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Pseudo-akuammigine, an alkaloid from Picralima nitida seeds, has anti-inflammatory and analgesic actions in rats
Abstract
Pseudo-akuammigine, an alkaloid from Picralima nitida seed extract was investigated for anti-inflammatory and analgesic actions using the carrageenan-induced rat paw oedema and the rat tail flick. The alkaloid, at 1.0, 5.0 and 50 mgkg(-1)(,) dose-dependently inhibited the mean maximal paw swelling attained during 6 h to 78.2+/-2.1, 74.7+/-4.3 and 59.5+/-2.3% of the mean control value respectively when administered p.o. 1 h before induction of oedema. At the same dose levels, the total paw swelling over the 6-h period was also significantly (P<0.05) reduced to 83.2+/-9.7, 73.0+/-5.0 and 55.8+/-8.3% of the mean control response respectively. When administered after induction of oedema, psi-akuammigine (5.0 mgkg(-1)) significantly (P<0.05) reduced established rat paw swelling to 82.8+/-4.6% of the control response after 5 h. As an analgesic, psi-akuammigine was 3.5 and 1.6 times less potent than morphine and indomethacin respectively. The ED(50) values were Morphine (2.9 microM), psi-akuammigine (10 microM) and indomethacin (6.3 microM). Naloxone (1.0 mgkg(-1)) significantly (P<0.05) antagonised the analgesic action of the alkaloid by 35.8+/-6.8%. Pseudo-akuammigine therefore exhibits anti-inflammatory and analgesic actions. The analgesic actions are mediated via interaction with opioid receptors.
... However, contrary to previous studies and the traditional use of P. nitida as an analgesic, 1-3 produced minimal pain-relieving effects. 18,19 Given the modest potency of these alkaloids at the µOR, we reasoned that a derivative with increased potency at the µOR would produce more effective antinociceptive effects. To test this hypothesis, here we report the first structure-activity relationship (SAR) study of the akuamma alkaloids 1 and 2. We employed strategic, chemoselective, late-stage functionalization of the indole nucleus, to introduce modifications at the C10, C11, and N1 positions of 1 and 2. Ultimately, these SAR studies resulted in the discovery of a µOR agonist with a 70-fold greater potency than the parent compound 2. ...
... To further investigate the impact of substitutions on the aromatic ring, halides were introduced at C10 of 2 and C11 of 1 employing an acid-mediated halogenation with Nbromosuccinimide and N-iodosuccinimide (17)(18)(19)(20). Intriguingly, the use of trifluoroacetic acid was necessary for the reaction to progress to completion. ...
... In contrast to the other C11-substituted derivatives, halogenation of 1 at C11 (19)(20) results in slightly improved affinity for the opioid receptors. Both 19 and 20 induced >50% displacement at 1 µM and possess an increased affinity to the µOR and κOR compared to 1 ( Figure 2A, Table 1). ...
Akuammine (1) and pseudo-akuammigine (2) are indole alkaloids found in the seeds of the akuamma tree (Picralima nitida) that are used as a traditional treatment for pain in West Africa. Both alkaloids are agonists of the mu-opioid receptor (µOR); however, they produce minimal effects in animal models of antinociception, likely due to their modest potency. To further probe the interactions of 1 and 2 at the opioid receptors, we have prepared a collection of semi-synthetic derivatives with modifications to the C10, C11, C16, and N1 positions of the indole core. Evaluation of this collection at the µOR and kappa opioid receptor (κOR) revealed structural-activity relationship trends and derivatives with improved potency at the µOR. Most notably, the introduction of a phenethyl moiety to the N1 of 2 produces a 70-fold increase in potency and a 7-fold increase in selectivity for the µOR. The in vitro potency of this compound was reflected in vivo in rodents, producing an ED50 = 77.6 mg/kg and 77.1 mg/kg in a tail-flick antinociception assay and a hot-plate assay, respectively. The improved potency of these analogs highlights the promise of exploring natural product scaffolds that can be used to probe the opioid receptors.
... 229 (À)-Tubifolidine was extracted from the Strychnos species by Amat and co-workers in 1997. 230 In 2020, Cho and co-workers reported 231 the enantioselective synthesis of (+)-uleine (204) and (À)-tubifolidine (210). The regioselective construction of enol triates from 2-azabicyclo[3.3.1]nonane ...
... ketones and also indolizations of the resulting ene-hydrazides permitted the effective formation of key indole intermediates, assisting the total synthesis of the desired natural alkaloids. The total synthesis of (+)-uleine (204) was commenced from the key chiral cyclohexenone 197 prepared in a 93% enantiomeric excess (ee) by using modication of the process previously published by Ma et al. from ethyl (E)-4-oxopent-2-enoate (196). 232 In the following, compound 197, aer ve steps, afforded the bicyclic ketone 198. ...
... 232 In the following, compound 197, aer ve steps, afforded the bicyclic ketone 198. The latter was reacted with potassium tert-butoxide and the Comins' reagent at À78 C in THF/DMF (1 : 6) to provide enol triate 199 as the main product, together with trace quantities of 199 0 , which was exposed to the two-step indolization reaction for the end-game synthesis of (+)-uleine (204). In this route, the carbon-nitrogen coupling of 199 and 199 0 with phenyl hydrazide 200 afforded enehydrazides 201 and 201 0 as an inseparable 37 : 1 mixture in a satisfactory yield (71% total yield). ...
Indoles are a significant heterocyclic system in natural products and drugs. They are important types of molecules and natural products and play a main role in cell biology. The application of indole derivatives as biologically active compounds for the treatment of cancer cells, microbes, and different types of disorders in the human body has attracted increasing attention in recent years. Indoles, both natural and synthetic, show various biologically vital properties. Owing to the importance of this significant ring system, the investigation of novel methods of synthesis have attracted the attention of the chemical community. In this review, we aim to highlight the construction of indoles as a moiety in selected alkaloids. This journal is
... While their potency is lower than morphine, the effects of 3 in these assays appeared to be longer lasting. 18,19 Previous investigations indicated the antinociceptive effects of the akuamma alkaloids are produced through their interaction with the opioid receptors. 16,17 However, the scope of these studies was limited to the opioid receptors and excluded other nervous system receptors, and the rigor of those findings is linked to the suboptimal tools available at the time to study the pharmacology of the akuamma alkaloids. ...
... As 3 has previously been demonstrated to be antinociceptive in Wistar rats when administered per os (p.o.; 5 mg/kg), experiments were conducted to reproduce these findings in mice (Table S14, Supporting Information). 19 Compound 3 did not produce antinociception in mice at 5 mg/kg dose (p.o.) in the tail-flick and hot plate assays of thermal nociception at any of the time points tested ( Figure 4A,B). In this experiment, subcutaneously (s.c.) administered morphine (6 mg/kg) served as a positive control and produced significant antinociception at the 30 min time point. ...
... However, no antinociception was measurable, indicating that metabolism of the compounds is unlikely to contribute to potential effects, as has been previously proposed (data not shown). 19 In a previous study in rats, the antinociceptive effects of 3 differed kinetically from those produced by morphine, with antinociceptive activity for 3 peaking at 180 min when administered p.o. 19 To account for potential delayed onset in antinociception for akuamma alkaloids, nociception was tested in mice at 50 and 110 min following s.c. administration with 1 and 2. However, with continued testing and after failing to detect convincing levels of antinociception, testing was adjusted to higher doses of 30 and 60−75 min in an attempt to capture either a rapid or delayed peak in antinociceptive efficacy. ...
The seeds of the akuamma tree (Picralima nitida) have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography was developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation. Five of these alkaloids, akuammine (1), pseudo-akuammigine (3), akuammicine (4), akuammiline (5), and picraline (6), were evaluated against a panel of >40 central nervous system receptors to identify that their primary targets are the opioid receptors. Detailed in vitro investigations revealed 4 to be a potent kappa opioid receptor agonist, and three alkaloids (1−3) were shown to have micromolar activity at the mu opioid receptor. The mu opioid receptor agonists were further evaluated for analgesic properties but demonstrated limited efficacy in assays of thermal nociception. These findings contradict previous reports of the antinociceptive properties of the P. nitida alkaloids and the traditional use of akuamma seeds as analgesics. Nevertheless, their opioid-preferring activity does suggest the akuamma alkaloids provide distinct scaffolds from which novel opioids with unique pharmacologic properties and therapeutic utility can be developed.
... While their potency is lower than morphine, the effects of 3 in these assays appeared to be longer lasting. [18][19] Previous investigations indicated the antinociceptive effects of the akuamma alkaloids are produced through their interaction with the opioid receptors. [16][17] However, the scope of these studies was limited to the opioid receptors, excluded other nervous system receptors, and the rigor of those findings is linked to the suboptimal tools available at the time to study the pharmacology of the akuamma alkaloids. ...
... As 3 has previously been demonstrated to be antinociceptive in Wistar rats when administered per os (p.o.; 5 mg/kg), we set out to reproduce these findings in mice (Supplementary Table 8). 19 In our observations, 3 did not produce antinociception in mice at 5 mg/kg dose (p.o.) in the tail flick and hot plate assays of thermal nociception at any of the timepoints tested ( Figure 5A-B). In this experiment, subcutaneously (s.c.) administered morphine (6 mg/kg) served as a positive control and produced significant antinociception at the 30 min timepoint. ...
... However, no antinociception was measurable, indicating that metabolism of the compounds is unlikely to contribute to potential effects as has been previously proposed (data not shown). 19 In a previous study in rats, the antinociceptive effects of 3 differed kinetically from those produced by morphine, with antinociceptive activity for 3 peaking at 180 minutes when administered p.o.. 19 To account for potential delayed onset in antinociception for akuamma alkaloids we tested nociception in our mice 50 and 110 minutes following s.c. administration with 1 and 2. However, with continued testing and after failing to detect convincing levels of antinociception, we adjusted testing of higher doses to 30 and 60-75 minutes in an attempt to capture either a rapid or delayed peak in antinociceptive efficacy. ...
p>The seeds of the akuamma tree ( Picralima nitida ) have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography is developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation. Five of these alkaloids, akuammine, pseudo-akuammigine, picraline, akuammicine, and akuammiline, were evaluated against a panel of >40 central nervous system receptors to identify that their primary targets are the opioid receptors. Detailed in vitro investigations revealed one alkaloid as a potent kappa opioid receptor agonist and three alkaloids with micromolar activity at the mu opioid receptor. The mu opioid receptor agonists were further evaluated for analgesic properties but demonstrated limited efficacy in assays of thermal nociception. These findings contradict previous reports of the antinociceptive properties of the akuamma alkaloids and the traditional use of akuamma seeds as analgesics. Nevertheless, their opioid preferring activity does suggest the akuamma alkaloids provide distinct scaffolds from which to develop novel opioids with unique pharmacologically properties and therapeutic utility.
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... Picralima nitida is a species of the genus Picralima. It belongs to the hunterieae tribe of Apocynaceae family and is commonly called Osi-Igwe in Ibo and Abere in Yoruba (Duwiejua et al., 2002). In other parts of West Africa, the plant is called Gbe-Fondagne in Benin Republic, Adangme in Ghana, Abureebissi in Cote d'Ivoire and Susubalunyi in Sierra Leon (Kpodar et al., 2015). ...
