## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Lactucin and Its Derivatives Lactucin, and Lactucipcrin  
Other compounds from the guaianolide subclass are lactucin (**7**) (C15H16O5) and its 8- and 15- (4-hydroxyphenylacetate) derivatives lactupicrin (**8**) and lactucopicrin (**9**), respectively (Figure 8). [PERSON] et al. [156] and [PERSON] et al. [157] had previously described the chemical structure of lactucin (**7**). These compounds are distributed within Asteraceae like _Lactuca serriola_[158], especially plants commonly used in salads. _Lactuca sativa_ (lettuce), _Cichorium intylus_ (chicory and radicchio), and _Cichorium endivia_ (endive) have been reported to contain lactucin (**7**) and lactucin-related substances [159; 160; 161; 162; 163; 164]. The content depends largely on the species, variety and the part of the plant analyzed. In fact, lettuce guaianolide content was high and reached concentrations between 61.7 mg/mL and 147.1 mg/mL in its latex [160] and 2.9 mg/g to 36.1 mg/g in the overall plant, expressed as dry weight [162]. The biological activities of lactucin (**7**) and lactucin-related compounds had already attracted interest at the end of the 19 th century, as they were credited to be responsible for the bitter taste and pharmacological effect of lactucarium or lettuce opium [165]. This is the condensed latex of wild lettuce _Lactuca virosa_. This dried exudate was used in Europe for centuries with similar applications to opium as an analgesic, antitussive, and sedative [163]. Due to its widespread use, it was described and standardized in the United States Pharmacopoeia (USP) and the British Pharmaceutical Codex as a sedative for irritable cough and as a mild hypnotic for insomnia [166; 167; 168]. Lactucopicrin (**9**) and lactucin (**7**) were identified as its major active compounds, although compound **7** was suggested to be one of the main metabolites related to the sedative and the sleep-promoting effects [163]. In an in vivo study in mice, both substances were confirmed to be analgesics, with an activity equal to or greater  
Figure 8: Structures of lactucin (**7**) and its derivatives lactupicrin (**8**) and lactucopicrin (**9**). Figure 7: Structure of invuiscolide (**6**). than ibuprofen. In addition, when lactucin (**7**) and lactucopicrin (**9**) were administered to mice on the hot plate, both compounds were revealed to have analgesic and sedative effects at concentrations of 15 and 30 mg/kg, respectively. Furthermore, in a spontaneous locomotor activity test, these compounds were active at concentrations of 30 mg/kg [168]. Although the pure compounds currently are not easily available on the market, several lettuce extracts and seed oils containing these sesquiterpene lactones as main active compounds are commercialized, e.g., Sedan(r) (Pharco Pharmaceutical Company, Egypt). The sedative effects were addressed in the pilot study by [PERSON] et al. [169]. The authors investigated if lettuce seed oil was efficient and safe to treat patients with sleep disorders. The results showed that the seed oil of _L. sativa_ was a potentially hazard-free agent, able to reduce sleeping difficulties and alleviate mild to moderate forms of anxiety in geriatric patients, without showing side effects [169; 170]. Additionally, the study performed by [PERSON] et al. [163] examined the sleep-inducing and sleep-prolonging effect of four lettuce varieties. The seed and leaf extracts were evaluated using a four-week-old ICR mouse model to analyze their effects on pentobarbital-induced sleep. The results showed that both extract types lengthened sleep duration and significantly reduced sleep latency at both evaluated doses of 80 mg/kg and of 160 mg/kg [163]. Although these studies in patients were performed with plant extracts reported to contain lactucin (**7**) and its derivatives as principal active pharmacological compounds, they confirm that their application for treatment of anxiety and sleep disorders is worthy of further evaluation.