Lantox—The Chinese Botulinum Toxin Drug—Complete English Bibliography and Comprehensive Formalised Literature Review

In 1997, lanbotulinumtoxinA (LAN) was introduced in China. It is now available in Asia, Latin America and Eastern Europe under various brand names including Hengli®, Lantox®, Prosigne®, Lanzox®, Redux®, Liftox®, HBTX-A and CBTX-A. The literature on LAN is mostly published in Chinese language, restricting its international accessibility. We, therefore, wanted to generate a complete English bibliography of all LAN publications and then use it for a comprehensive formalised literature review. Altogether, 379 LAN publications (322 in Chinese and 57 in English) were retrieved from PubMed and Science and Technology Paper Citation Database. Indications covered are motor (257), glandular (16), pain (32) and aesthetics (48). Topics are neurological (250), aesthetic (48), paediatric (38), ophthalmological (18), urological (9), methodological (6), gastroenterological (5), ear, nose and throat (4) and surgical (1). Seventy-one publications are randomised controlled trials, forty-one publications are interventional studies and observational studies, fifteen publications are case studies, eighteen publications are reviews, and two publications are guidelines. LAN publications cover all relevant topics of BT therapy throughout a period of more than 20 years. This constitutes a publication basis resembling those of other BT drugs. None of the LAN publications presents data contradictory to those generated with other BT type-A drugs. LAN seems to have a similar efficacy and safety features when compared to onabotulinumtoxinA using a 1:1 LAN– onabotulinumtoxinA conversion ratio. Large controlled multicentre studies will become necessary for LAN’s registrations in Europe and North America.


Introduction
Botulinum toxin (BT) is produced by the anaerobic bacterium Clostridium botulinum. In the early 19th century, Justinus Kerner first recognised BT as the cause of botulism. In 1980, Alan B. Scott invented BT's therapeutic use by applying it as a muscle relaxant for the treatment of strabismus in children [1]. In the meantime, BT's use has expanded tremendously into numerous therapeutic indications and into widespread aesthetic use.

General
As shown in Table 1, altogether 379 LAN publications were retrieved: 322 publications are in Chinese, and 57 publications are in English. Five of the fifty-seven English publications appear in Chinese journals, and fifty-two publications come out of non-Chinese sources. Publication languages other than English and Chinese were not retrieved.
Two-hundred and fifty-seven publications cover motor indications, sixteen publications include glandular indications, thirty-two publications include pain, forty-eight publications include aesthetic indications, six publications include methodological aspects, and twenty publications are reviews and guidelines.
Two-hundred and fifty publications are research in the neurological field, forty-eight publications are in the aesthetic field, thirty-eight publications are in the paediatric field, eighteen publications are in ophthalmologic field, nine publications are about urologic indications, five publications are about gastroenterologic indications, four publications are regarding ear, nose and throat, and one publication is regarding surgical indications. Two-hundred and thirty-one publications are about observational studies, seventyone publications are about randomised controlled trials, forty-one publications are about interventional studies, eighteen publications are reviews, fifteen publications are case studies, and two publications are guidelines.
In the following, we will summarise the number of publications and discuss in detail some selected randomised controlled trials, interventional studies, reviews and guidelines for each indication.

Motor Indications
Motor indications are indications where the therapeutic effect is based on the blockade of the cholinergic innervation of hyperactive muscle tissue. Those are the first indications of BT therapy. Whether the entire therapeutic effect relies on a direct peripheral effect alone is not entirely clear. Retrograde axonal transport [8] may also affect spinal or higher central nervous system structures [9]. Additionally, indirect effects on the central nervous system may also contribute to BT's therapeutic effect.