... The flowers are white (about 3 cm long) and they have ovoid fruits which become yellowish when mature. The leaves are broad (3-10 cm) and oblong (6-20 cm long) with tough tiny lateral nerves of about 14 to 24 pairs (Duwiejua et al., 2002). ...
... Various parts of the plant such as the leaves, seeds, stem, bark and roots are used by herbalists for the treatment of fever, hypertension, jaundice, gastro-intestinal disorders and malaria (Falodun et al., 2006). Preparations from different parts of the plant are employed as crude drug or crude herbal extract as remedy for various kinds of human diseases (Duwiejua et al., 2002). The seeds are widely used in West Africa especially in Nigeria, Cote d'Ivoire and Ghana as antipyretic, aphrodisiac agents, and for the treatment of malaria, pneumonia and other chest-conditions (Falodun et al., 2006). ...
... It belongs to the hunterieae tribe of the Apocynaceae family. The plant is called by different local names in Nigeria such as Osu (Edo), Osi-Igwe (Igbo), and Abere (Yoruba) (Duwiejua., 2002). Botanically, is a tree that can reach up to 4-3.5m in height. ...
... diseases have been prepared from various parts of the plant (Duwiejua, 2002). The existence of flavonoids, alkaloids, saponins, terpenoids, steroids, tannins and glycosides in the plant has been discovered by the screening of possible phytochemicals present in the plant (Nkere and Iroegbu,2005;Mabeku., 2008;Obasi., 2012;Ubulom., 2012;Kouitcheu., 2013).This was supported by the Isolation of several alkaloids from the seeds of the plant, as well as polyphenols from other parts of the plant (Ansa- Asamoah,1990;Menzies, 1998;Tan., 2002). ...
... akuammine, akuammicine, akuammidine, picratidine, akuammigine, pseudoakuammigine, picralineand picralicine) [107,108]. The plant has also been reported to have anti-inflammatory antioxidant and analgesic properties [109]. Moreover, Erharuyi et al. [110] reported that chronic administration could reduce the chances of fertility in females and develop low sperm count in males what will make them infertile. ...
... Various parts of this plant have been revealed to be effective antipyretic and antitussive [101,102]. Anti-inflammatory, antioxidant and analgesic were also retrieved in Picralima nitida [109]. Antiplasmodial activity of Rauwolfia vomitoria were demonstrated [115]. ...
COVID-19 is a severe acute respiratory syndrome-related corona-virus SARS-CoV-2, that constitutes a pandemic threat to global public health. Unfortunately, there are no specific available therapies. This research work presents the findings of an investigation on traditional Cameroonian remedies of respiratory tract infections, malaria and viral infections, and also recipes that could serve as a baseline for the prevention, alleviate symptoms, treatment and perhaps may help for the anti-COVID-19 drugs discovery. Data on the medicinal plants were collected from traditional healers, Cameroonian medicinal plants books, the internet, and in addition to our personal experience as researchers and herbalists. Details of 85 plant species used to manage these three mentioned diseases in Cameroon and their pharmacological properties are recorded. Due to their ethnomedicinal uses and pharmacological activities, twenty-eight (28) plant species and 13 recipes are suggested for COVID-19 prevention, alleviate symptoms, treatment and baseline for anti-COVID-19 drug discovery. Amongst the proposed plants we have the following, Curcuma longa, Azadirachta indica, Zingiber officinale, Allium sativum and Ocimum gratissimum which were reported to possess certain inhibition properties against COVID-19 protease.
... Phytochemical investigation has led to the isolation of several potent bioactive compounds among which are; the alkaloids (akuammine, akuammigine, akuammenine); polyphenols (coumestan glycosides and its derivatives) [15,16]. Several investigations have reported the pharmacological activity of extracts of the seeds, leaves, fruits or the alkaloid compounds from P. nitida. ...
... However, the magnitude of antinociceptive activity of WDP (400 mg/kg) was less than that of Pentazocine (5 mg/kg). The analgesic activity of pseudo-akuammigine (isolated alkaloid from the seed of P. nitida) has been shown to be partly dependent on action at the opioid receptors [15,17,41]. WDP showed inhibition of peripherally mediated pain in the acetic acid-induced abdominal writhing test. ...
Objectives
Blend of seeds and leaves of Picralima nitida herein referred to as West African Durand powder (WDP) was investigated for antinociceptive and anti-inflammatory properties.
Methods
Acute toxic effect of the aqueous extract was evaluated in mice of both sexes. Antinociceptive effect of WDP (100–400 mg/kg) was evaluated in models of acetic acid-induced writhing and thermal nociception on hot plate in mice. Carrageenan-induced paw oedema and air pouch rat models were used to evaluate the anti-inflammatory activity of the extract.
Results
WDP (2,000 mg/kg) showed no toxic effect in mice. WDP at 100, 200 and 400 mg/kg inhibited abdominal writhings by 59.9, 66.0 and 79.0%, respectively. There was a significant increase in reaction time on the hot plate tests in mice treated with WDP (400 mg/kg). The paw oedema was reduced by WDP (100, 200 and 400 mg/kg) 5 h post-carrageeenan. Exudate volume was significantly reduced to 39.8 and 44.8% by 200 and 400 mg/kg WDP, respectively. WDP reduced Leucocytes counts (23.3 and 57.1%, respectively) and neutrophil counts (28.1 and 60.0%, as well as reduced nitrites, malondialdehyde levels and increased glutathione concentrations in the air pouch.
Conclusions
These results suggest that aqueous extract of blend of seeds and leaves of P. nitida possesses antinociceptive and anti-inflammatory properties.
... Investigation of the analgesic effects of seeds collected from Ghana established that the aqueous seed extract possessed significant antinociceptive effect in murine models tested by the hot plate assay. Indole alkaloids isolated from the seeds, namely akuammidine, akuammine, akuammicine, akuammigine and pseudoakuammigine also exhibited potent analgesic effects in an isolated tissue and radio-ligand binding assay, demonstrating varying degrees of agonist and antagonist activity at μ-, δ-, and κ-opioid receptors [77,78]. ...
... The total alkaloidal extract at 75-300 mg/kg p.o. caused a significant dose-dependent inhibition of total oedema formation in carrageenan-induced paw oedema assay and reduced adjuvant-induced knee joint swelling in rats [79]. Pseudoakuammigine displayed significant dose-dependent suppression of total paw oedema by 82.8 ± 94.6% [78]. ...
... Picralima nitida extracts have been reported to be effective for hypertension and gastrointestinal disorders [17]; it's used as a cough suppressant [19], treatment of viral infections [20] and hypoglycaemic agent in the treatment of diabetes [19]. It also possesses antibacterial effect [21,22], anti-inflammatory and antipyretic activity [23], analgesic activity [24,25], and anti-parasitic effect [26,27]. Ciprofloxacin {1-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid} and pefloxacin {1-ethyl-6-fluoro-7-(4-methyl piperazin-1-yl)-4-oxoquinoline-3-carboxylic acid} are synthetic broadspectrum antibiotic active against both grampositive and gram-negative bacteria [28]. ...
... From the phytochemical analysis, Picralima nitida was found to possess many secondary metabolites with several activities experimentally observed like cough suppressant anodyne, anesthetic and aphrodisiac [31], antibacterial [21,22], antiparasitic and antileishmanial [26,27,[32][33][34], antiviral [35], anti and antipyretic [23,25], analgesic [24], hypoglycemic [31,[36][37][38][39], hypotensive [40], hypocholesterolemic, anticarcinogenic, antioxidant, antimutagenic and the abilit modify gene expression [41]. ...
Aim: The shelf-life of Picralima nitida (herbal drug) and two orthodox drugs (ciprofloxacin, and pefloxacin) has been examined. Methodology: The stability studies were carried out using the bio-based concentration-activity relationship technique. Accelerated stability studies were applied on the basis of first-order degradation kinetics to determine the shelf-life of the drugs at different temperatures (45 – 70°C) and storage times (1, 2, 3 and 4 wks). Ciprofloxacin and pefloxacin were used as the comparative drugs for the estimation of the specifications for Picralima nitida. Their half-life (t1/2) and temperature coefficient (Q10) were also investigated. Results: All the drugs proved to be broad spectrum antibiotics and their concentrations were found to decrease with increase in storage time and temperature. Ciprofloxacin proved to be more active and stable than pefloxacin followed by Picralima nitida, but lost its activities against the organisms at the stressed condition, respectively. Picralima nitida retained its activity more at stressed condition because of the presence of active metabolites. The shelf-life (including the half-life) of ciprofloxacin was found to be 80.31 wks (533.08 wks) against Bacillus subtilis, pefloxacin was found to be 43.5 wks (288.75 wks) against Bacillus subtilis and 0.25wks (1.65 wks) against Samonella typhi; Picralima nitida found to be 5.83wks (38.72wks) against Bacillus subtilis, 0.41 wks (2.69 wks) against Samonella typhi and 0.52 wks (3.45 wks) against Pseudomonas aureginosa. Conclusion: The shelf-life of Picralima nitida, ciprofloxacin, and pefloxacin were successfully determined using the bio-based concentration-activity relationship technique; ciprofloxacin and pefloxacin were also successfully used as the comparative drugs for the estimation of the specifications for Picralima nitida in treatment based on their inhibitory activity but varies with sensitivity activities on different bacteria (or micro-organisms).
... In most cases they are dried before reducing into powdery form for easy packaging, transportation and preservation. Among these plants is picralima nitida (family Apocynaceae), used traditionally in African medicine for the treatment of diverse diseases like malaria, typhoid fever, anemia, hypertension, tumor, Jaundice, gastro-intestinal disorders and dysmenorrhea because of the presence of natural bioactive compounds [1][2][3]. The plant is a shrub 20 m high, found around tropical Africa [2]. ...
... The most important part of the plant is the seed processed and sold in 250 mg capsules commercially as "picap" in some African countries. Before extraction, the seed is embedded in pulp inside the fruit (Fig. 1) and it is known to be a large source of anti-oxidants [4] and has anti-inflammatory, antipyretic, antimalarial, Antiulcer and analgesic actions [1,3] and [5]. It also contains a mixture of alkaloids prominent among them is Akuammine, an indole alkaloid also called vicamajoridine [6] and structurally related to yohimbine and mitragynine with effective application in medicine. ...
Interest in picralima nitida is growing over the years because of its therapeutic application in human and animal medicine. In many countries the dried seed is compounded and sold as drugs but there is limited information on the process variables associated with its thermal processing. The study therefore, is focused on the evolution of physical properties, heat and mass transfer coefficient, specific heat capacity, energy utilization and quality characteristics of the seed during oven and microwave drying. The goal is to generate data using theoretical and empirical steps for process model development that can be applied in dryer design. The results obtained showed that the coefficient of heat and mass transfer varied from 0.0421 – 1.326 W/m2K and 1.49 x 10 -7 – 8.47 x 10-6 m/s
respectively while the specific heat capacity ranged between 1189 - 2531 J/ kg K . The volume of the seed shrank gradually with a non-linear exponential shape for all drying treatments. The intrinsic particle and bulk densities decreased while the porosity of the seed increased with drying period, indicating an increase in internal voids of the seeds. The energy and specific energy utilized for drying peaked after 14 h, 12 h and 7 h of continuous drying at 50, 60 and 70 oC for oven drying treatment. Effective moisture diffusivities for all treatments ranged from 5.37x10-10 – 1.45 x 10 -7 m/s2 with activation energy of 27.82 kJ/mol and 20 W/g for oven and microwave respectively. Flavonoide was the least stable at high temperature among the screend compound.
