## 2 Timeline of Historical Events about BoNTs Discovery  
The term botulism, which derives from the Latin word \"bottulus\" (meaning sausage), was used in Europe in the 18 th century to describe a highly lethal disease with muscle paralysis leading to respiratory arrest after eating raw sausages. In the period 1817-1822, \begin{table}
\begin{tabular}{c c c} \hline \hline \multicolumn{3}{c}{**Tox-Action of _Clostridium_ spp.**} \\ \hline
**Enterotoxic** & **Neurotoxic** & **Histolytic** \\ \hline _C. colinum_ & & _C. dunovoi_ \\ _C. difficile_ & & _C. hnemoliticum_ \\ _C. perfrringens_ & _C. botulinum_ & _C. histolytica_ \\ _C. septicum_ & _C. tetuni_ & _C. perfrringens_ \\ _C. piliforme_ & & _C. novyi_ \\ _C. sordelli_ & & _C. septicum_ \\ _C. spiroforme_ & & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Classification of pathogenic _Clostridium_ spp. according to the toxins’ target. the German Dr. [PERSON] (1786-1862) first described botulism, a food poisoning after consumption of meats, performing confirmative studies. It is noteworthy that he was also the first physician to propose the therapeutic use of the botulinum toxin. In 1897, after an epidemic of botulism in the city of Elezel (Belgium) due to the consumption of ham of homemade pork, the microbiologist [PERSON], discovered the bacterium and concluded that the disease was caused by the anaerobic growth of the microorganism and that the endospores produced a toxin [11]. In the 1920s, scientists were able to isolate one of the seven toxins produced by _Clostridium_, such as the toxin BoNT-A, which is now the active form of the commercial drug Botox(tm). During the Second World War, the research on the manufacture of biological weapons that could infect and affect the nervous system had a strong impulse, so two military laboratories, one in the United States and one in England, studied the effects of toxin B [11; 12]. After the end of the II World war, in the 1950s and 1960s, research revealed the mechanism of action of the toxin, but the medical use of botulinum toxin began in 1977. In fact, in 1978, [PERSON], an American ophthalmologist, decided to try the toxin to treat strabismus that caused the rolling of the eyes, thus becoming the first to use the botulinum neurotoxin drug in humans [12]. The results of his studies were published in medical journals in the 1980s and then many doctors applied his technique to treat eyelid twitching and other muscle spasms. The drug was originally called _Oculinum_, from the Latin oculi, which means eyes [13]. Since the 1970s the BoNT-A, has been used not only for aesthetic purposes but also as a medicine in a wide variety of diseases and its indications have increased over time. Its action appears a few days after administration and usually lasts between 7 and 10 days. In fact, BoNT-A was first used extensively for the neurological disorder as treatment of focal dystonia and is now used in other diseases such as in the field of dermatology, urology, gastroenterology, and others. In 1982 discovered that the drug had a side effect of eliminating skin wrinkles at the injection site. Later, the same drug was recalled Botox, and was licensed by the American FDA for wrinkles. Botox has already caused a small revolution in cosmetic plastic surgery in an easy, simple, and safe way [11; 14]. In England, in 1993, [PERSON] and [PERSON] were the first to use BTX-A for nonmuscular problems demonstrating that injections of toxins inhibit sweating and can therefore be useful in the treatment of hyperhidrosis [15]. In 1996, other aesthetic applications began and in 2002, he obtained FDA approval for these. In 2010, the FDA approved intramuscular injections for the prophylactic treatment of migraines and headaches and in 2014, the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) approved BoNTA for the treatment of limited ankle movement (due to stroke-related spasticity of the lower limbs) [16].