Dystonia
Dystonia was-after strabismus and together with hemifacial spasm-the second group of indications developed. It is still the largest indication group for BT's therapeutic use. Altogether, 106 LAN publications refer to the treatment of dystonia. In most publications, more than one dystonia manifestations are covered. Publications on blepharospasm also include the treatment of Meige syndrome, hemifacial spasm and sometimes cervical dystonia.
Thirty-five publications (thirty-two as primary topic publications and three as secondary topic publication) cover blepharospasm. They deal with the efficacy and safety of LAN therapy, injection sites, injection patterns and its comparison to that of surgical treatment. Sometimes, large cohorts are reported, and long-term experience is shared. Table  2 shows two randomised controlled trials on LAN in blepharospasm. One of them [10] showed no difference in efficacy and safety between LAN and ONA. The other one [11] showed that sparing the medial lower eyelid improves tear film stability and lacrimal fluid drainage. One cross-over interventional study [12] found no difference in efficacy and safety between LAN and ONA. All comparisons were based on a dose conversion ratio between LAN and ONA of 1:1. Seventeen publications (thirteen as primary topic publicationss and four as secondary topic publications) cover Meige syndrome. They deal with the efficacy and safety of LAN therapy, combinations with spasmolytic drugs and combinations with wrinkle treatment. Sometimes, large cohorts are reported, and long-term experience is shared. Most studies also include patients with blepharospasm and hemifacial spasm. Thirty-two publications (all as primary topic publications) cover cervical dystonia. They deal with injection guidance by electromyography or ultrasound, variations of LAN concentrations, drug comparisons between LAN, ONA and ABO, combinations of LAN and orthoses, combinations of LAN and thermocoagulation of peripheral nerves, the treatment of tardive cervical dystonia, as well as long-term studies and reports on larger cohorts. Table 2 shows six selected randomised controlled trials for cervical dystonia. One study [13] compared LAN and ONA at a 1:1 dose conversion ratio, and one study [3] compared LAN and ABO at a 1:3 dose conversion ratio. Both studies did not find a difference in efficacy and safety between both drugs. One study [14] showed that LAN together with orthopaedic joint braces has a better efficacy than LAN alone, whereas oral drugs are not effective. One study [15] showed that electromyographic guidance produces identical efficacy and less adverse effects but was more painful. Therapeutic effects are also longer. Two studies [16,17] demonstrated that different LAN dilutions do not affect efficacy and safety.
Five publications (all as primary topic publications) cover craniocervical dystonia, two publications are about writer's cramp (all as primary topic publications), tweleve publications are about dystonias (eleven as primary topic publications and one as a secondary topic publication), and three are about spasmodic dysphonia (all as primary topic publications). They mainly report larger cohorts, long-term follow-ups and general efficacy and safety data. Table 2 shows the randomised controlled trial on adductor-type spasmodic dysphonia [18]. It was demonstrated that LAN with a dose of 10 MU produces longer effects than LAN with dose of 5 MU whereas peak efficacy and safety of these two doses are not different.
Three publications refer to the treatment of temporomandibular joint dysfunction, with all as primary topics. The aetiology of the condition is mixed (habitual dislocation, masticatory spasms and masticatory pain), and potential therapeutic mechanisms remain unclear. Table 2 shows the randomised controlled trial on temporomandibular joint disorders [19]. It was demonstrated that semiconductor laser therapy with LAN has better efficacy on inflammation and pain than semiconductor laser therapy alone.

Hemifacial Spasm
Hemifacial spasm is together with dystonia the second indication developed for BT therapy following strabismus. As shown in Table 1, 35 LAN publications refer to the treatment of hemifacial spasm (17 as primary topic publications and 18 as secondary topic publications). Table 2 shows two randomised controlled trials and two interventional studies on LAN for hemifacial spasm, one randomised controlled trial [10] and one interventional study [12] by comparing LAN and ONA, and no difference in efficacy and safety was found when converted on a LAN and ONA dose conversion ratio of 1:1. One randomised controlled trial [20] showed additional posterior auricular muscle injections can reduce acoustic symptoms, and one interventional study [21] showed that the LAN dose of 50 MU/mL produces longer therapeutic effects and more adverse effects than that of 25 MU/mL whereas the peak efficacies at these two doses are identical.

Tics
Tics have been tried successfully on several occasions, because of their similarity with dystonia, especially cranial dystonia. As shown in Table 1, one LAN publication (as a primary topic publication) refers to tics and is an observational study.

Spasticity
Spasticity is another main indication for BT therapy. Historically, it was developed after strabismus, dystonia and hemifacial spasm. As shown in Table 1, 40 LAN publications (all as primary topic publications) refer to spasticity. Apart from general data on efficacy and safety, they cover different aetiologies (stroke, spinal cord injury and brain damage), combinations with other methods (rehabilitation training, physiotherapy, acupuncture, Shujin Huoluo lotion-a traditional Chinese medicine to reduce spasticity and electric stimulation), different LAN doses, different LAN concentrations, different BT drugs, different spasticity locations (arms and legs) and injection guidance with ultrasound and electromyography. Table 3, 10 randomised controlled trials deal with spasticity. Five of them are about arm spasticity, and five are about leg spasticity. One randomised controlled trial [22] demonstrated the general efficacy and safety of LAN against placebo. Four randomised controlled trials [23][24][25][26] demonstrated that LAN improves rehabilitation. One randomised controlled trial demonstrated that LAN improves acupuncture [27], and two randomised controlled trials reported that ankle brace [28] and spasmodic muscle training [29] improve LAN therapy. One randomised controlled trial [30] showed that intensified physiotherapy improves LAN therapy compared with regular physiotherapy, and one randomised controlled trial [31] suggested that using higher LAN doses (i.e., 400 MU) with lower concentrations (i.e., 50 MU/mL) may improve LAN therapy outcome.