... Another plant, Plumeria rubra, which is also a member of the family Apocynaceae, has a well-established anti-fertility activity (Dabhadkar et al, 2012). Picralima nitida has also been shown to possess antidiarrheic (Kouitcheu et al., 2006;Kouitcheu, 2007), antidiabetic (Aguwa et al., 2001), analgesic (Duwiejua et al., 2002), opioid (Menzies et al., 1998), anti-plasmodial (Ezeamuzie et al., 1994), anti-microbial (Fakeye et al., 2004), anti-inflammatory (Obiri 1997;Duwiejua et al., 2002), anti-pyretic (François et al., 1996), trypanocidal (Wosu and Ibe 1989), as well as anti-leishmanial (Iwu et al., 1992) activities. The bark is also used to prepare remedies for male sexual impotence (Adjanohoun et al., 1996). ...
... Another plant, Plumeria rubra, which is also a member of the family Apocynaceae, has a well-established anti-fertility activity (Dabhadkar et al, 2012). Picralima nitida has also been shown to possess antidiarrheic (Kouitcheu et al., 2006;Kouitcheu, 2007), antidiabetic (Aguwa et al., 2001), analgesic (Duwiejua et al., 2002), opioid (Menzies et al., 1998), anti-plasmodial (Ezeamuzie et al., 1994), anti-microbial (Fakeye et al., 2004), anti-inflammatory (Obiri 1997;Duwiejua et al., 2002), anti-pyretic (François et al., 1996), trypanocidal (Wosu and Ibe 1989), as well as anti-leishmanial (Iwu et al., 1992) activities. The bark is also used to prepare remedies for male sexual impotence (Adjanohoun et al., 1996). ...
In search for medicinal plants with renowned reputation of contraceptive and fertility-modulating ability, this work was designed to evaluate the effects of ethanolic fruit extract of Picralima nitida on conception and oestrogenicity using twentyone sexually mature and twenty-four sexually immature female Sprague Dawley rats respectively. For the anti-conceptive study, 0 mg/kg, 50 mg/kg and 500 mg/kg of the extract was administered from day 1to day 4 of gestation (7 rats per group). On the 20th day of gestation, percentage of pregnant females (PPF), live foetal number (LFN), corpora lutea number (CLN), resorbed embryo number (REN), foetal crown-rump length (FCRL) and fertility indices (FI) were evaluated. For the anti-estrogenic study, Groups 1 to 3 (ovariectomized immature female rats) received 0.1 mg/kg of Stilboestrol, 50 mg/kg of the extract, and 0.2 ml of paraffin respectively, once daily for four consecutive days. Group 4 comprised of sham-operated immature female rats with their ovaries intact. The extract elicited absolute conception failure in 42.86% of the treated animals. The extract significantly (p < 0.05) reduced the FCRL, LFN and FI, but increased the REN. Evaluation of the allometric weights of the uterine tissues, endometrial thickness and vaginal opening revealed that the extract at 50 mg/kg body weight was antioestrogenic in activity. Findings from this research strongly suggest that the ethanolic fruit extract of Picralima nitida possesses significant post-coital anti-fertility activity in rats, which could not be attributed to its oestrogenic activity.
... une activité analgésique centrale d'un extrait de graines chez le Rat, ainsi qu'une activité antiinflammatoire significative dans des tests usuels chez cette espèce ; -une forte activité analgésique locale pour l'akuammine et l'akuammidine (supérieure à celle de la cocaïne, chez le Rat) ; -un effet de la pseudo-akuammigine sur l'oedème de la patte induit par le carraghénane chez le Rat, à 1, 5 et 50 mg/kg par voir orale. L'effet analgésique est antagonisé par la naloxone (antagoniste opioïde) (Duwiejua, 2002). Ce caractère analgésique est mentionné pour le fruit, dont la consommation est décrite comme anesthésiant la bouche (« amertume excessive suivie d'une anesthésie de la muqueuse buccale ») . ...
Le paludisme est endémique en Côte d’Ivoire, où la majeure partie de la population a recours à des médications traditionnelles. L’objectif de notre travail était de contribuer au développement de l’enregistrement de médicaments traditionnels à base de plantes par les autorités sanitaires. Une enquête ethnobotanique a été réalisée en 3 volets : classiquement auprès de vendeuses de plantes à d’Abidjan en comparaison aux données bibliographiques ; de manière originale par un inventaire des produits antipaludiques à base de plantes reçus pour soumission à un enregistrement par le Programme National de Promotion de la Médecine Traditionnelle et la Direction des Activités Pharmaceutiques ivoiriens ; par la collecte de produits manufacturés commercialisés. Une vérification d’activité antiplasmodiale in vitro et une contribution au Contrôle botanique ont été réalisés. Une étude d’une préparation traditionnelle originale à base de pulpe de fruits de Picralima nitida (Stapf) TH. et H. Durand (Apocynaceae), étayée d’un point de vue micrographique utile au contrôle, a permis : une caractérisation par CLHP-MS/MS d’alcaloïdes indolomonoterpéniques ; une étude de variabilité chimique qualitative et quantitative par le biais du dosage des composés principaux après isolement et par une approche métabolomique ; une étude d’activité antiplasmodiale in vitro de plusieurs lots; une vérification d’activité in vivo dans un modèle murin mettant en évidence l’intérêt de la préparation. Les autres parties du fruit ont également été étudiées d’un point de vue qualitatif en recourant aux mêmes outils analytiques.
... Many herbalists have claimed to use the leaves, roots, seeds or stembark for treatment of various fevers, hypertension, jaundice, gastrointestinal disorders and malaria (Iwu, 1993 andEtukudo, 2003). This plant also has a very high anti-malarial activity (Duwiejua et al., 2002). Two third of the world's population mainly in the developing countries relies entirely on medicinal plants as their primary form of health care. ...
The acute toxicity of root methanol extract of Picalima nitida was studied in Swiss albino rats. The rats were randomly distributed into four groups of three animals each. The groups were respectively administered 0, 10, 100 and 1000mg/kg body weight methanol extract of Picalima nitida intra peritoneally in a single dose and monitored frequently for 24h and daily for 13 days in the first phase of the experiment. In the second phase of the experiment, the animals were administered single doses of the extract at 0, 200, 400, 800 and 1600mg/kg body weight (bw) of the extract intraperitoneally and monitored frequently for 24h and 13 days respectively. The number of deaths in a group was recorded. The results of the second phase experiment were used to calculate the LD50 of the plant extract. All surviving animals were sacrificed after 14 days. Selected organs of the animals i.e. liver and kidney of both the dead and sacrificed animals were removed and stored in 10% formal saline ready for histopathological analysis. Tissue specimens of the organs were examined histopathologically after processing and staining with haematoxylin and eosin. The results of the biochemical parameters indicated elevations. Lesions were observed in the liver and kidney of rats administered 800, 1000 and 1600mg/kg of methanol extract of Picralima nitida. From this result, the LD50 was calculated to be 557 mg/kg. The results indicate that the extract may be toxic at high doses.
... . Picralima nitida seeds contain a mixture of alkaloids producing antipyretic and antiinflammatory effects along with analgesia in animal studies [7]. ...
Introduction: Picralima nitida is a seed bearing tree whose dried seeds are used in traditional medicine throughout West Africa, particularly in Ghana, Ivory Coast and Nigeria. The seeds are crushed and taken orally for the treatment of malaria, diarrhoea, pain, hypertension, jaundice, dysmenorrheal, and gastrointestinal disorders. There is paucity of data on the toxicity and safety profile of Picralima nitida, thus the need for this study. Acute toxicity study was carried out on Picralima nitida aqueous and 80% ethanolic extract in order to determine its acute toxicity and LD 50. ABSTRACT Introduction: Picralima nitida is a seed bearing tree whose dried seeds are used in traditional medicine throughout West Africa, particularly in Ghana, Ivory Coast and Nigeria. The seeds are crushed and taken orally for the treatment of malaria, diarrhoea, pain, hypertension, jaundice , dysmenorrheal, and gastrointestinal disorders. There is paucity of data on the toxicity and safety profile of Picralima nitida, thus the need for this study. Acute toxicity study was carried out on Picralima nitida aqueous and 80% ethanolic extract in order to determine its acute toxicity and LD 50. Methods: Phytochemical analysis was carried out on Picralima nitida to identify its active phytochemical constituents both qualitatively and quantitatively. Acute oral toxicity tests were done using female Swiss albino mice that weighed 20-23g following the OECD methods. Fixed doses of 300mg/kg, 2000mg/kg and 5000 mg/kg of Picralima nitida aqueous and 80% ethanolic extracts were administered to the animals once and then observed for 14days. The control group received distilled water only ad libitum. At the end of the 14days, the animals were sacrificed and analyzed for histopatho-logical changes. Results: The LD 50 of the aqueous and ethanolic extract of Picralima nitida were found to be ≥2000mg/kg. The heart of the animals that received only distilled water, and those that received 300mg/kg, 2000mg/kg, and 5000mg/ kg of Picralima nitida aqueous extract had no histopathological damages. The photomicrogra-ph of the liver, kidneys, lungs of the untreated and treated groups of aqueous extract show some histopathological alterations. While, the histologic sections of the heart, liver, kidney, and lungs of the animals that received 2000mg/kg and 5000mg/kg of ethanolic extract of Picralima nitida had some histopathological changes. Similar injuries were also seen in the untreated group. Conclusion: The phytochemical screening revealed that Picralima nitida contains important antioxidants and other phytochemicals with various health benefits. While the acute toxicity assessment of the aqueous and 80% ethanolic extracts of Picralima nitida indicate that Picra-lima nitida is safe.
... Many herbalists have claimed to use the leaves, roots, seeds or stembark for treatment of various fevers, hypertension, jaundice, gastrointestinal disorders and malaria (Iwu, 1993 andEtukudo, 2003). This plant also has a very high anti-malarial activity (Duwiejua et al., 2002). Two third of the world's population mainly in the developing countries relies entirely on medicinal plants as their primary form of health care. ...
