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Antipyretic Activity and Acute Toxicity Evaluation of Ceiba pentandra (Malvaceae) and Ipomoea pes-caprae (Convolvulaceae) Extracts

Gniènèfèrètien Nounaféri Awa SILUE *^a, Lenoir Thierry Ayoman DJADJI ^a, Mohamed Bonewendé BELEMLILGA ^b, Jean Noël KOUSSE ^b, Gisèle KOUAKOU-SIRANSY ^a

^a Unité pédagogique Pharmacologie, Physiologie humaine, Anatomie, Sémiologie et Pharmacie Hospitalière, UFR Sciences Pharmaceutiques et Biologiques, Université Félix Houphouët-Boigny, O1 BP V34 Abidjan 01, Côte d'Ivoire

^b Laboratoire de Recherche-Développement de Phytomédicaments et Médicaments (LR-D/PM), Institut de Recherche en Sciences de la Santé (IRSS), Centre National de la Recherche Scientifique et Technologique (CNRST) BP 7047 Ouagadougou 03, Burkina Faso

 

 

A fever is defined as a temperature of 38.0°C or higher^{1, 2}. It may indicate a bacterial or viral infection, or an inflammatory process³. The most common and widespread conventional antipyretics are synthetic molecules, particularly acetaminophen, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)⁴. While they have proven their effectiveness, they are now known to cause many serious adverse effects. Acetaminophen is the most widely used analgesic-antipyretic in the world, and although it is considered safe with few adverse effects, it is the active substance most commonly involved in cases of drug poisoning, whether voluntary or involuntary⁵. It also poses a significant risk of hepatotoxicity⁶; in England and the United States, acetaminophen is the leading cause of acute hepatitis, ahead of viral and other iatrogenic causes⁷. Other active substances with antipyretic activity, particularly NSAIDs, are not exempt from this issue. Indeed, despite being widely prescribed, these drugs can cause adverse effects such as gastric irritation and ulceration, prolonged bleeding, kidney failure and itchiness^{8, 9}. Similarly, a large number of hospitalisations are drug-related and attributable to NSAIDs¹⁰. Exploring natural antipyretic substances, particularly plant-derived active principles, could provide alternative therapeutic options.

The Ceiba pentandra (Malvaceae) tree, commonly known as the kapok tree, is native to tropical regions of the Americas. This giant of the plant kingdom occupies a significant cultural place in tropical Africa, where many communities revere it as a “palaver tree” and “fetish tree”^{11, 12}. It is now widely cultivated in all tropical regions and is particularly prevalent in West and Central Africa, from Cape Verde to Chad and down to Angola. It is also found in East Africa and Southeast Asia, notably in Indonesia and Thailand, where intensive cultivation takes place¹³. Different parts of the plant have traditionally been used to treat various conditions⁶. The bark and leaves of Ceiba pentandra are traditionally used as a febrifuge. Bark infusion is recognised for its antipyretic properties¹⁴, while macerated leaves, particularly in combination with Ananas comosus leaves, are used as an external or oral antipyretic¹⁵.

Ipomoea pes-caprae (Convolvulaceae) is a prostrate, perennial, herbaceous plant with stems up to 30 m long that contain latex and root at the nodes¹⁶. It establishes and develops on tropical and subtropical beach dunes. It has a pantropical distribution and has been observed on the coasts of North and South America, Asia, Africa (the central, eastern and western coasts) and Australia. There are numerous well-documented traditional uses for Ipomoea pes-caprae, including the treatment of lumbar muscle tension, rheumatic joint pain, fatigue, weakness, and pain and inflammation resulting from bites, arthritis, and rheumatism. It is also used to treat various intestinal disorders, such as ulcers, dysentery and cramps; skin conditions, such as boils, bedsores and dermatitis; and diabetes. Traditional preparation methods include infusions, decoctions, plant-based poultices and vegetable oils, which are primarily administered orally or topically according to the therapeutic indications targeted^{16, 17}. Pharmacologically, Ipomoea pes-caprae's anti-inflammatory activity is one of its main documented biological effects¹⁸. In some regions of Africa, particularly Burkina Faso, the leaves of these two species are traditionally combined to make decoctions for treating fever¹⁹.

Although the antipyretic properties of Ceiba pentandra have been scientifically documented^20–22, the effectiveness of its combination with Ipomoea pes-caprae has not been evaluated according to the literature reviewed.