Cerebral Palsy
Cerebral palsy is a syndrome consisting of various neurologic deficits all caused by perinatal brain damage. Motor deficits are the hallmark, frequently including dystonic and spastic elements which have been treated successfully with BT therapy for many years. Economically, cerebral palsy turns out to be one of the most important BT indications, not only because of its prevalence, but also because of the usually high BT doses applied. As shown in Table 1, 38 LAN publications refer to the treatment of cerebral palsy, all as primary topics. They cover general efficacy and safety, prognosis of cerebral palsy under LAN therapy, dosing issues, co-therapies with serial casting and herbal baths, application guidance with electric stimulation and ultrasound, special or individual target muscles (arms, iliopsoas and triceps surae) and long-term follow-ups. Table 4 shows six randomised controlled trials dealing with cerebral palsy. Two randomised controlled trials showed that LAN improves rehabilitation [32,33], and one randomised controlled trial showed that rehabilitation improves LAN therapy [34]. One randomised controlled trial suggested that LAN with a 6 MU/kg body weight has a stronger effect in more severe cerebral palsy [35], whereas one randomised controlled trial [36] found that LAN with different body weights (i.e., 3, 4 or 5 MU/kg) does not produce different effects. One randomised controlled trial showed that BT injection combining traditional Chinese medicine and Ueda, a physical therapy method for spasticity, could improve CPs more effectively, especially in motor function and balance ability [37].

Strabismus
Strabismus is the first indication developed by Alan B. Scott for BT therapy. Its relevance today is limited. As shown in Table 1, 18 LAN publications refer to the treatment of strabismus, with 17 as primary topic publications and 1 as a secondary topic publication. The topics covered include general data on efficacy and safety, application together with hyaluronate, application guidance by ultrasound or electromyography, different aetiologies (idiopathic, intermittent exotropia, concomitant esotropia, thyroid ophthalmopathy and cranial nerve palsy) and comparison with surgery. One randomised controlled trial [38] showed that LAN injections with sodium hyaluronate have identical efficacy as LAN injections alone, but produce less ptosis.

Bladder Dysfunction
BT therapy for bladder disorders is one of the established indications for BT therapy. Altogether, eight LAN publications refer to bladder dysfunction (all as primary topic publications). They cover different aetiologies (spinal cord injury and idiopathic), different LAN doses and different BT drugs. Different terminologies are used, such as overactive bladder, detrusor hyperreflexia, interstitial cystitis, bladder pain syndrome and neurogenic incontinence. Table 5 shows three randomised controlled trials on bladder dysfunctons. One of them [39] showed that LAN is more effective in female overactive bladder than oral drugs, and one [40] showed that LAN with a dose of 200 MU including the trigonum and LAN with a dose of 300 MU excluding the trigonum produce identical efficacy and safety.
One randomised controlled trial [41] showed that LAN with a dose of 200 MU combined with electroacupuncture is more effective than LAN with a dose of 200 MU alone.

Gastroenterological Indications
Gastroenterological indications are a collection of mainly experimental indications with achalasia being the most robust one studied. As shown in Table 1, altogether five LAN publications refer to gastroenterological indications. One publication as a primary topic covers gastroparesis, two publications are about achalasia (both as primary topic publications), one publication is about oesophageal strictures (as a primary topic publication) and one publication is about dysphagia (as a primary topic publication). One randomised controlled trial [42] indicated that LAN is effective and safe for the prevention of oesophageal strictures. All other studies are either case studies or observational studies.

Other Indications
There are publications dealing with Raynaud syndrome (as a primary topic publication) [43], Anismus (as a primary topic publication) [44] and Tinnitus (as a primary topic publication) [45]. The studies are case studies or observational studies and showed LAN is effective and safe.

Glandular Indications
Glandular indications are indications where the therapeutic effect is based on an activity reduction of exocrine glands innervated by the cholinergic autonomic nervous system. Affected glands may be sweat glands, salivary glands and lacrimal glands. Additional exocrine glands may be used for therapeutic purposes in the future. Injections into smooth muscles which are also innervated by the cholinergic autonomic nervous system will be covered in the section "Muscle indications". Glandular indications are very rewarding indications for BT therapy. Especially, hyperhidrosis is an important indication because of its prevalence, the lack of successful treatment alternatives and the excellent results of BT therapy. As shown in Table 1, altogether 16 publications refer to glandular indications.