The acute toxicity of root methanol extract of Picalima nitida was studied in Swiss albino rats. The rats were randomly distributed into four groups of three animals each. The groups were respectively administered 0, 10, 100 and 1000mg/kg body weight methanol extract of Picalima nitida intra peritoneally in a single dose and monitored frequently for 24h and daily for 13 days in the first phase of the experiment. In the second phase of the experiment, the animals were administered single doses of the extract at 0, 200, 400, 800 and 1600mg/kg body weight (bw) of the extract intraperitoneally and monitored frequently for 24h and 13 days respectively. The number of deaths in a group was recorded. The results of the second phase experiment were used to calculate the LD50 of the plant extract. All surviving animals were sacrificed after 14 days. Selected organs of the animals i.e. liver and kidney of both the dead and sacrificed animals were removed and stored in 10% formal saline ready for histopathological analysis. Tissue specimens of the organs were examined histopathologically after processing and staining with haematoxylin and eosin. The results of the biochemical parameters indicated elevations. Lesions were observed in the liver and kidney of rats administered 800, 1000 and 1600mg/kg of methanol extract of Picralima nitida. From this result, the LD50 was calculated to be 557 mg/kg. The results indicate that the extract may be toxic at high doses.
... In pharmacology, previous studies (Duwiejua et al., 2002) have shown that P. nitida is rich in alkaloids. The methanol fruit extract has shown an anti-pyrexia effect (Ezeamuzie et al., 1994). ...
Today, despite its status as a key sector, agriculture faces many problems due to fungi and the use of synthetic pesticides. This study evaluated the antifungal potential of Picralima nitida fruits against Fusarium oxysporum. The extracts were obtained by the Total Aqueous Extraction method (TEA) and Hydroethanolic extraction (EE70%) method. Two dilution types of the extracts in PDA medium were tested: (1) dilution before autoclaving (AvA) and (2) dilution after autoclaving (ApA). The extracts of two fruit morphotypes from two climatic zones were tested at a concentration of 3 mg.ml⁻¹. The yield of fruit extracts from Dahomey Gap (DG) was significantly higher (more than 8%) than that from the Guinea-Congolese region (GC). A significant difference was observed in yield (p<0.05) between TEA type and the EE70% type with a higher inhibition rate (27%) of EE70% on Fusarium oxysporum. No significant difference was observed between the pathogen inhibition rates in the dilution type (p > 0.05). The inhibition rate of the pathogen was 25.65% for the short fruit morphotype and 25.08% for the large fruit morphotype. This study demonstrated possibility of using extracts of Picralima nitida in agriculture.
... Our analysis revealed that the leaf, root and seed extracts of P. nitida contain phenols, flavonoids, saponins and tannins. The presence of these phytochemicals shows that the leaf, seed and root extracts of P. nitida possess antioxidant properties, which is in agreement with previous reports (Duwiejua et al. 2002;Okunji et al. 2005;Fulgence et al. 2015). However, our findings indicate that the leaf extract had the highest flavonoid, phenolic and saponin content while the seed extracts had the highest tannin. ...
Picralima nitida is widely used in herbal medicine due to its numerous health benefits. We investigated the effects of extracts of P. nitida in alloxan-induced diabetic rats. Thirty Wistar rats were randomized into 6 groups of 5 rats each and treated as follows; Group I — normal control rats, Group II — diabetic rats treated with glibenclamide, Group III — diabetic rats not treated, Group IV — diabetic rats treated with methanol extract of P. nitida leaf, Group V — diabetic rats treated with methanol extract of P. nitida seed, Group VI — diabetic rats treated with methanol extract of P. nitida root. Phytochemical analysis of the methanol extracts of P. nitida revealed significantly (p < 0.05) higher tannin (83.183 mgTAN/g) content in the seed extract, phenolic (289.377 mgGAE/g) and flavonoid (343.681 mgQUE/g) content in the leaf extract. Administration of P. nitida extracts resulted in steady significant (p < 0.05) decreases in the fasting blood glucose levels, AST, ALT and ALP of the alloxan-induced diabetic rats. Administration of the extracts resulted in significant (p < 0.05) increases in the activity of CAT and GSH in the serum, liver, heart and kidney of the experimental rats. Treatment with the extracts resulted in significant (p < 0.05) decreases in the LPO activity in the serum, liver, heart and kidney of the rats. The leaf, seed and root extracts of P. nitida showed significant antidiabetic properties and protect against hepatotoxicity and oxidative stress, which are comparable to that of the standard drug, glibenclamide.
... Then, prostaglandins are the key players in the second phase of inflammation that occurs around 3 h after carrageenan injection [33]. These events provoke the release of several pro-inflammatory mediators, where inhibition terminates the inflammatory process [34]. Local inflammation is associated with oxidative burst and increased production of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6 and nitric oxide [35]. ...
In our in vitro and in vivo studies, we used Acalypha indica root methanolic extract (AIRME), and investigated their free radical scavenging/antioxidant and anti-inflammatory properties. Primarily, phytochemical analysis showed rich content of phenols (70.92 mg of gallic acid/g) and flavonoids (16.01 mg of rutin/g) in AIRME. We then performed HR-LC-MS and GC-MS analyses , and identified 101 and 14 phytochemical compounds, respectively. Among them, ramipril glucuronide (1.563%), antimycin A (1.324%), swietenine (1.134%), quinone (1.152%), oxprenolol (1.118%), choline (0.847%), bumetanide (0.847%) and fenofibrate (0.711%) are the predominant phy-tomolecules. Evidence from in vitro studies revealed that AIRME scavenges DPPH and hydroxyl radicals in a concentration dependent manner (10-50 μg/mL). Similarly, hydrogen peroxide and lipid peroxidation were also remarkably inhibited by AIRME as concentration increases (20-100 μg/mL). In vitro antioxidant activity of AIRME was comparable to ascorbic acid treatment. For in vivo studies, carrageenan (1%, sub-plantar) was injected to rats to induce localized inflammation. Acute inflammation was represented by paw-edema, and significantly elevated (p < 0.05) WBC, platelets and C-reactive protein (CRP). However, AIRME pretreatment (150/300 mg/kg bodyweight) significantly (p < 0.05) decreased edema volume. This was accompanied by a significant (p < 0.05) reduction of WBC, platelets and CRP with both doses of AIRME. The decreased activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase in paw tissue were restored (p < 0.05 / p < 0.01) with AIRME in a dose-dependent manner. Furthermore, AIRME attenuated carrageenan-induced neutrophil infiltrations and vascular dilation in paw tissue. For the first time, our findings demonstrated the potent antioxidant and anti-inflammatory properties of AIRME, which could be considered to develop novel anti-inflammatory drugs.
... 9,10 These alkaloids have various biological activities, including anti-tumor 11 and analgesic activities. [12][13][14] These activities, together with the complex structures including a characteristic cage-like motif, have attracted the interest of synthetic chemists. 15 In 2005, Overman and co-workers reported the first total synthesis of minfiensine (2) with tetracyclic hydrocarbazole 9 as a key intermediate (Scheme 1). 1 They employed an enantioselective intramolecular Heck reaction of 6 followed by iminium ion mediated intramolecular cyclization of amine to construct the corresponding tetracyclic hydrocarbazole 9, which lead them to the synthesis of 2. In the report, Overman mentioned about the utility of the tetracyclic hydrocarbazole 9 for constructing those types of alkaloids. ...
... The seeds of Picralima nitida have been employed in the treatment of malaria, used as analgesic in pain management and as prophylactics in diarrhoea treatment [12]. These seeds comprise a combination of alkaloids such as akuammine, pericine and others which have been documented in scientific animal studies to have ability to reduce fever and pains with anti-inflammatory effects [13,14]. Many traditionalists have averred that various parts Picralima nitida tree has been effective in the treatment of various diseases such malaria, hypertension, and gastro-intestinal disorders [15]. ...
Background: Plants like herbs has been extensively used for different kinds of nutritional and medicinal purposes, however, scientific studies has shown that these medicinal plants may have deleterious effects on some vital organs of the body if not taken at the recommended doses. Thus, there is a need for safety evaluation of these plants to ascertain their actions on organ’s physiological functions. This present study evaluates the effects of ethanol seed extract of Picralima nitida on the haematological examines and some enzymes activities in the serum of albino rats. Twenty-five rats were equally randomized into five groups. Group A (control) received distilled water while graded doses (50, 100, 150 and 200 mg/kg body weight) of ethanol seed extract of Picralima nitida were administered to rats in groups B, C, D and E respectively for 14 days. Haematological studies were carried out on the rats’ blood samples while concentrations of total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine were measured in the serum. Results: Result obtained revealed that treatment of rats with various graded doses of ethanol seed extract of Picralima nitida caused marked increase in urea and creatine compared to the control. Rats treated with 150 and 200mg/kg bw of the extract showed marked elevation in serum levels of the enzymes suggesting that the extract may have adverse effects at this dose. There was also a marked elevation in serum electrolytes of rats treated with 150 and 200mg/kg bw of the extract. Rats treated with low concentrations (50 and 100 mg/kg bw) of the extract demonstrated no marked differences or alteration in haematological parameters, protein profile and enzyme activities in the serum. Conclusion: The results of this study indicated that consumption of ethanol seed extract of Picralima nitida as a therapeutic treatment is nontoxic at lower dose. However, if taken at high doses, the extract might be detrimental to some vital organs and systems.
... The seeds of Picralima nitida have been employed in the treatment of malaria, used as analgesic in pain management and as prophylactics in diarrhoea treatment [12]. These seeds comprise a combination of alkaloids such as akuammine, pericine and others which have been documented in scientific animal studies to have ability to reduce fever and pains with anti-inflammatory effects [13,14]. Many traditionalists have averred that various parts Picralima nitida tree has been effective in the treatment of various diseases such malaria, hypertension, and gastro-intestinal disorders [15]. ...
ABSTRACT
Background: Plants like herbs has been extensively used for different kinds of nutritional and medicinal purposes, however, scientific studies has shown that these medicinal plants may have deleterious effects on some vital organs of the body if not taken at the recommended doses. Thus, there is a need for safety evaluation of these plants to ascertain their actions on organ’s physiological functions. This present study evaluates the effects of ethanol seed extract of Picralima nitida on the haematological examines and some enzymes activities in the serum of albino rats. Twenty-five rats were equally randomized into five groups. Group A (control) received distilled water while graded doses (50, 100, 150 and 200 mg/kg body weight) of ethanol seed extract of Picralima nitida were administered to rats in groups B, C, D and E respectively for 14 days. Haematological studies were carried out on the rats’ blood samples while concentrations of total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine were measured in the serum.
Results: Result obtained revealed that treatment of rats with various graded doses of ethanol seed extract of Picralima nitida caused marked increase in urea and creatine compared to the control. Rats treated with 150 and 200mg/kg bw of the extract showed marked elevation in serum levels of the enzymes suggesting that the extract may have adverse effects at this dose. There was also a marked elevation in serum electrolytes of rats treated with 150 and 200mg/kg bw of the extract. Rats treated with low concentrations (50 and 100 mg/kg bw) of the extract demonstrated no marked differences or alteration in haematological parameters, protein profile and enzyme activities in the serum.
... Oxoassoanine and crinamidine which are phytoconstituents present in P. aquilinum fiddleheads extract have been reported to exhibit acetylcholnesterase inhibitory activities [51,52] . The antimicrobial activities of buphanidrine, undulatine, ambelline and akuammidine have been reported [53,54] , and akuammidine is said to possess antipyretic and antiinflammatory activities [55,56] . Voacangine, another bioactive compound in the extract of P. aquilinum fiddleheads has been ...