This study aimed to evaluate the antipyretic activity of a Ceiba pentandra and Ipomoea pes-caprae extract mixture on a brewer's yeast-induced fever model in rats.

2.1.  Plant material

The plant material consisted of Ceiba pentandra leaves and leafy Ipomoea pes-caprae branches. The Ceiba pentandra leaves were collected in Nabélékaha, a village in the Komodorougou department in northern Côte d'Ivoire, while the Ipomoea pes-caprae leafy branches were collected in Toukoro-Sambla, a village in the Karangasso-Sambla department in the Bobo-Dioulasso province of Burkina Faso. Specimens of these plants were identified and authenticated by the National Centre for Floristics (CNF) in the Botany Department at Félix Houphouët-Boigny University in Abidjan. The Ceiba pentandra leaves were washed and dried in the shade before being pulverised using a RETSCH® SM 100 knife mill. The fine powder was stored in a clean, dry jar.

Aqueous extraction by decoction was performed on fresh aerial parts of Ipomoea pes-caprae and dried Ceiba pentandra leaf powder separately. Five litres of distilled water were added to 500 g of the fresh aerial parts of Ipomoea pes-caprae and two litres to 50 g of the dried Ceiba pentandra leaf powder. Each mixture was boiled for 30 minutes. The resulting decoctions were successively filtered through hydrophilic cotton, followed by Whatman No. 1 filter paper. The extracts were then evaporated to dryness in an oven at 50 °C for 72 hours. The resulting anhydrous material was scraped off, ground up, and the dry extracts obtained were stored in a refrigerator at 4°C for subsequent antipyretic activity studies.

Experiments were performed on Wistar rats (Rattus norvegicus) weighing between 125 and 170 g and NMRI mice weighing between 25 and 36 g. These animals were sourced from the animal facilities of the Pharmacology, Clinical Pharmacy and Therapeutics Laboratory at the Faculty of Pharmaceutical and Biological Sciences at Félix Houphouët-Boigny University in Abidjan and the Institute of Health Sciences Research (IRSS). The animals were kept in a controlled environment at a temperature of 24 ± 1 °C, with a 12-hour light/dark cycle. They had free access to water and food. All experiments were conducted in accordance with international animal welfare standards, as recommended by the European Union (EEC 86/609 and EU 2010/63 directives).

The following substances and reagents of a pharmacological nature were used in the study: sodium chloride solution (NaCl 0.09%, exp: 27/11/2021, lot: 18 332 A 03), brewer's yeast (Saccharomyces cerevisiae, Arkopharma® laboratories, exp: 03/2021, lot H01615A), and acetaminophen (Doliprane® 100 mg sachet, exp: 09/2019, lot: 2691). All pharmaceutical products were purchased from retail pharmacies.

The antipyretic effect of Ceiba pentandra and Ipomoea pes-caprae extracts was studied in accordance with the protocol outlined by Wang et al.²³. The rats were fasted for 12 hours prior to experimentation, after which their baseline rectal temperatures were recorded. Hyperthermia was then induced by the subcutaneous administration of a 20% saline suspension of brewer's yeast at a rate of 10 mL/kg body weight in the dorso-lumbar region. Sixteen hours after administration, the rectal temperature of each rat was measured again, and those showing hyperthermia (a thermal variation of more than 0.5°C) were selected and divided into homogeneous groups of six according to the level of hyperthermia reached. These groups then received a 0.09% NaCl solution (negative control), Ceiba pentandra leaf extract (125 and 200 mg/kg), mixtures of Ceiba pentandra and Ipomoea pes-caprae extracts (125+3.125, 125+12.5, and 200+25 mg/kg) or the reference substance acetaminophen (100 mg/kg) by gavage. Rectal temperatures were measured by inserting a lubricated 12-probe digital thermometer (TMP 812 RS™) approximately 2 cm into the rats' rectums. This thermometer displays temperatures with 0.1°C precision. Measurements were taken 30 minutes after substance administration, then every hour for four hours, and the recorded values were noted down.

Inhibition percentages were calculated relative to the control (NaCl 0.9%) according to the following formula:

%Inhibition = [(T° n - T°-16) Control - (T° n - T°-16) Treated] /(T° n - T°-16) Control ×100

T°n = temperature measured post-treatment; T°-16 = baseline temperature.

