Allamanda cathartica: A Review of the Phytochemistry, Pharmacology, Toxicology, and Biotechnology

In this work, we explore the current knowledge about the phytochemistry and in vitro and in vivo evaluations of the extracts and, where appropriate, the main active components characterized and isolated from the Allamanda cathartica. Of the 15 Allamanda species, most phytochemical, pharmacological, and toxicological studies have focused on A. cathartica. These plants are used for the treatment of various health disorders. Numerous phytochemical investigations of plants from the A. cathartica have shown the presence of hydrocarbons, alcohols, esters, ethers, aldehydes, ketones, fatty acids, phospholipids, volatile compounds, phenolic compounds, flavonoids, alkaloids, steroids, terpenes, lactones, and carbohydrates. Various studies have confirmed that extracts and active substances isolated from the A. cathartica have multiple pharmacological activities. The species A. cathartica has emerged as a source of traditional medicine used for human health. Further studies on the phytochemical, pharmacological, and toxicological properties and their mechanisms of action, safety, and efficacy in the species of A. cathartica is recommended.


Introduction
The plant Allamanda is a very widespread group throughout the world. It belongs to the family Apocynaceae and, according to the "The Plant List," contains approximately 15 species (A. augustifolia, A. blanchetti, A. caccicola, A. cathartica, A. doniana, A. laevis, A. martii, A nobilis, A. oenotherifolia, A. polyantha, A. puberula, A. schottii, A. setulosa, A. thevetifolia, and A. weberbaueri) [1]. The objective of this work is to present complete information about the current research on the distribution, phytochemistry, pharmacology, toxicity, and biotechnology of Allamanda cathartica; to identify its therapeutic potential; and to direct future research opportunities. The most relevant data were searched using the keyword "Allamanda cathartica" in "Google Scholar", "PubMed", "ScienceDirect", "Scopus", "Taylor & Francis", "Web of Science", and "Wiley". The taxonomy was validated using the "The Plant List".

Botanical Characterization
The genus Allamanda is endemic to South America [2]. The genus is named after the Swiss botanist Jean Frédéric-François Louis Allamand, who collected seeds in Suriname and sent them to Carlos Linnaeus to be named in 1771 [3]. A. cathartica plants are robust shrubs growing up to 6 m tall. The leaves are elliptical to obovate, opposite, or in whorls. The flowers are yellow and trumpet-shaped, with corolla tubes. The flowers are similar in size to the leaves. The fruits are capsules with spins, The leaves are elliptical to obovate, opposite, or in whorls. The flowers are yellow and trumpetshaped, with corolla tubes. The flowers are similar in size to the leaves. The fruits are capsules with spins, and the seeds are compressed and winged. The shrubs, with their beautiful yellow flowers, are popular ornamentals [4]. The species flowers grow all year round, and fruits grow from April to July and in October. In botanical texts, A. cathartica is reported to have a wide global distribution in warm climates ( Figure 1) [2]. Based on these data, a more exhaustive analysis of the scientific literature was performed.
Only these groups of chemical compounds have been isolated and identified, and no anthraquinones, anthocyanins, coumarin, quinones, or lignins have been found. The Marvin program was used to draw the structures of organic chemical compounds [55].

Hydrocarbons
The presence of 3 hydrocarbons has been confirmed in A. cathartica flowers (Table 1 and Figure 2).
Only these groups of chemical compounds have been isolated and identified, and no anthraquinones, anthocyanins, coumarin, quinones, or lignins have been found. The Marvin program was used to draw the structures of organic chemical compounds [55].

Alcohol, Ester, Ether, Aldehyde, and Ketone
Seven alcohol compounds were identified, as well as 9 esters, 1 ether, 6 aldehydes, and 1 ketone in various extracts of flowers, leaves, and stems (Table 2 and Figure 3).

Alcohol, Ester, Ether, Aldehyde, and Ketone
Seven alcohol compounds were identified, as well as 9 esters, 1 ether, 6 aldehydes, and 1 ketone in various extracts of flowers, leaves, and stems (Table 2 and Figure 3).

Fatty Acids and Phospholipids
A fatty acid composition analysis resulted in the identification of 37 compounds and a compound of very unusual structure (59). Two phospholipids were also identified. The flowers, leaves, and stems were used for the isolation of these compounds (Table 3 and Figure 4).

Fatty Acids and Phospholipids
A fatty acid composition analysis resulted in the identification of 37 compounds and a compound of very unusual structure (59). Two phospholipids were also identified. The flowers, leaves, and stems were used for the isolation of these compounds (Table 3 and Figure 4).

Volatile Compounds
A total of 43 volatile compounds have also been identified, mostly in flowers and leaves (Table  4 and Figure 5).