Pteridium aquilinum fiddleheads are eaten as vegetable by the Ogonis of Nigeria, and decoctions taken as remedy for malaria. The analyses of bioactive compounds in extract from fiddleheads of P. aqiulinum from Khana, Southern Nigeria were done using GC-FID. Results revealed the present of quercetin-7-methyl ether, quercetin-3-o-rutinoside, quercetin-4-methyl ether, quercetin-3,7-dimethyl ether, kaempferol-3-0-rutinoside, kaemferol-4'-methyl ether, taxifolin-4'-methyl ether, taxifolin-7-methyl ether, aromadendrin-4'-methly ether, naringenin-4'-methyl ether, and eroidictyol-7,4'-dimethyl ether, as flavonoids, tannic acid, as the only tannin, digoxin, ouabain, salicin, amygdalin, arbutin, and digitoxin, as glycosides, avenacin A-1, and avenacin B-1 as saponin, buphanidrine, crinamidine, crinane-3α-ol, epoxy-3,7-dimethoxycrinane-11-one, oxoassoanine, dihydro-oxo-demethoxyhaemanthamine, 1-β, 2-β-epoxyambelline, 6-hydroxypowelline, undulatine, 6-hydroxyundulatine, powelline, augustamine, ambelline, 6-hydroxybuphanidrine, 9-octadecenamide, voacangine, mitraphylin, and akuammidine as alkaloids present in P. aquilinum extract. The results showed that P. aquilinum fiddleheads extract contained phytocconstituents with pharmacological potentials that makes it a good health promoting vegetable and a potential raw material for the production of supplements and novel drugs.
... (Apocynaceae), commonly known as Akuamma seed and Abere in Yoruba or Osu igwe in Igbo languages of Nigeria, is used in ethnomedicine for fever and malaria as well as primary hypertension (Iwu 2014). The plant was investigated for anti-trypanosomal (Wosu and Ibe 1989), anti-inflammatory and analgesic (Duwiejua et al. 2002), anti-diarrhoeal (Kouitcheu et al. 2006), antimicrobial (Nkere and Iroegbu 2005), in vitro and in vivo antiplasmodial Okokon et al. 2007) and hypoglycaemic as well as antileishmanial Inya-Agha 1999) activities, respectively. Studies on the extract from an aqueous preparation of P. nitida (100-400 mg/kg) in mice revealed that it did not significantly alter the renal function and albumin levels; however, the activities of liver enzymes were significantly reduced. ...
Safety of natural products is a priority before they are acceptable for consumption. Alstonia boonei De Wild (Apocynaceae) stem-bark and Picralima nitida (Stapf) T. & H. Dur. (Apocynaceae) seed are combined into a powder dosage form for the treatment of malaria fever. This study evaluated the central nervous system effects and the toxicity of the remedy on acute and repeated doses with a view to providing information on its safety. The powder mixture (ratio 1:2) of A. boonei stem-bark and P. nitida seed was extracted with water by the decoction method, concentrated in vacuo and freeze-dried. The acute toxicity of the extractive was determined by Lorke’s method. For the novelty-induced behaviour tests, 24 mice (18–22 g) of four groups (six mice per group) were orally given the aqueous solution of the extractive at 12.5, 25 and 50 mg/kg while the control group was given distilled water once daily for 30 days, after which the liver, kidney, brain, spleen and testes of each animal were humanely harvested for histopathological examination. At 25 mg/kg, a significant increase (P < 0.05) was observed in the grooming activity of the mice on acute and repeated doses. Histopathological analysis revealed that all the organs were essentially normal when compared with the control. The repeated oral administration of the extractive was relatively safe at each of the doses tested.
... This process involves the release of several proinflammatory mediators. These events represent the early exudative inflammatory phase and its inhibition terminate the inflammatory process [112]. Carrageenan model is typically linked with the activation of the cyclooxygenase pathway. ...
Inflammation is one of the common events in the majority of acute as well as chronic debilitating diseases and represent a chief cause of morbidity in today’s era of modern lifestyle. If unchecked, inflammation leads to development of rheumatoid arthritis, diabetes, cancer, Alzheimer’s disease, and atherosclerosis along with pulmonary, autoimmune and cardiovascular diseases. Inflammation involves a complex network of many mediators, a variety of cells, and execution of multiple pathways. Current therapy for inflammatory diseases is limited to the steroidal and non-steroidal anti-inflammatory agents. The chronic use of these drugs is reported to cause severe adverse effects like gastrointestinal, cardiovascular, and renal abnormalities. There is a massive need to explore new anti-inflammatory agents with selective action and lesser toxicity. Plants and isolated phytoconstituents are promising and interesting sources of new anti-inflammatories. However, drug development from natural sources has been linked with hurdles like the complex nature of extracts, difficulties in isolation of pure phytoconstituents, and the yield of isolated compounds in minute quantities that is insufficient for subsequent lead development. Although various in-vivo and in-vitro models for anti-inflammatory drug development are available, judicious selection of appropriate animal models is a vital step in the early phase of drug development. Systematic evaluation of phytoconstituents can facilitate the identification and development of potential anti-inflammatory leads from natural sources. The present review describes various techniques of anti-inflammatory drug screening with its advantages and limitations, elaboration on biological targets of phytoconstituents in inflammation and biomarkers for the prediction of adverse effects of anti-inflammatory drugs. The systematic approach proposed through present article for anti-inflammatory drug screening can rationalize the identification of novel phytoconstituents at the initial stage of drug screening programs.
... Other alkaloids isolated include picraphylline, picraline, picralicine, picracine, picratidine, burnamine, picranitine, and pericine [11]. The seed is sold around the world as drugs after drying, milling, and encapsulating [13,14]. Most of the studies on Picralima nitida focused on the effectiveness of the extract in medicine [11,15,16], but parameters that will help in the industrial processing are scarce in the open literature. ...
This research studied the effect of the moisture content and the three orthogonal axes
on the physical, mechanical and the phytochemical properties of piclirima nitida fruits
and the seeds. The results showed that the compression force, the compression shear
strength, the deformation, and the Poisson’s ratio depend on the compression axis and
the moisture content. Rupturing the fruit through the intermediate diameter showed
higher strength than rupturing the fruit along the major and the minor diameter. The
Poisson’s ratio ranged from 0.468–0.432 at the moisture content range of 75-88.3%
wb. Phyto-chemical screening of the seed showed that saponins, tannins, and
flavonoid were present in the seeds. Losing moisture was associated with the loss of
the phyto-chemicals but flavonoid showed a higher susceptibility to the moisture loss.
The frequency distribution of the axial dimensions showed that 85% of the seed major
diameters fell within the median class of 27.5 mm. The surface area of the fruits ranged
from 409.88-987.12 cm2.
... Animal studies were also used to assess the antiinflammatory ability of a great number of medicinal plant extracts using the carrageenan-induced rat paw oedema model. Plants investigated include seed extracts of Picralima nitida [399], crude methanol extract of the root of Moringa oleifera [469], powdered leaves and root of Mallotus oppositifolium [167], methanolic extract of Picralima nitida fruit [400], hot water extract of Alstonia boonei root-bark, Rauvolfia vomitoria root-bark, and Elaeis guineensis nuts [56], secondary root aqueous extract of Harpagophytum procumbens [303], crude extracts of Sphenocentrum jollyanum [272], aqueous and methanolic extracts of Hypoxis hemerocallidea corm [482], aqueous and methanolic extracts of Sclerocarya birrea stem-bark [483], aqueous extract of Mangifera indica stem-bark [13], aqueous extracts of Leonotis leonurus leaves [484], leaf extracts of Bryophyllum pinnatum [148], methanol extracts of the stem-bark of Alstonia boonei [485], aerial parts of Amaranthus caudatus [486], methanolic extracts of Kigelia pinnata flower [415], and leaf and twig extracts of Dorstenia barteri [276]. In all of these studies, the antiinflammatory effect against carrageenan-induced rat paw oedema was attributed to flavonoids and other polyphenolic compounds. ...
The use of traditional herbal remedies as alternative medicine plays an important role in Africa since it forms part of primary health care for treatment of various medical conditions, including wounds. Although physiological levels of free radicals are essential to the healing process, they are known to partly contribute to wound chronicity when in excess. Consequently, antioxidant therapy has been shown to facilitate healing of such wounds. Also, a growing body of evidence suggests that, at least, part of the therapeutic value of herbals may be explained by their antioxidant activity. This paper reviews African herbal remedies with antioxidant activity with the aim of indicating potential resources for wound treatment. Firstly, herbals with identified antioxidant compounds and, secondly, herbals with proven antioxidant activity, but where the compound(s) responsible for the activity has not yet been identified, are listed. In the latter case it has been attempted to ascribe the activity to a compound known to be present in the plant family and/or species, where related activity has previously been documented for another genus of the species. Also, the tests employed to assess antioxidant activity and the potential caveats thereof during assessment are briefly commented on.
... Therefore, the need for the study of their safety. Picralima nitida extracts have been reported to be effective as cough suppressant [6], antibacterial effect [7,8], treatment of viral infections [9], anti-inflammatory and antipyretic activity [10], analgesic activity [11,12] and anti-parasitic effect including malaria parasite [13,14]. Ciprofloxacin {1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid} and Pefloxacin {1-ethyl-6-fluoro-7-(4methyl piperazin-1-yl)-4-oxo-quinoline-3-carboxylic acid} are synthetic broad-spectrum antibiotic active against both gram-positive and gramnegative bacteria [15]. ...
Shelf life is one of the important property of a drug for safety and quality. The shelf life of Picralima nitida (herbal drug) and three orthodox drugs (glibenclamide, ciprofloxacin, and pefloxacin) has been investigated. The stability study was done using UV spectrometry method. Their shelf life was determined by accelerated stability studies on the basis of first-order degradation kinetics and t10% (the time required to degrade 10% of a drug at 27°C). The stability was studied at temperatures of 45°C, 60°C and 70°C during the course of one month at one-week interval (1, 2, 3 and 4 weeks). The initial concentration of 5, 2.5, 25 and 100 mg/ml was used for Picralima nitida, glibenclamide, ci profloxacin, and pefloxacin, respectively in the study. Influence of storage time and temperature on the drug samples were investigated. The half-life was also evaluated. All experiments were carried out in the year 2012. The concentrations of the drug samples were found to decrease with increase in storage time and temperature. The shelf life of ciprofloxacin, pefloxacin, and glibenclamide were found to be 535.18, 298.17 and 134.31 weeks, respectively. The half-life of ciprofloxacin, pefloxacin and glibenclamide were also found to be 3553.85, 1980 and 891.89 weeks, respectively. The shelf life and half-life of Picralima nitida could not be determined using UV spectrometry technique because of the presence of complex metabolites, which results in the irregular increase in absorbance and instability. Storage time and temperature was found to have a great influence on the concentration of the drug substances.