Hyperhidrosis
Eleven publications (all as primary topic publications) cover hyperhidrosis. Topics include general data on efficacy and safety, different LAN doses, different regions affected (axillary and palmar) and different aetiologies (primary and secondary). Often, unusual terminology is applied, such as bromhidrosis, osmidrosis and hircismus.
As shown in Table 6, two randomised controlled trials on axillary hyperhidrosisone of them [46] demonstrated that LAN with a dose of 200 MU per axilla has longer efficacy than LAN with a dose of 50 MU per axilla. The other randomised controlled trial [47] suggested that LAN is more effective for mild and moderate axillary hyperhidrosis, whereas surgical gland excision is more effective for severe one.

Sialorrhea
Four studies (all as primary topic publications) deal with sialorrhea or hypersalivation. Topics cover general data on efficacy and safety, ultrasound guidance of parotid and submandibular gland injections and different aetiologies (cerebral palsy and brain damage). As shown in Table 6, one randomised controlled trial [48] showed that the electrical stimulation of tongue, orbicular oris and buccinators muscles with LAN is more effective than electrical stimulation alone.

Prostate Hyperplasia
As shown in Table 6, one observational study [49] suggested the effect of LAN on benign prostate hyperplasia. The mechanism involved remains unclear.

Pain Indications
Pain indications are indications where the therapeutic effect is based upon modulations of nociception, pain transmission and pain processing. Involved neural structures are not entirely understood. Where and how BT might interfere is not well investigated. Central nervous system effects may exist. BT can also achieve pain reduction by reduction excessive muscle hyperactivity. Additional nociceptive effects may be caused by potentially anti-inflammatory effects.
Pain indications are the latest major extension of BT therapy with chronic migraine being all dominant. As shown in Table 1, altogether 33 LAN publications refer to pain indications. Twenty publications (all as primary topic publications) cover migraine, nine publications are about trigeminus neuralgia (all as primary topic publications), and three publications are about postherpetic neuralgia (all as primary topic publications). Table 7 shows four randomised controlled trials dealing with migraine: one of them [50] showed the efficacy and safety of LAN against placebo, and one study [51] demonstrated that LAN is more efficient than lidocaine combined with prednisolone injections. one study [52], the authors found that LAN with oral drugs is more effective than oral drugs alone, and one publication [53] showed that LAN application in acupuncture points is more efficient than application-fixed injection sites. Three randomised controlled trials deal with chronic migraine: one of them [54] demonstrated the efficacy and safety of LAN against placebo, and the other two [55,56] showed that LAN combined with infrared light is more efficient than LAN alone, infrared light alone and oral drugs alone.

Trigeminal Neuralgia
Three randomised controlled trials examined LAN in trigeminal neuralgia: one of them showed efficacy and safety against placebo [57], one [58] showed that LAN with a dose of 75 MU is not more effective than LAN with a dose of 25 MU, and one [59] found that doubling the LAN dose as a booster injection does not increase efficacy.

Tension-Type Headache
One randomised controlled trial [60] found that LAN is more effective than oral drugs in tension-type headaches.

Post-Herpetic Neuralgia
One randomised controlled trial [61] demonstrated the efficacy and safety of LAN against placebo in post-herpetic neuralgia.

Aesthetic Indications
Aesthetic indications are indications where BT is not used to treat a disease, but to improve appearance. All indications presented here are medical procedures reserved for physicians. They are generally not covered by reimbursement systems. Aesthetic indications were developed very early on by neurologists treating blepharospasm. Soon, their potential for aesthetic medicine was realised and strategically developed. Around 50% of global medical BT use is in the field of aesthetic medicine. The contouring of the masseter and the calf muscles is specific to Asian countries. Altogether, 48 LAN publications refer to aesthetic indications. Thirty-eight publications (37 as primary topic publications and one as a secondary topic publication) cover wrinkles, six publications refer to calf reduction (all as primary topic publications), two publications refer to masseter hypertrophy (both as primary topic publications), two publications are about scars (both as primary topic publications) and one publication is about acne (as a primary topic publication). As shown in Table 8, all five randomised controlled trials studied LAN in forehead wrinkles and glabellar lines. One study [62] showed LAN's efficacy and safety against placebo in forehead wrinkles. Four of them [63][64][65][66] showed that lower LAN doses produce identical peak efficacy, but shorter effect duration in forehead wrinkles and glabellar lines at a slightly less risk of adverse effects.