Phenolic Compounds and Flavonoids
From the flowers and stems, 5 phenolic compounds and 6 flavonoids have been identified (Table  5 and Figure 6).

Phenolic Compounds and Flavonoids
From the flowers and stems, 5 phenolic compounds and 6 flavonoids have been identified (Table  5 and Figure 6).

Alkaloids
Two alkaloids present in the stems are the only ones reported in the literature [38] (Table 6  and Figure 7).

Alkaloids
Two alkaloids present in the stems are the only ones reported in the literature [38] (Table 6 and Figure 7).

Steroids and Terpenes
Carotenoids are terpene compounds. They can be yellow, orange, or red in pigment, and they are widely distributed in nature. In plants, they play an important role in photosynthesis and in the colouring of flowers and fruits [62]. A. cathartica carotenoids have been found in flowers, leaves, and stems (

Steroids and Terpenes
Carotenoids are terpene compounds. They can be yellow, orange, or red in pigment, and they are widely distributed in nature. In plants, they play an important role in photosynthesis and in the colouring of flowers and fruits [62]. A. cathartica carotenoids have been found in flowers, leaves, and stems (Table 7 and Figure 8).

Alkaloids
Two alkaloids present in the stems are the only ones reported in the literature [38] (Table 6 and Figure 7).

Steroids and Terpenes
Carotenoids are terpene compounds. They can be yellow, orange, or red in pigment, and they are widely distributed in nature. In plants, they play an important role in photosynthesis and in the colouring of flowers and fruits [62]. A. cathartica carotenoids have been found in flowers, leaves, and stems (

Carbohydrates
The presence of 6 carbohydrates in the leaves, stems, and nectar has been shown (Table 9 and Figure 10).

Pharmacological Activity
A. cathartica has been reported in traditional medicine, and the first biological and pharmacological studies were documented in 1943 [68]. A more general view of the pharmacological investigations on various crude extracts and isolated chemical compounds of the species are described below.

Carbohydrates
The presence of 6 carbohydrates in the leaves, stems, and nectar has been shown (Table 9 and Figure 10).

Carbohydrates
The presence of 6 carbohydrates in the leaves, stems, and nectar has been shown (Table 9 and Figure 10).

Pharmacological Activity
A. cathartica has been reported in traditional medicine, and the first biological and pharmacological studies were documented in 1943 [68]. A more general view of the pharmacological investigations on various crude extracts and isolated chemical compounds of the species are described below.

Pharmacological Activity
A. cathartica has been reported in traditional medicine, and the first biological and pharmacological studies were documented in 1943 [68]. A more general view of the pharmacological investigations on various crude extracts and isolated chemical compounds of the species are described below.

Analgesic
In a previous study conducted in our laboratory, it was observed that the ethanol extract from the aerial parts of A. cathartica showed an analgesic activity in the murine model.

Anti-Inflammatory
The inhibition of haemolysis in human erythrocytes by an aqueous fraction from a methanol extract was evaluated, with rates of 69.49 ± 0.49% compared to the positive control acetyl salicylic acid (0.1 mg/mL), which showed a 72.79% inhibition [69]. In another study, the compound (119) obtained from fresh A. cathartica flowers was evaluated for anti-inflammatory activity using an in vitro haemolytic membrane stabilization study. The effect of inflammation was studied using erythrocytes exposed to a hypotonic solution. The results indicated that the obtained compound showed a membrane stabilizing activity, which was highest with 75 µg [70]. In an in vivo model, the compound (145) from a flower ethanol extract was evaluated for activity against ulcerative colitis induced by dextran sulfate sodium (DSS) in female mice. As a standard control, 5-Amino-Salicylic Acid was used, and the mice were administered either compound at the same dose (100 mg/kg/day for 7 days). Treatment with the (145) compound resulted in less shortening of the colon, improved histological damage, and less mucin depletion of the intestinal mucosa compared to the group only treated with the vehicle [71].

Antidepressant
The antidepressant activity of the compound (145) was evaluated in Swiss Webster female mice (0.5, 1, and 2 µg/kg i.p). Doses of 1 and 2 µg/kg showed a significant difference p < 0.001 with respect to the negative control. Imipramide (20 mg/kg i.p.) was used as a positive control [61].

Antidiabetic
Aqueous extracts from the aerial parts of A. cathartica (400 mg/kg for 28 days) reduced blood glucose levels in diabetic rats with streptozotocin, compared to glibenclamide (5 mg/kg) as a standard, with a statistical significance p < 0.001 [48].