... On the other hand, we could also suggest that the T cell proliferative effects of total juices might be related to the absence of alkaloids in these juices, as we have previously demonstrated that the immunosuppressive activity might be attributed to the alkaloids contained in three medicinal plants [32]. Other investigators have also proven the immunosuppressive and anti-inflammatory activity of alkaloids derivates contained in plants [42,43]. The latter hypothesis could not be retained, since we also observed that filtered juices, which did not show alkaloids, inhibited T cell proliferation upon activation. ...
The mechanism of action of the antidiabetic capacity of Momordica charantia is still under investigation. Here, we assessed
phytochemical compositions, antioxidant activity, and effects of total and filtered fruit and leafy stem juices ofMomordica charantia
on human T cell proliferation and differentiation through quantification of Th1/Th2 cytokines. In the absence of stimulation, total
fruit and leafy stem juices induced significant T cell proliferation. Under PHA stimulation, both juices potentiated plant-induced
T cell proliferation. However, the filtered fruit and leafy stem juices significantly inhibited PHA-stimulated T cell proliferation,
while neither juice influenced T cell proliferation. Moreover, total and filtered fruit juice increased IL-4 secretion, while total
and filtered leafy stem juice enhanced IFN-𝛾 production. Phytochemical screening revealed the presence of tannins, flavonoids,
anthocyans, steroids, and triterpenoids in both juices. Alkaloids, quinone derivatives, cardenolides, and cyanogenic derivatives
were undetectable. The saponins present in total juices were undetectable after filtration. Moreover, both juices had appreciable
antioxidant capacity. Our study supports the type 1 antidiabetic effect of filtered fruit juice of M. charantia which may be related
to its immunosuppressive and T-helper 2 cell inducing capacities. Due to their immune-stimulatory activities and their ability to
increase T-helper 1 cell cytokines, total fruit and leafy stem juices may serve in the treatment of immunodeficiency and certain
infections.
... On the other hand, we could also suggest that the T cell proliferative effects of total juices might be related to the absence of alkaloids in these juices, as we have previously demonstrated that the immunosuppressive activity might be attributed to the alkaloids contained in three medicinal plants [32]. Other investigators have also proven the immunosuppressive and anti-inflammatory activity of alkaloids derivates contained in plants [42,43]. The latter hypothesis could not be retained, since we also observed that filtered juices, which did not show alkaloids, inhibited T cell proliferation upon activation. ...
The mechanism of action of the antidiabetic capacity of Momordica charantia is still under investigation. Here, we assessed phytochemical compositions, antioxidant activity, and effects of total and filtered fruit and leafy stem juices of Momordica charantia on human T cell proliferation and differentiation through quantification of Th1/Th2 cytokines. In the absence of stimulation, total fruit and leafy stem juices induced significant T cell proliferation. Under PHA stimulation, both juices potentiated plant-induced T cell proliferation. However, the filtered fruit and leafy stem juices significantly inhibited PHA-stimulated T cell proliferation, while neither juice influenced T cell proliferation. Moreover, total and filtered fruit juice increased IL-4 secretion, while total and filtered leafy stem juice enhanced IFN- γ production. Phytochemical screening revealed the presence of tannins, flavonoids, anthocyans, steroids, and triterpenoids in both juices. Alkaloids, quinone derivatives, cardenolides, and cyanogenic derivatives were undetectable. The saponins present in total juices were undetectable after filtration. Moreover, both juices had appreciable antioxidant capacity. Our study supports the type 1 antidiabetic effect of filtered fruit juice of M. charantia which may be related to its immunosuppressive and T-helper 2 cell inducing capacities. Due to their immune-stimulatory activities and their ability to increase T-helper 1 cell cytokines, total fruit and leafy stem juices may serve in the treatment of immunodeficiency and certain infections.
... The pericarp of the fruit contains latex known as the rind (Nyunaï and Njifutié, 2006). It has been reported that the aqueous extract of P. nitida seeds has anti-diabetic activities (Aguwa et al., 2001), rich in alkaloids (Tane et al., 2002) and possess antiinflammatory and analgesic actions in rats (Duwiejua et al., 2002). ...
Diabetes, a metabolic syndrome, is characterized by disordered metabolism including hyperlipidaemia. Orthodox approach of managing diabetes poses risk of inflicting heart diseases amongst others, hence, the search for alternative therapy. In Nigeria, many herbalists have claimed to use coconut water extract of Picralima nitida seed and aqueous extract of Tapinanthus bangwensis leaf in the management of diabetes, amongst which are their lipid lowering actions. This study aims to provide evidence for the presence of some phytochemicals which have been found to enhance the lipid lowering actions of the plant extracts in the diabetic state. The experimental rabbits (Chinchilla) (1.12 ± 0.09 kg) were grouped into six and extracts administered orally, once daily for five weeks. Groups 1 and 2 (non-diabetic) received only distilled water and coconut water respectively, group 3 (diabetic) received 200 mg/kg body weight aqueous extract of T. bangwensis leaf, group 4 (diabetic) received 400 mg/kg body weight of coconut water extract of P. nitida seed, groups 5 and 6 (diabetic) received only distilled water and coconut water respectively. The lipid lowering effects of extracts on total lipid and cholesterol concentration in both the plasma and selected tissues (liver, kidney and heart) were assessed. The results revealed that the extracts independently lowered significantly (p<0.05) the blood total lipid and cholesterol levels of the diabetic rabbits. Both extracts significantly (p<0.05) decreased the total lipid concentrations in the tissues. The extracts revealed the presence of some phytochemicals (Alkaloids, Flavonoids, Saponins amongst others) which possibly contributed to their lipid lowering actions Overall, aqueous extract of T. bangwensis leaf and coconut water extract of P. nitida seed respectively, can be advocated plants as lipid lowering agents in the management of diabetes.
... Apart from the evidence obtained from the indigenous population with regard to its efficacy in cough, other pharmacological properties confirmed on the plant by retrospective researchers give good reasons why the antitussive effect should be confirmed experimentally: the alkaloids in the plant have demonstrated significant activity on opioid receptors (12). Antiinflammatory (13,14) antibacterial (15)(16)(17) as well as stimulatory effect on the β 2adrenoreceptors in the trachea may all contribute to it being a potential therapeutically effective antitussive against several forms and etiologies of cough. ...
Picralima nitida is used traditionally for management of cough. This study, therefore, investigated the antitussive, expectorant, and analgesic properties of the ethanolic seed extract of Picralima nitida (PNE), and ascertained its safety for use. Presence of secondary metabolites, and safety of PNE (10-2000 mg/kg) were evaluated by preliminary phytochemical screening, and by Irwin's test respectively. Percentage reduction in cough count, percentage increase in latency of cough, and percentage protection offered by PNE were established by the citric acid-induced cough, acetylcholine- and Histamine-induced bronchoconstriction models. Dunkin-Hartley guinea pigs were treated with 100-500 mg/kg PNE or reference drugs, dihydrocodiene, atropine, mepyramine. Expectorant property of PNE (100-1000 mg/kg) was determined using the tracheal phenol red secretion; with ammonium chloride as a reference medication. Percentage maximal possible analgesic effect in the tail immersion test and the total nociceptive score in acetic acid-induced abdominal writhes, after treatment of BALB/c mice with PNE (100-500 mg/kg), diclofenac, and morphine were also estimated. Phytochemical screening revealed the presence of tannins, alkaloids, glycosides, saponins, steroids, terpenoids and anthraquinones. PNEdid not cause any extract-related physical, pharmacological and CNS toxicities or mortality; sedation was observed at doses 1000-2000 mg/kg. It showed significant dose-dependent reduction in cough count, and increased cough latency. PNE (1000 mg/kg) enhanced tracheal phenol red secretion. PNE (100-500 mg/kg) significantly and dose dependently increased tail withdrawal latencies, and nociceptive score. PNE has antitussive, expectorant, and analgesic properties, with an LD50>2000 mg/kg.
... The percentage rise in paw volume was calculated by following formula. 33 ...
The fruits of Barringtonia racemosa are traditionally used in Indian medicine for the treatment of pain and inflammatory conditions. In this study, a fraction of ethyl acetate extract of fruits of B. racemosa (BREAF) was investigated for anti-inflammatory activity in experimental models of acute and chronic inflammation. Activity against acute inflammation was evaluated in inflammogens induced rat paw edema models. Whereas, effect in chronic inflammation was evaluated in cotton pellet granuloma and oxazolone induced delayed type hypersensitivity (DTH) model in mice. The BREAF exhibited dose dependent anti-inflammatory activity in both acute and chronic models at oral doses of 5, 10 and 20 mg/kg. BREAF inhibited both phases of carrageenan induced rat paw inflammation. The reduction in paw inflammation by BREAF was also evident in histamine and serotonin induced inflammation in rats. Effect of BREAF on DTH indicates inhibition of immune mediated inflammation. The reduction in cotton pellet granuloma by BREAF treatment shows inhibition of proliferative changes associated with chronic inflammation. Analysis of BREAF after chromatographic separations showed presence of bartogenic acid as a major constituent. Hence, it is proposed that anti-inflammatory effects of BREAF can be partially attributed to its bartogenic acid content. The minute doses at which this fraction shows anti-inflammatory effects emphasizes the need for further investigations on its efficacy in the immuno-inflammatory conditions.
The phytochemical investigation of Dialium corbisieri seeds led to the isolation of five monoterpenoid indole alkaloids along with a phytoserotonin, 1-6 and among the known compounds, the spectroscopic data of (5S)-methoxy-akuammiline (1) was reported for the first time. The structures were elucidated based on NMR spectroscopic techniques such as UV, IR, HRESITOFMS, and ECD spectrum calculations. The isolated compounds were evaluated for their cytotoxicity and cell progression in the human acute promyelocytic leukemia HL60 cell line.
Akuammine (1) and pseudoakuammigine (2) are indole alkaloids found in the seeds of the akuamma tree (Picralima nitida). Both alkaloids are weak agonists of the mu opioid receptor (μOR); however, they produce minimal effects in animal models of antinociception. To probe the interactions of 1 and 2 at the opioid receptors, we have prepared a collection of 22 semisynthetic derivatives. Evaluation of this collection at the μOR and kappa opioid receptor (κOR) revealed structural-activity relationship trends and derivatives with improved potency at the μOR. Most notably, the introduction of a phenethyl moiety to the N1 of 2 produces a 70-fold increase in potency and a 7-fold increase in selectivity for the μOR. The in vitro potency of this compound resulted in increased efficacy in the tail-flick and hot-plate assays of antinociception. The improved potency of these derivatives highlights the promise of exploring natural product scaffolds to probe the opioid receptors.
Covering: 2011 to 2022The natural world is a prolific source of some of the most interesting, rare, and complex molecules known, harnessing sophisticated biosynthetic machinery evolved over billions of years for their production. Many of these natural products represent high-value targets of total synthesis, either for their desirable biological activities or for their beautiful structures outright; yet, the high sp3-character often present in nature's molecules imparts significant topological complexity that pushes the limits of contemporary synthetic technology. Dearomatization is a foundational strategy for generating such intricacy from simple materials that has undergone considerable maturation in recent years. This review highlights the recent achievements in the field of dearomative methodology, with a focus on natural product total synthesis and retrosynthetic analysis. Disconnection guidelines and a three-phase dearomative logic are described, and a spotlight is given to nature's use of dearomatization in the biosynthesis of various classes of natural products. Synthetic studies from 2011 to 2021 are reviewed, and 425 references are cited.