Acute general toxicity was evaluated according to OECD guideline 423²⁴. Aqueous decoctions of Ceiba pentandra and Ipomoea pes-caprae leaves were administered orally to male mice that had undergone a four-hour fasting period beforehand. A limit test was conducted at a dose of 2000 mg/kg body weight: the extract was administered by gavage to three mice via a gastric tube, and the mice were then observed individually for two hours before being refed. The mice were then monitored daily for 14 days to note any mortality or signs of intoxication, including cutaneous and hair modifications, ocular and mucosal changes, and the possible presence of convulsions, salivation, diarrhoea, lethargy, somnolence and coma. Water consumption was monitored daily throughout the study. Food consumption, as well as the individual weight of each animal, was determined once per week. At the end of the test, the surviving animals were weighed, anaesthetised with ketamine (50 mg/kg), and then subjected to macroscopic autopsy. Vital organs, such as the heart, kidneys, liver, lungs and spleen, were isolated, cleaned and examined macroscopically for any abnormalities in shape, size or colour. All organs were weighed on a precision scale (Sartorius®) to determine their relative weight and all macroscopic pathological alterations were recorded.

The relative weight of organs of each rat was calculated according to the following formula:

Relative organ weight (%) = [organ weight (g) ÷ animal weight (g)] × 100

The results were processed using Excel and GraphPad Prism version 7.0 software. The results are presented as the mean ± standard error of the mean (SEM). Data comparisons between groups were performed using analysis of variance (ANOVA), followed by a Tukey–Kramer post-test. Differences were considered statistically significant at p < 0.05. * p < 0.05; ** p < 0.01; *** p < 0.001.

3. RESULTS
4.  
5.  
   3. Antipyretic activity of Ceiba pentandra 

Figure 1 illustrates the effect of the aqueous extract of Ceiba pentandra on brewer's yeast-induced hyperthermia. Table 1 shows the percentage inhibition of fever by the Ceiba pentandra extract over a 4-hour period.

 

 

 

 

Figure 1: antipyretic activity of Ceiba pentandra at doses of 125 mg/kg and 200 mg/kg after fever induction by brewer's yeast (n=6).

Table 1: Inhibition percentages of Ceiba pentandra

Treatments (mg/kg)			Time(hours)
	T0.5h	T1h	T2h	T3h	T4h
CP 125  CP 200 Acetaminophen 100	27.59 62.07 18.97	45.56 70.00 45.56	54.74 89.47 82.11	55.88 63.24 111.76	71.25 76.25 101.25

Administering Ceiba pentandra at doses of 125 mg/kg and 200 mg/kg caused a significant decrease in the body temperature of rats compared to the control group. This antipyretic effect was observed between the first and fourth hours after administration. Furthermore, the extract administered at 200 mg/kg demonstrated a superior hypothermic effect to that of the reference drug acetaminophen during the first two hours of observation.

3. Antipyretic activity of the mixture of Ceiba pentandra and Ipomoea pes-caprae extracts after brewer's yeast-induced fever
4. Effects of the mixture of Ceiba pentandra 125 mg/kg and Ipomoea pes-caprae at doses of 3.125 and 12.5 mg/kg on brewer's yeast-induced fever

 

Figure 2: Antipyretic activity of the mixture of Ceiba pentandra 125 mg/kg and Ipomoea pes-caprae extracts at doses of 3.125 and 12.5 mg/kg after fever induction by brewer's yeast. (n=6).

Table 2: Inhibition percentages of Ceiba pentandra at 125 mg/kg dose in association with Ipomoea pes-caprae

Treatments (mg/kg)			Time (hours)
	T0.5h	T1h	T2h	T3h	T4h
CP 125  + IPC 3.125  CP 125 + IPC 12.5	41.38 53.45	42.22 56.67	73.68 102.11	58.82 91.18	62.50 68.75

 

 

Figure 2 shows the antipyretic activity of the 125 mg/kg dosage of the aqueous Ceiba pentandra extract in combination with the 3.125 and 12.5 mg/kg doses of Ipomoea pes-caprae extract. These combinations produced an antipyretic effect similar to that observed with a single 125 mg/kg administration of Ceiba pentandra. However, the therapeutic efficacy of the combinations was superior to treatment with Ceiba pentandra alone. The Ceiba pentandra (125 mg/kg) and Ipomoea pes-caprae (12.5 mg/kg) combination demonstrated more pronounced antipyretic activity than the combination with Ipomoea pes-caprae (3.125 mg/kg).