Methods
As shown in Table 1, six publications refer to methodological issues. Three publications (as primary topics) cover LAN comparisons with ONA and ABO, one publication refers to remote effects (as a primary topic), and two publications are about allergic effects (as primary topics). All comparative studies suggest similar efficacy and safety, when LAN is converted to ONA at a 1:1 LAN-ONA dose conversion ratio [10] and to ABO at a 1:3 LAN-ABO dose conversion ratio [67]. Rare allergic reactions contribute to LAN's bovine gelatine content [68,69].

Reviews and Guidelines
Altogether, 20 publications are reviews and guidelines. Eighteen reviews cover BT use in China in areas of neurology, cervical dystonia, autonomic disorders, hyperhidrosis, urology, overactive bladder, prostate hyperplasia, scars, aesthetic applications, calf hypertrophy and depression. Two guidelines deal with BT therapy in plastic surgery and adult limb spasticity.

Discussion
This paper presents the first complete English bibliography of all LAN publications until 1 July 2018. It is based on the English database PubMed and the Chinese data base Science and Technology Paper Citation Database (STPCD). It shows, for the first time, all authors' names, publication titles and source names in English, thus making them accessible to the international English-speaking audience. Supplementary Materials can be found. This paper also presents the first comprehensive review of all LAN publications until 1 July 2018. It is based on the English bibliography above and additional English translations of all LAN articles originally published in Chinese. It is structured as a formalised literature review.
LAN publications have been produced over a period of more than 20 years, making LAN one of the three longest used BT drugs worldwide.
LAN is used for motor, glandular, pain and aesthetic indications. Medical specialties involved are neurology, aesthetics, paediatrics, ophthalmology, urology, gastroenterology, ENT and surgery. Therefore, LAN is used in all major BT indications other BT drugs have been used for. This also documents the widespread use of LAN in China.
Of the 379 publications retrieved, 71 are randomised controlled trials, 41 are interventional studies, 231 are observational studies, 15 are case studies, 18 are reviews, and 2 are guidelines. This constitutes a publication basis similar to the ones of other international BT drugs. Relatively low percentages of randomised controlled trials and interventional studies are also typical for other BT drugs.
None of the publications presents data contradictory to those generated for other BT type-A drugs. Based on a 1:1 LAN-ONA conversion ratio, LAN seems to have a similar efficacy and safety features compared to ONA. A recent publication studying the biological potency of LAN, ONA and INCO in a direct comparison did not detect differences in their potency labelling [70], thus confirming this equipotency.
Large controlled multicentre studies will eventually become necessary for LAN's registrations in Europe and North America. Further studies on LAN's product details, including its specific biological potency, its production consistency and its stability, will then become necessary. LAN's increased international presence will increase the number of international studies published in international journals.

Methods
This review is based upon comprehensive literature searches in the English data base "PubMed" (National Center of Biomedical Information, United States National Library, Medicine and National Institutes of Health) and the Chinese data base "STPCD" within Wanfang data. The searches include all references published until 1 July 2018. They were performed along two axes with the following search words: Axis 1: Botulinum toxin and China or Chinese or Lanzhou, Prosigne, Lantox, Hengli, HBTX-A, Lanzox, Redux, Liftox, CBTX-A.
All publications contain at least one item on each axis. All retrieved publications appearing in Chinese were first translated into English, before they were referenced with their authors' names, publication year, study design, title and source. Within their sections, all references were ordered by their authors' names using the English alphabet and by their publication years. The complete bibliography is presented as Supplementary Materials. Each reference was classified under the terms motor indications, glandular indications, pain indications, aesthetic indications, methods and reviews and guidelines, as shown in Table 1. All publications were further classified according to their study design as randomised controlled trial, interventional study, observational study and case study, review and guideline. In Table 1, all references were also classified into primary topic publications where the topic is the primary one and secondary topic publications where the topic is an additional one. Selected publications classified as randomised controlled trial, interventional study, review and guideline may be discussed in detail in the main text and the tables of this article. Discussions will include efficacy and adverse effects.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/toxins13060370/s1. Author Contributions: D.D. design, data evaluation, data interpretation, writing; L.P. data acquisition, data evaluation, data interpretation, writing; J.S. data evaluation, data interpretation, writing; F.T. data evaluation, data interpretation, writing; L.J. design, data interpretation. All authors have read and agreed to the published version of the manuscript.