Picralima nitida is a shrub or a tree used in folk medicine in the treatment of several diseases including malaria, diabetes, and cancers. The plant displayed analgesic, antimalarial and antimicrobial potential, antidiabetic, and anticancer activities. In the present chapter, the phytochemical composition, as well as the antibacterial potential of this plant, is reviewed. Several classes of secondary metabolites like alkaloids (akuammine, picraline or akummicin), saponins, phenolic compounds (coumestans and glycosidic coumestans) have been identified from the plant. The methanol extract of this plant had interesting antibacterial effects on both drug-sensitive and drug-resistant phenotypes. Data compiled herein indicate that this plant can be a source of an herbal drug to combat bacterial infections.
The effect of ground seeds of Picralima nitida incorporated diets on serum lipid profile of albino rats was studied. Twenty five albino rats randomly distributed into five groups of five rats were fed with 5%, 10%, 20% and 30% w/w concentrations of ground seeds of Picralima nitida incorporated diets for 28 days. The concentrations of serum triacylglycerols (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), positive atherogenic index (HDL-C/TC) and negative atherogenic index (LDL-C/HDL-C) of the serum of albino rats fed with these percentage concentrations of ground seeds of Picralima nitida incorporated diets were determined using standard methods. Albino rats fed with guinea feed without ground seeds of Picralima nitida served as the control. Results obtained show that there was a significant (p<0.05) decrease in the concentrations of triacylglyceroles, low-density lipoprotein as the concentrations of ground seeds of Picralima nitida increased in contrast to a gradual significant (p>0.05) increase in the concentrations of serum cholesterol at 10% and a significant (p<0.05) reduction in the concentrations of high-density lipoprotein cholesterol (LDH-C) at high concentration of 30% of the ground seeds of P. nitida incorporated diets, when compared to those of the control. Positive atherogenic index (HDL-C/TC) showed a significant (p<0.05) reduction at 30% while negative atherogenic index (LDL-C/HDL-C) was significantly (p<0.05) lower from 10% when compared to those of the control. These observed changes, as a result of administration of ground seeds of P. nitida incorporated diets indicate that these plant seeds have hypolipidaemic potential on the serum of experimental albino rats.
Ethnopharmacological relevance:
The choice of extraction solvent is a significant consideration in ethnomedicine as optimal extraction could influence the bioactivity of the herbal medicinal product.
Aim of study:
This study investigated the possible influence of the choice of solvents (methanol and water) for extracting MAMA Powder (MP) against Plasmodium berghei-infected mice to optimize its antimalarial activity and for developing other pharmaceutical dosage forms.
Materials and methods:
Aqueous and methanol extracts of MP, obtained through the decoction and soxhlet methods, respectively, were subjected to liquid chromatography-mass spectroscopy (LC-MS) for their respective fingerprints. The antimalarial activities of the methanol and aqueous extracts (12.5-100 mg/kg) were evaluated orally using the chemosuppressive test model on chloroquine-sensitive Plasmodium berghei-infected mice. The methanol extract was subjected to the established infection and prophylactic antimalarial tests with chloroquine (10 mg/kg) and pyrimethamine (1.25 mg/kg) as positive controls, respectively. The aqueous extract was investigated in chloroquine-resistant P. berghei using the chemosuppressive (12.5-800 mg/kg) and established infection (25-400 mg/kg) antimalarial models.
Results:
The LC-MS fingerprints of both aqueous and methanol extracts revealed similar indole alkaloid contents. Chemosuppressive activity of the aqueous extract (75.3%) was significantly (p < 0.05) higher than the methanol extract (67.6%). In the chloroquine-resistant P. berghei infection experiments, the aqueous extract (400 mg/kg) exhibited significant parasite clearance (72%).
Conclusion:
The study concluded that the water extract with higher antimalarial activity could be optimized for chloroquine-resistant malaria and can thus facilitate the production of liquid and solid dosage forms.
In the era of air pollutants, respiratory diseases are a very common diagnosis in children, adolescents, and adults. Disorders of the respiratory system can affect both upper and lower respiratory system, and cause an immense worldwide health, economical and psychological burden.
Considerable attention is drawn to the use of plant-based products for the prevention and cure of health challenges, with respect of their eco-friendliness and very few side effects. Exposure to nature and active plant interaction is considered beneficial to physical and mental health. Plant-based drugs primarily target the immune and cardiovascular systems. Biologically active substances with different value can be identified from both terrestrial or marine botanicals, whose therapeutic abilities are an efficient control of an array of diseases.
In view of the potential of plant agents to positively influence respiratory diseases, this review will provide the reader with recent objective findings in the field of plant therapy and pharmaceutical agents and their ability to alter the physical and psychological complications of airborne diseases.
In this mini-literature review, the traditional use, nutritional value, phytochemistry and biological properties of P. nitida, a plant used as a conventional African medicine is described. The literature discussed in this investigation established that extracts from P. nitida were very efficient in the treatment of several diseases including malaria. Hence we anticipate that it may be effective against Covid-19 virus also. We suggest that in vitro and in vivo assays should be conducted to confirm the activity of the plant against SARS-CoV-2.
Heterocyclic compounds constitute one of the largest and most versatile family of organic compounds. Today there are many heterocyclic compounds that are being isolated from natural sources and day by day the number is increasing rapidly due to their enormous utility. Nitrogen containing heterocyclic compounds have a prominent role in most fields of sciences such as medicinal chemistry, biochemistry also another area of sciences. In this review, we cover most biological active nitrogen containing heterocyclic compounds that are extracted from the natural sources including indole, Carbazole, Quinoline, Isoquinoline and Benzthiazole ring system. These isolated nitrogen containing heterocyclic compounds renders antifungal, anti-inflammatory, antibacterial, antioxidants, anticonvulsant, antiallergic, herbicidal and anticancer properties.
Picralima nitida (Stapf) T. Durand and H. Durand (Apocynaceae), over the years has shown wide range of usage in African folk medicine and its safety profile in instances of prolonged use and pregnancy are major concerns. The study aimed to extensively investigate the toxicological effects of Picralima nitida in albino rodents and make appropriate extrapolations to humans.
In the first phase of the experiment which evaluated the genotoxicity and subchronic toxicity of P. nitida, a total of 40 albino rats (male and female) were randomized into 4 groups of 10 animals per group. Group 1 (control group) was orally administered with 10 ml/kg of distilled water. Animals in Groups 2 to 4 were administered with aqueous seed extract of the plant at 100, 200, 400 mg/kg body weight/day, respectively. Oral administration at the designated doses was continued for 90 days after which they were sacrificed by cervical dislocation for subchronic toxicological assessment. In the genotoxicity phase, 30 female mice were randomized into 5 groups, the control group was treated with 10 ml/kg of distilled water, groups 2 to 4, treated with 100 mg/kg, 200 mg/kg and 400 mg/kg doses of extract, and the 5th group had cyclophosphamide (0.1 mg/kg). The mice were sacrificed on the 28th day for bone marrow sampling for genotoxicity testing.
In the second phase of the experiment which evaluated the teratogenicity of P. nitida, graded doses of the extract were administered to pregnant rats from day 1–19. Three groups of 6 female rats per group were administered 75, 150 and 300 mg/kg aqueous extract of P. nitida and a fourth group of 6 rats used as control was administered distilled water at 10 ml/kg. On day 20, 3 dams from each group were sacrificed and the foetuses were harvested through abdominal incision for physical examination. The 3 remaining dams were allowed to litter. The litters were sacrificed at 6 weeks for biochemical, haematological and histological analyses.
The LD50 determined was 707.107 mg/kg. The aqueous seed extract of P. nitida was found to be genotoxic at all the test doses. There were no significant alterations in haematologic and renal parameters following subchronic administration. Notable dynamics were observed in hormonal characteristics: there was a significant dose-dependent reduction in FSH while oestradiol and progesterone showed dose-dependent increase. Furthermore, P. nitida may cause hepatopathy as shown by hepatic venous and sinusoidal congestion on hepatic histology. Also, there is non-significant reduction in total cholesterol and LDL. No significant alteration in glucose level.
Furthermore, the extract produced a statistically significant decrease in birth weight (p < 0.0001). The extract induced a significant (p < 0.05) increase in creatinine and transaminase levels in the first filial of group 150 mg/kg. The platelet count was increased in all treated group (p < 0.005). All the histology of kidney in 150 mg/kg group showed vascular congestion.
In conclusion, the aqueous seed extract of P. nitida has teratogenic effects and should not be used in pregnant women. Also, P. nitida is highly genotoxic and may cause hepatic damage and depletion of glutathione pool on chronic use, thereby causing oxidative stress and its potential sequelae.
Opioid use disorder continues to be a significant source of morbidity and mortality in the USA and the world. Pharmacologic treatment with methadone and buprenorphine has been shown to be effective at retaining people in treatment programs, decreasing illicit opioid use, decreasing rates of hepatitis B, and reducing all cause and overdose mortality. Unfortunately, barriers exist in accessing these lifesaving medications: users wishing to start buprenorphine therapy require a waivered provider to prescribe the medication, while some states have no methadone clinics. As such, users looking to wean themselves from opioids or treat their opioid dependence will turn to alternative agents. These agents include using prescription medications, like clonidine or gabapentin, off-label, or over the counter drugs, like loperamide, in supratherapeutic doses. This review provides information on the pharmacology and the toxic effects of pharmacologic agents that are used to treat opioid use disorder. The xenobiotics reviewed in depth include buprenorphine, clonidine, kratom, loperamide, and methadone, with additional information provided on lofexidine, akuamma seeds, kava, and gabapentin.
The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (–)-2(S)-cathafoline, (+)-akuammiline, and (–)-Ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection–cyclization cascade. The total syntheses of (–)-Ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (–)-10-demethoxyvincorine and a new analogue thereof.
Humans perceive physical information about the surrounding environment through their senses. This physical information is registered by a collection of highly evolved and finely tuned molecular sensory receptors. A multitude of bioactive, structurally diverse ligands have evolved in nature that bind these molecular receptors. The complex, dynamic interactions between the ligands and the receptors lead to changes in our sensory perception or mood. Here, we review our current knowledge of natural products and their derived analogues that interact specifically with human G protein-coupled receptors, ion channels, and nuclear hormone receptors to modulate the sensations of taste, smell, temperature, pain, and itch, as well as mood and its associated behaviour. We discuss the molecular and structural mechanisms underlying such interactions and highlight cases where subtle differences in natural product chemistry produce drastic changes in functional outcome. We also discuss cases where a single compound triggers complex sensory or behavioural changes in humans through multiple mechanistic targets. Finally, we comment on the therapeutic potential of the reviewed area of research and draw attention to recent technological developments in genomics, metabolomics, and metabolic engineering that allow us to tap the medicinal properties of natural product chemistry without taxing nature.