Hyperthermia inhibition percentages induced by the Ceiba pentandra 125 mg/kg + Ipomoea pes-caprae 3.125 mg/kg association, evaluated from the 30^th minute to the 4^th hour post-administration, were significantly lower than those measured with the Ceiba pentandra 125 mg/kg + Ipomoea pes-caprae 12.5 mg/kg combination (Figure 2 and Table 2).

 

 

 

Figure 3: Antipyretic activity of the mixture of Ceiba pentandra 200 mg/kg and Ipomoea pes-caprae extracts at 25 mg/kg dose after fever induction by brewer's yeast (n=6).

 

Table 3: Inhibition percentages of Ceiba pentandra at 200 mg/kg dose in association with Ipomoea pes-caprae

Treatments (mg/kg)			Time(hours)
	T0.5h	T1h	T2h	T3h	T4h
CP 200 + IPC 25	67.24	81.11	100.00	101.47	80.00

 

 

Figure 3 shows the antipyretic activity of a combination of 200 mg/kg of aqueous Ceiba pentandra extract and 25 mg/kg of aqueous Ipomoea pes-caprae extract. The experimental results demonstrate that the combination of Ceiba pentandra (200 mg/kg) and Ipomoea pes-caprae (25 mg/kg) has a significantly greater antipyretic effect than Ceiba pentandra (200 mg/kg) administered alone. Furthermore, the percentages of inhibition of induced hyperthermia, measured with this combination from the 30^th minute to the 2^nd hour post-administration, are superior to those obtained with acetaminophen at 100 mg/kg, which was used as the therapeutic reference (Figures 3 and Table 3).

3. Variations in inhibition percentages: interest of the mixture of Ceiba pentandra and Ipomoea pes-caprae extracts
4. Effect of the mixture of Ceiba pentandra 125 mg/kg and Ipomoea pes-caprae extracts at doses of 3.125 and 12.5 mg/kg compared to the activity of Ceiba pentandra 125 mg/kg alone

Table 4 summarizes the difference in inhibition percentages between the mixture and Ceiba pentandra 125 mg/kg extract alone.

 

 

Table 4: Variations in inhibition percentages: mixture of Ceiba pentandra 125 mg/kg and Ipomoea pes-caprae at doses of 3.125 and 12.5 mg/kg

Treatments (mg/kg)	Time (hours)
	T0.5h	T1h	T2h	T3h	T4h
(CP 125 + IPC 3.125) - CP 125 (CP 125 + IPC 12.5) - CP 125	+13.79 +25.86	-3 .33 +11.11	+18.95 +47.87	+2.94 +35.29	-8.75 -2.50

 

 

This table illustrates the improvement in antipyretic efficacy that occurs with increasing doses of Ceiba pentandra and Ipomoea pes-caprae when used in combination. A comparative analysis of the differences in inhibition percentages reveals that adding a 12.5 mg/kg dose of Ipomoea pes-caprae considerably increases the activity of a 125 mg/kg dose of Ceiba pentandra, particularly in the initial phases of treatment. This potentiation of the antipyretic effect is evident at T1h (+11.11% vs. -3.33%) and is further accentuated at T2h (+47.87% vs. +18.95%), thus confirming the optimisation of antipyretic efficacy through an increased concentration of Ipomoea pes-caprae in the combination. However, the negative values observed at later time points (T3h and T4h) for the high-dose combination suggest a potential decrease in this enhancement beyond two hours.

Table 5 summarizes the difference in inhibition percentages between the mixture and Ceiba pentandra 200 mg/kg extract alone.

 

 

Table 5: Difference in inhibition percentages: mixture of Ceiba pentandra 200 mg/kg and Ipomoea pes-caprae at 25 mg/kg dose

Treatments (mg/kg)	Time (hours)
	T0.5h	T1h	T2h	T3h	T4h
(CP 200 + IPC 25) - CP 200	+5.17	+11.11	+10.53	+38.24	+3.75

 

 

These data reveal constant improvement in the antipyretic efficacy of Ceiba pentandra (200 mg/kg) when combined with Ipomoea pes-caprae (25 mg/kg). The inhibition gains observed were +5.17% at T0.5h, +11.11% at T1h and +10.53% at T2h, reaching a maximum of +38.24% at T3h before decreasing to +3.75% at T4h. Therefore, the combination exhibits a potentiating effect, reaching peak activity at the third hour post-administration.

Effect of Ceiba pentandra and Ipomoea pes-caprae on behavior, physiology, and mortality

 

 

Table 6: Effect of aqueous extracts of Ceiba pentandra (CP) and Ipomoea pes-caprae (IP) in single administration on some physiological parameters in mice.