Antifertility
The oral administration of aqueous leaf extracts of A. cathartica (150 mg/kg/day for 14, 28, and 42 days) induced infertility and changes in various male reproductive endpoints in Parkes strain mice. Histologically, the testes from the extract-treated mice showed nonuniform degenerative changes in the seminiferous. The treatment also had adverse effects on motility, viability, morphology, and the number of spermatozoa in the cauda epididymides. The fertility of the extract-treated males was also suppressed [72]. The oral administration of (145) (15 mg/rat/day for 60 days) in male Wistar rats significantly reduced the weight of the testes, epididymides, seminal vesicles, and prostate compared to the negative controls, and the mobility of the sperm and Sertoli cells also decreased significantly and without systemic side effects. The number of mature Leydig cells was decreased, and a complete suppression of fertility was observed. The content of protein and sialic acid in the testes, epididymides, seminal vesicle, and prostate, as well as the glycogen content of the testes and fructose in the seminal vesicles were reduced. However, testicular cholesterol was elevated [73].

Wound Healing
Aqueous leaf extracts of A. cathartica (150 mg/kg/day for 14 days) promoted the wound healing activity in Sprague-Dawley rats. Compared to the controls, treated rats had higher rates of wound contraction, decreased periods of epithelialisation, a higher skin breaking strength, a significantly higher weight of the granulation tissue, and more hydroxyproline content. Histological studies of the granulation tissue in treated rats showed less inflammatory cells and increased collagen formation [8].

Thrombolysis
A. cathartica leaves were extracted with methanol and subsequently partitioned with hexane, carbon tetrachloride, chloroform, and water. The thrombolytic activity of the resulting preparation was evaluated in vitro with the concentration of extract at 0.1 mg/100 µL. As a positive control, streptokinase was used. All extracts showed thrombolytic activity with respect to the negative control with a significant difference of p < 0.001. The chloroform-partitioned extract presented the highest rate of clot lysis (34.51%) [30].

Purgative Effect
The purgative effect of the aqueous leaf extract of A. cathartica was evaluated at different doses (20,40,80,160, and 320 mg/kg orally). As a positive control, the Senna extract was used under the same conditions and the saline solution was used as a negative control; the extract showed a dose-dependent effect [28].

Tyrosinase
The tyrosinase inhibitory activity of the methanol stem powder extracts of A. cathartica was examined, and compound (113) was identified as having the highest inhibitory activity against tyrosinase (IC 50 : 2.93 µM), which was 15 times stronger than the kojic acid used as a positive control (IC 50 : 43.7 µM) [59].

Antiviral
Through an in silico method, it was determined that some compounds present in A. cathartica have an antiviral activity against human hepatitis B viral capsid protein [58]. The antirabic activity of methanol and aqueous extracts of leaves was evaluated; however, the extracts did not inhibit the rabies virus at the concentrations evaluated [31].

Antimicrobial
The methods most commonly used to evaluate antimicrobial activity are carried out by plaque, disk, and dilution methods. Table 10 describes the different studies carried out with extracts obtained from different parts of A. cathartica.

Antimalarial
In an in vivo model in albino rats, the antimalarial activity of a leaf ethanol extract from A. cathartica was evaluated at different doses (50, 100, and 200 mg/mL). As a positive control, the compound (128) was used (200 mg/kg), and the extract showed an effect similar to (128) that was dose-dependent [88].

Nematicide
Bark methanol extracts were evaluated on Bursaphelenchus xylophilus (pinewood nematode), where a minimum effective dose (MED) of 5 mg/cotton ball was found [19]. Fractions of hexane extracts of the leaves and stem from A. cathartica were evaluated in vitro for nematicidal activity at 0.06, 0.1, and 0.2 mg/mL against juvenile larvae of Meloidogyne incognita. The extract showed a nematicidal activity from the first hours of exposure with a rate of 16.87% [89].

Antihaemorrhagic
Extracts of 96% ethanol made from the leaves, branches, and stems of A. cathartica were evaluated for an in vitro haemorrhagic neutralization activity using the blood of a Swiss Webster mouse with 10 µg Bothrops atrox venom, and the results obtained showed a neutralization of 72 ± 8%. However, it was not clear if the parts of the plant were evaluated together or separately [12].

