreatment or regarding Dysport dose (p>0.05). There was a significant improvement in patient satisfaction after each retreatment as expressed on the VAS (p<0.001). There was a significant reduction in IEF score and pads/condoms use in the first 4 wk after each treatment (p<0.0001). CONCLUSION:After repeated injections the effect of BoNTA remained constant. 10.1016/j.eururo.2007.09.034
    Six-year follow-up of botulinum toxin A intradetrusorial injections in patients with refractory neurogenic detrusor overactivity: clinical and urodynamic results. Giannantoni Antonella,Mearini Ettore,Del Zingaro Michele,Porena Massimo European urology BACKGROUND:Most reports in the literature on botulinum toxin A (BoNTA) therapy for neurogenic detrusor overactivity (NDO) are based on the results of a single injection. Because most patients may require retreatment, the efficacy and safety of multiple injections must be addressed clearly. OBJECTIVE:To investigate the effectiveness and safety of BoNTA intradetrusorial injections in a group of spinal cord-injured (SCI) patients with refractory detrusor overactivity (DO). DESIGN, SETTING, AND PARTICIPANTS:Seventeen SCI patients were prospectively included in the study and followed up to 6 yr. INTERVENTION:All patients received repeat intradetrusorial injections of BoNTA 300 units (Botox, Allergan, Irvine, CA) under cystoscopic control on an inpatient basis. MEASUREMENTS:The preliminary assessment included voiding diary, urodynamics, kidney and bladder ultrasound, and cystourethrography. Patients also completed a standardised quality-of-life (QoL) questionnaire. Clinical evaluation, urodynamics, urinary tract imaging, and QoL assessment were repeated every year throughout the follow-up. RESULTS AND LIMITATIONS:Before treatment, all patients complained of urinary incontinence and had DO. Bilateral and monolateral renal pelvis dilatation were detected in six and five patients, respectively, and a monolateral and third-grade vesicoureteral reflux was observed in three. At 6-yr follow-up, a significant decrease in the frequency of daily incontinence episodes (p<0.01), a significant increase in first uninhibited detrusor contraction and in maximum bladder capacity (p<0.001 for both), and a significant decrease in maximum pressure of these contractions (p<0.01) were observed. Fifteen patients (88.2%) were completely continent. Renal pelvis dilatation and vesicoureteral reflux resolved in all cases, and the QoL index significantly increased. Limitations of the study are related to the small number of included patients. CONCLUSIONS:In SCI patients with refractory NDO who do not want or are unfit for invasive reconstructive surgery, BoNTA intravesical treatment represents a valid alternative to control DO and urinary incontinence and to preserve upper urinary tract function over a long-term follow-up. 10.1016/j.eururo.2008.08.048
    Botulinum toxin a versus placebo for refractory detrusor overactivity in women: a randomised blinded placebo-controlled trial of 240 women (the RELAX study). Tincello Douglas G,Kenyon Sara,Abrams Keith R,Mayne Christopher,Toozs-Hobson Philip,Taylor David,Slack Mark European urology BACKGROUND:Emerging data suggest botulinum toxin is an effective treatment for detrusor overactivity (DO), but large studies confirming efficacy and safety are lacking. OBJECTIVE:Study the efficacy and safety of onabotulinumtoxinA (onaBoNTA) for the treatment of DO. DESIGN, SETTING, AND PARTICIPANTS:A double-blind placebo-controlled randomised trial in eight UK urogynaecology centres was conducted between 2006 and 2009. A total of 240 women with refractory DO were randomised to active or placebo treatment and followed up for 6 mo. INTERVENTION:Treatment consisted of 200 IU onaBoNTA or placebo injected into the bladder wall (20 sites; 10 IU per site in 1ml saline). MEASUREMENTS:Primary outcome was voiding frequency per 24h at 6 mo. Secondary outcomes included urgency and incontinence episodes and quality-of-life data. Intention-to-treat analysis was used with imputation of missing data. RESULTS AND LIMITATIONS:A total of 122 women received onaBoNTA and 118 received the placebo. Median (interquartile range) voiding frequency was lower after onaBoNTA compared with placebo (8.3 [6.83-10.0] vs 9.67 [8.37-11.67]; difference: 1.34; 95% confidence interval [CI], 1.00-2.33; p=0.0001). Similar differences were seen in urgency episodes (3.83 [1.17-6.67] vs 6.33 [4.0-8.67]; difference: 2.50; 95% CI, 1.33-3.33; p<0.0001) and leakage episodes (1.67 [0-5.33] vs 6.0 [1.33-8.33]; difference: 4.33; 95% CI, 3.33-5.67; p<0.0001). Continence was more common after botulinum toxin type A (BoNTA; 31% vs 12%; odds ratio [OR]: 3.12; 95% CI, 1.49-6.52; p=0.002). Urinary tract infection (UTI; 31% vs 11%; OR: 3.68; 95% CI, 1.72-8.25; p=0.0003) and voiding difficulty requiring self-catheterisation (16% vs 4%; OR: 4.87; 95% CI, 1.52-20.33; p=0.003) were more common after onaBoNTA. CONCLUSIONS:This randomised controlled trial of BoNTA for refractory DO, the largest to date, confirms efficacy and safety of the compound. UTI (31%) and self-catheterisation (16%) are common. A third of women achieved continence. TRIAL REGISTRATION:The study received ethical committee approval from the Scottish Multicentre Research Ethics Committee (reference: 04/MRE10/67). The trial has a EudraCT number (2004-002981-39), a clinical trial authorisation from the UK Medicines and Healthcare Regulatory Agency, and it was registered on Current Controlled Trials (ISRCTN26091555) on May 26, 2005. 10.1016/j.eururo.2011.12.056
    Botulinum toxin injection in epicardial fat pads can prevent recurrences of atrial fibrillation after cardiac surgery: results of a randomized pilot study. Pokushalov Evgeny,Kozlov Boris,Romanov Alexander,Strelnikov Artem,Bayramova Sevda,Sergeevichev David,Bogachev-Prokophiev Alexander,Zheleznev Sergey,Shipulin Vladimir,Salakhutdinov Nariman,Lomivorotov Vladimir V,Karaskov Alexander,Po Sunny S,Steinberg Jonathan S Journal of the American College of Cardiology 10.1016/j.jacc.2014.04.062
    Botulinum toxin A for upper limb spasticity. Kwakkel Gert,Meskers Carel G M The Lancet. Neurology 10.1016/S1474-4422(15)00222-7
    Botulinum Toxin to Treat Endometriosis Pain. Rubin Rita JAMA 10.1001/jama.2019.12350