Parameters	Groups
	Control	CP (2000mg/kg)	IP (2000 mg/kg)
Hair Eyes Convulsions Salivation Diarrhea Lethargy Somnolence Coma Mortality	N N A A A A A A A	N N A A A A A A A	N N A A A A A A A

N : normal ; A : absent ; P : present

 

 

Table 6 summarises the effects of Ceiba pentandra (CP) and Ipomoea pes-caprae (IP) on mouse physiology during the evaluation of acute toxicity. No deaths were recorded in the control group or the treated groups within 14 days of a single 2000 mg/kg dose being administered. According to OECD guidelines, the median lethal dose (LD₅₀) is therefore estimated to be greater than 2000 mg/kg body weight.

 

 

 

 

 

Effect of Ceiba pentandra (CP) and Ipomoea pes-caprae (IP) on weight and relative organ Weight

 

Figure 4: Effect of a single dose of Ceiba pentandra (CP) on mouse weight evolution

 

Figure 5: Effect of a single dose of Ipomoea pes-caprae (IP) on mouse weight evolution

 

 

Figures 4 and 5 show how the weight of mice subjected to acute toxicity testing changed over time. It can be seen that the weight curve increases in a similar way for all the mice during the treatment period, regardless of whether they are given Ceiba pentandra or Ipomoea pes-caprae extracts. Statistical analysis of these results shows that there is no significant difference in average weight between treated mice and those in the control group.

 

Table 7: effect of Ceiba pentandra (CP) in single administration on relative organ weight in mice.

Organs	Groups
	Control	CP (2000 mg/Kg)
Liver Kidney Lungs Heart Spleen	4.84 ± 0.25 1.51 ± 0.24 0.49 ± 0.09 0.59 ± 0.09 0.37 ± 0.03	4.93 ± 0.50 1.26 ± 0.07 0.59 ± 0.21 0.54 ± 0.01 0.38 ± 0.09

Values are presented as mean ± standard deviation (SD).

Table 8: Effect of Ipomoea pes-caprae in single administration on relative organ weight in mice.

Organs	Groups
	Control	IP (2000 mg/Kg)
Liver Kidney Lungs Heart Spleen	4.37 ± 0.41 1.02 ± 0.33 0.56 ± 0.12 0.69 ± 0.06 0.51 ± 0.04	4.89 ± 0.48 0.92 ± 0.10 0.55 ± 0.04 0.62 ± 0.08 0.46 ± 0.19

Values are presented as mean ± standard deviation (SD).

Tables 4 and 5 illustrate the relative weight of the organs of control mice and mice treated with aqueous extracts of Ceiba pentandra or Ipomoea pes-caprae. The data obtained revealed no significant differences in the relative weight of the liver, heart, lungs, kidneys and spleen between the treated mice and the control group.

 

This study aimed to evaluate the antipyretic activity of Ceiba pentandra and Ipomoea pes-caprae extract combinations on a brewer's yeast-induced fever model in rats.

The aqueous extract of Ceiba pentandra leaves was found to effectively lower the body temperature of febrile rats, exhibiting significant and early antipyretic activity from the thirtieth minute post-treatment. This finding corroborates the work of Saptarini et al., who demonstrated the antipyretic activity of Ceiba pentandra leaf extract in mice at doses of 189, 378, and 756 mg/kg²¹. This confirms the superiority of Ceiba pentandra leaf extract over Gossypium arboreum, which belongs to the same family (Malvaceae). These results also align with the observations of Djadji et al.²⁰, who evaluated the curative activity of the extracts on brewer's yeast-induced fever and the onset of action of the extracts on turpentine-induced fever.

The antipyretic effect was significantly increased when the Ceiba pentandra decoction was associated with Ipomoea pes-caprae extracts. Indeed, the fever inhibition percentages obtained with Ceiba pentandra extract alone improved by between 5.17 and 47.37 percentage points in the presence of Ipomoea pes-caprae.

The improvement in the antipyretic effect observed with Ipomoea pes-caprae extracts is based on the documented biological properties of this plant, particularly its well-established anti-inflammatory properties^{25, 26}. These properties could complement the antipyretic properties of aqueous Ceiba pentandra decoction, thereby explaining the increased efficacy observed when the two are combined. Indeed, it has been demonstrated that Ipomoea pes-caprae exhibits anti-inflammatory effects at doses of 200 and 400 mg/kg in rats²⁷. The anti-inflammatory effect involves the inhibition of COX-1 and COX-2; therefore, the antipyretic activity would operate through the same mechanism. Thus, Ipomoea pes-caprae would reduce PGE2 synthesis induced by pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and IFN-γ), which are produced following the injection of brewer's yeast, by inhibiting COX.