Antioxidants
The antioxidant activity of A. cathartica was evaluated in vitro using the FRAP and TEAC methods with Methanol:Acetic acid:Water extracts (50:3.7:46.3 v/v/v) as well as the water-soluble and fat-soluble fraction from flowers, which showed antioxidant activities via FRAP of 18.95 ± 0.34 and 4.56 ± 0.11 µmol Fe (II)/g, respectively. By the TEAC method, the antioxidant activity was 7.35 ± 0.26 and 1.46 ± 0.21 µmol Trolox/g, respectively [24]. The ethanol extracts from the leaves had an antioxidant activity (based on the DPPH method) that was dose-dependent at concentrations of 0.5, 1, 2, and 5 mg/mL [92]. The methanol extracts from the flowers showed an antioxidant activity by the DPPH method at a concentration of 0.6 mg/mL [93]. Different plant parts were analysed for their antioxidant activity in vitro where it was higher in shoot > root > leaves > flowers. The relative peroxidase and superoxide dismutase (SOD) activities were in the order of root > shoot > leaves > flowers [17]. The relative in vitro antioxidant activity of various leaf extracts of A. cathartica was in the following order: butylated hydroxyl toluene (BHT) > Dia-Ion resin Absorbed > Chloroform > Ethyl acetate (EtOAc) > Methanol (MeOH) > Petroleum ether (PE) [76]. The carbon tetrachloride fraction from a methanol extract from the leaves had an IC 50 of 47.5 ± 0.11 µg/mL in the DPPH model [69]. In the study of isolated compounds, (145) (100 mg/kg orally) administered to female Swiss mice significantly decreased the levels of lipid hydroperoxides (LOOH) and reduced the glutathione (GSH) levels and SOD activity, whereas the catalase (CAT) activity remained unchanged compared with the untreated group. The standard drug 5-ASA reduced the LOOH content and increased the SOD activity compared to the vehicle (VEH) group, whereas treatment with (145) promoted a complete improvement of the oxidative unbalance, restoring all the parameters [71]. In an in vivo model using albino rats, the antioxidant activity of the ethanol extract of leaves (50, 100, and 200 mg/mL) was evaluated, and as a positive control, the compound (128) was used (200 mg/kg), showing a significant increase in TBARS, with a decrease in GSH and CAT levels [88].

Toxicity
A. cathartica is reported to be a venomous plant due to the presence of a cardiotoxic glycoside [25]. All parts of the plant cause dermatitis [29]. It has been reported that the leaves and sap produce persistent diarrhoea with high consumption rates. Also, skin irritation has been reported, but the responsible compounds have not been identified [3]. Studies have been carried out on the cytotoxicity and genotoxicity of hexane extracts of leaves of A. cathartica. It was demonstrated that a concentration of 315 mg/mL is cytotoxic to lymphocytes with a 79% cellular viability. In HeLa cells, an IC 50 of 13.5 mg/mL was found. These results showed a genotoxicity (p < 0.01) for both cell types, which led the authors to suggest that A. cathartica not be used as a medicinal plant [94]. However, it is necessary to standardize the HPLC samples for at least one compound present in the plant. In the evaluation of acute toxicity (i.p.) in mice, it was observed that the LD 50 was 1320 ± 15 mg/kg [28]. The oral administration of 2 mg/kg of ethanolic extract of flowers and the compound (145) in Swiss Webster mice administered as a single dose and evaluated at 14 days showed no toxic effects, no changes in biochemical or haematological parameters, and no genotoxic effects [61]. The toxicological evaluation of the petroleum ether extract of leaves in albino mice showed no toxicity at doses of 100 to 1000 mg/kg p.o. for 72 h [81].

Biotechnological Use
The effects of 2,4-dichlorophenoxyacetic acid (2,4-D) and 6-benzylaminopurine (BAP) on the induction of callus from leaf and stem explants were investigated. The regeneration of plants from the nodal explants was achieved. The explants were cultured in a Murashige and Skoog (MS) medium, supplemented with different concentrations of 2,4-D (0.5 and 1.0 mg/L) or in combinations of 2,4-D (0.5, 1.0, and 1.5 mg/L) with BAP (0.5, 1.0, and 1.5 mg/L). In the study of plant regeneration, the nodal explants were cultivated in an MS medium supplemented with BAP at 1.0, 3.0, or 5.0 mg/L for the multiplication of shoots. The MS basal medium was used as a control and was also used for the elongation of the shoots. All cultures were incubated under a photoperiod of 16 h of light and 8 h of darkness. For callus induction, the explants of leaves and stems grown at 1.0 mg/L of 2,4-D and 1.0 mg/L of BAP gave the best callus response (100%). For the multiplication of shoots, the MS medium supplemented with 5 mg/L of BAP gave the best response (100%) with multiple buds formed [46].

Conclusions
This review details the ethnomedical, phytochemical, pharmacological, toxicological, and biotechnological uses of A. cathartica. Although there have been several studies on the pharmacological activity of A. cathartica, the potential of this plant is as an analgesic, anti-inflammatory, antidepressant, antidiabetic, antihyperlipedaemic, antifertility agent, wound healing, trombolytic, purgative, tyrosine, amylase, antimicrobial, antimalarial, nematicide, antioxidant, etc. agent.
Author Contributions: All authors contributed to this work, prepared the manuscript, and approved this version of the article.