Furthermore, the presence of compounds such as 3,4-dihydro-8-hydroxy-3-methylisocoumarin, eugenol, 4,4,7-trimethyl-1,4-dihydro-2-hydroxy-1-naphthalenone and 4-vinyl-guaiacol gives Ipomoea pes-caprae the ability to inhibit prostaglandin synthesis, thereby opposing inflammatory processes and fever²⁸. Similarly, the presence of secondary metabolites, particularly flavonoids^{29, 30}, in the aerial parts of the plant would contribute to its antipyretic activity by suppressing TNF-α ³¹.

This improvement in efficacy demonstrates the potential advantages of combining different plant substances in phytotherapy, where they can work together to optimise the therapeutic effect³². This approach improves pharmacological efficacy by acting on multiple targets simultaneously while reducing the required dosage of individual components and minimising side effects³³. Possible mechanisms include the enzymatic facilitation of bioactive compounds in Ipomoea pes-caprae, which could enhance the effect of Ceiba pentandra decoction; improved absorption of water-soluble active principles; and complementary action on different pathways of thermoregulation and inflammation. These results scientifically validate the traditional combination of Ceiba pentandra and Ipomoea pes-caprae for treating fever, demonstrating the rationale behind local phytotherapeutic practices.

An evaluation of the acute oral toxicity of a single 2000 mg/kg dose of aqueous extracts of Ceiba pentandra and Ipomoea pes-caprae administered to NMRI mice revealed no mortality or severe morbidity within 14 days. Therefore, the LD₅₀ for each plant extract is greater than 2000 mg/kg. Therefore, the aqueous extracts of Ceiba pentandra leaves and the aerial parts of Ipomoea pes-caprae can be classified as category 5 substances under the Globally Harmonized System of Classification²⁴, i.e. substances without acute toxic effects.

Also, the relative weight of vital organs such as the heart, liver, kidneys, lungs and spleen should be considered. Evaluating organ weight variation is one of the most reliable ways of detecting the toxicity of an experimental substance^{34, 35}. This approach has the advantage of revealing significant changes in the weight of target organs in exposed animals compared to the control group, even when there are no observable morphological alterations³⁴.

Thus, determining vital organ weight constitutes an early and sensitive biomarker, enabling the identification of potential harmful effects of a tested substance before any detectable anatomical changes appear.

The maintenance of the physical integrity of vital organs suggests a favourable safety profile for aqueous extracts of Ceiba pentandra and Ipomoea pes-caprae. This safety profile is a major asset when it comes to developing a phytomedicine for use as an antipyretic. 

This study scientifically validates the traditional use of the Ceiba pentandra–Ipomoea pes-caprae combination as an antipyretic by demonstrating that its therapeutic efficacy is superior to that of Ceiba pentandra alone. An LD₅₀ greater than 2000 mg/kg indicates an acceptable safety profile for this combination. These results confirm the ethnopharmacological approach and traditional phytotherapeutic practices based on the combination of multiple plant species. However, elucidation of the molecular mechanisms of action and evaluation of subacute toxicity are still necessary to characterize the interactions between the bioactive compounds and establish the potential for pharmaceutical development of this combination.

Acknowledgments: The authors would like to express their sincere appreciation to the Health Sciences Research Institute (Ouagadougou, Burkina Faso) and the Faculty of Pharmaceutical and Biological Sciences (Abidjan, Côte d’ivoire), whose exemplary collaboration made this work a reality.

Conflict of Interest: The authors declare that they have no conflicts of interest.

Authors’ contributions: Study conception, data analysis, and manuscript writing were performed by GNAS. Experimental supervision and resource acquisition were conducted by GKS. Experiments were carried out by GNAS and JNK. Data analysis, manuscript revision, study conception, and study implementation were undertaken by LTAD and MBB.

Source of Support: Nil

Funding: The authors declared that this study has received no financial support.

Informed Consent Statement: Not applicable. 

Data Availability Statement: The data presented in this study are available on request from the corresponding author. 

Ethical approval: All experiments were conducted in accordance with international animal welfare standards, as recommended by the European Union (EEC 86/609 and EU 2010/63 directives).

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