For decades, akuammiline alkaloids have attracted synthetic chemists due to their intriguing molecular architecture. Among the different structural elements embedded in their carboskeleton, the methanoquinolizidine system constitutes the signature structural element of this alkaloid family. Herein, we describe a novel synthetic access to this system which relies on a [2,3]-Stevens rearrangement and results in the formal synthesis of strictamine.
The ORL1 receptor, an orphan receptor whose human and murine complementary DNAs have recently been characterized, structurally resembles opioid receptors and is negatively coupled with adenylate cyclase. ORL1 transcripts are particularly abundant in the central nervous system. Here we report the isolation, on the basis of its ability to inhibit the cyclase in a stable recombinant CHO(ORL1+) cell line, of a neuropeptide that resembles dynorphin A9 and whose amino acid sequence is Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln. The rat-brain cDNA encodes the peptide flanked by Lys-Arg proteolytic cleavage motifs. The synthetic heptadecapeptide potently inhibits adenylate cyclase in CHO(ORL1+) cells in culture and induces hyperalgesia when administered intracerebroventricularly to mice. Taken together, these data indicate that the newly discovered heptadecapeptide is an endogenous agonist of the ORL1 receptor and that it may be endowed with pro-nociceptive properties.
Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.
A 12-step scheme representing initiation and development of acute carrageenan inflammation in the rat has been devised. Simultaneous quantitative temporal measurement of the number of inflammatory cells mobilized and edema volume produced as carrageenan pleurisy developed helped elucidate several of the early steps, In the pleurisy a 20-min lag phase preceded both the mobilization of neutrophils and edema formation. Temporal histological studies suggested that the lag phase represents the time needed for the neutrophil chemotactic factor to be generated and/or released (steps 2 and 3) in addition to the time required for these cells to move through the walls of the capillaries into the pleural space (steps 4 and 5). The neutrophil chemotactic factor is unknown. The complement system is not involved since cobra venom factor-treated animals produced a normal edematous and cellular response to carrageenan in spite of severely depressed complement levels. The mobilized neutrophils are believed to phagocytize the carrageenan(step6). In this process lysosomal enzymes are released (step 7). Drug inhibition studies suggest that lysosomal enzymes are not the edemagenic agents in carrageenan inflammation. In the scheme these enzymes are responsible for activation of the prostaglandin biosynthetic chain (step 8). Prostaglandin biosynthesis (step 9) leads to the release of an intermediate (step 10), as yet unidentified, which is responsible for increased tissue permeability (step 11) and edema formation (step 12). Histamine, serotonin, bradykinin, arachidonic acid, and prostaglandin's E1 and E2 are not deemagenic in the rat pleural cavity and therefore cannot be responsible for edema formation. Aspirin and indomethacin reduce the edema produced by carrageenan in a dose-related manner without affecting the magnitude or the time course of neutrophil mobilization. These findings led to the concept that edema formation is not the result of inflammatory cell mobilization but is rather a consequence of cellular activity, presumably phagocytosis, after mobilization.
The effect of two commonly used methods to immobilize the animals, viz. tube restrainer and wrapping in a diaper (chux) on the tail flick latency in immersion test, was evaluated in mice using a stimulus temperature of 50 degrees C. The animals were immobilized either in the tube or chux briefly (25-30 sec) during the tail flick measurements. The basal tail flick latency was 2.8 +/- 0.2 in the tube restrained and 5.5 +/- 0.3 sec in chux restrained groups (p less than 0.001). The analgesic effect of morphine (1, 3, 4, 7, and 10 mg/kg) was significantly higher in the chux-restrained animals as indicated by the dose ratio of 2.16 for the 50% analgesic response in the chux versus tube restrained mice. The tail flick latency, 15 min after naloxone injection (1 and 3 mg/kg), expressed as % of predrug latency was significantly reduced in the chux- but not the tube-restrained group. The hyperalgesic effect of naloxone could not be detected in chux-restrained animals, when the water temperature was increased to 55 degrees C. The results demonstrate that the restraining procedure will influence the analgesic effects of test drugs in tail immersion test. Furthermore, the stimulus temperature appears to be an important variant that could influence the results in this test. The present results demonstrate the hyperalgesic effect of naloxone after systemic administration in the tail immersion test and supports the concept that tail flick response is tonically inhibited by endogenous opioid systems.
A sequential 43-step pathway scheme for the inflammatory response of the rat to interdermal injection of carrageenan (C) was devised. It consisted of a nonphagocytic inflammatory response (NPIR) followed by a phagocytic inflammatory response (PIR) in the dermis and an epidermal NPIR. The dermal NPIR comprised edema, hyperemia, and hyperalgesia followed by hypoalgesia. Antiserotonin agents inhibited the hypoalgesia and part of the edema. These findings and histological observations suggested that dermal mast cells were injured by C. The hyperalgesia and part of the edema were sensitive to arachidonate cyclooxygenase inhibitors (AACOIs). It is speculated that injured mast cells metabolize arachidonic acid and reactive intermediates, not prostaglandins, mediate the NPIR hyperalgesia and part of the edema. The dermal PIR consisted of mobilization of neutrophils, edema, hyperalgesia, mobilization of monocytes, and proliferation of fibroblasts and vascular tissue. Selective drug actions revealed that the edema, hyperalgesia, and monocyte mobilization of the PIR depended on the mobilization of neutrophils. After the mobilization of neutrophils, AACOIs reduced edema formation and hyperalgesia. Arachidonic acid metabolism by neutrophils is speculated to produce the mediators of phagocytic inflammatory (PI) edema and hyperalgesia. Monocyte function was associated with cessation of PI edema formation and phagocytosis of neutrophils and cellular debris. Interleukin 1 is speculated to mediate the adherence of neutrophils to injured dermal endothelium. The epidermal NPIR consisted of edema, hyperplasia, and hyperkeratosis. These parameters were not studied mechanistically. There was no evidence for histamine, bradykinin, platelets, clotting factors, or complement mediating any events in the pathway.
A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP- binding
protein (G protein)- coupled receptor (LC132) that is similar in sequence to opioid receptors. This peptide, orphanin FQ,
has a primary structure reminiscent of that of opioid peptides. Nanomolar concentrations of orphanin FQ inhibited forskolin-stimulated
adenylyl cyclase activity in cells transfected with LC132. This inhibitory activity was not affected by the addition of opioid
ligands, nor did the peptide activate opioid receptors. Orphanin FQ bound to its receptor in a saturable manner and with high
affinity. When injected intracerebroventricularly into mice, orphanin FQ caused a decrease in locomotor activity but did not
induce analgesia in the hot-plate test. However, the peptide produced hyperalgesia in the tail-flick assay. Thus, orphanin
FQ may act as a transmitter in the brain by modulating nociceptive and locomotor behavior.
Selective PCR amplification of human and mouse genomic DNAs with oligonucleotides encoding highly conserved regions of the delta-opioid and somatostatin receptors generated a human DNA probe (hOP01, 761 bp) and its murine counterpart (mOP86, 447 bp). hOP01 was used to screen a cDNA library from human brainstem. A clone (named hORL1) was isolated, sequenced and found to encode a protein of 370 amino acids whose primary structure displays the seven putative membrane-spanning domains of a G protein-coupled membrane receptor. The hORL1 receptor is most closely related to opioid receptors not only on structural (sequence) but also on functional grounds: hORL1 is 49-50% identical to the murine mu-, delta- and kappa-opioid receptors and, in CHO-K1 cells stably transfected with a pRc/CMV:hORL1 construct, ORL1 mediates inhibition of adenylyl cyclase by etorphine, a 'universal' (nonselective) opiate agonist. Yet, hORL1 appears not to be a typical opioid receptor. Neither is it a somatostatin or sigma (N-allylnormetazocine) receptor. mRNAs hybridizing with synthetic oligonucleotides complementary to mOP86 are present in many regions of the mouse brain and spinal cord, particularly in limbic (amygdala, hippocampus, septum, habenula, ...) and hypothalamic structures. We conclude that the hORL1 receptor is a new member of the opioid receptor family with a potential role in modulating a number of brain functions, including instinctive behaviours and emotions.
Mitragynine is a major alkaloidal constituent extracted from the young leaves of Mitragyna speciosa Korth. (Rubiaceae). We investigated an antinociceptive activity of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injection of this alkaloid by the tail-pinch and hot-plate tests in mice, and evaluated the mechanisms of the action using naloxone, an opioid receptor antagonist. Mitragynine (5.0-30 mg/kg, i.p. and 1.0-10 micrograms/mouse, i.c.v.) exerted a dose-dependent antinociceptive activity which was maximal at 15-45 min after injection in the tail-pinch and hot-plate tests, but it did not induce a morphine-like behavioral change. the antinociceptive actions of i.p. mitragynine were completely abolished by both s.c. (2 mg/kg) and i.c.v (10 micrograms/mouse) naloxone. The action of i.c.v. mitragynine (10 micrograms/mouse) was also antagonized by i.c.v. naloxone (10 micrograms/mouse). These results indicate that mitragynine itself can induce antinociception by acting in the brain, and that the supraspinal opioid systems are at least partly involved in the antinociceptive action of mitragynine in mice.
Extracts of the seeds of Picralima nitida (fam. Apocynaceae) have been reported to have opioid analgesic activity. In this investigation, isolated tissue bioassays and radioligand binding assays have been used to determine the opioid activity of five alkaloids--akuammidine, akuammine, akuammicine, akuammigine and pseudoakuammigine--extracted from the seeds of P. nitida. Akuammidine showed a preference for mu-opioid binding sites with Ki values of 0.6, 2.4 and 8.6 microM at mu-, delta- and kappa-opioid binding sites, respectively. The agonist actions of akuammidine in the mouse-isolated vas deferens were antagonised by naloxone and the mu-opioid receptor selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) confirming an action at mu-opioid receptors. In contrast, akuammine also showed highest affinity for mu-opioid binding sites (Ki 0.5 microM) but was an antagonist at mu-opioid receptors with a pK(B) of 5.7 against the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO). Akuammicine has the highest affinity for kappa-opioid binding sites (Ki 0.2 microM) and was a full agonist at kappa-opioid receptors in the guinea pig ileum preparation but a partial kappa-opioid receptor agonist in the vasa deferentia of the mouse and the rabbit. Akuammigine and pseudoakuammigine showed little or no efficacy in the opioid bioassays. None of the alkaloids had significant activity for opioid receptor-like binding sites (ORL1-binding sites) with Ki values > 10 microM. These data show that some alkaloids extracted from the medicinal plant P. nitida possess varying degrees of agonist and antagonist activity at opioid receptors but possess neither high affinity nor selectivity for mu-, delta- or kappa-opioid receptors or the ORL1-receptor.
A method is presented for measuring the edema induced by injection of 0.05 ml of 1% solution of carrageenin, an extract of Chondrus, into the plantar tissues of the hind paw of the rat. Peak edema develops within the first 3 to 4 hours, and is inhibited by pretreatment of the animals by single oral doses of antiinflammatory agents, steroid or non-steroid. Log dose responses to drugs are linear and parallel, and yield potency ratios with relatively narrow confidence limits. The potency ratios obtained for aspirin, phenylbutazone and hydrocortisone are fairly close to the ratios of their respective daily doses in the treatment of rheumatic disease. A potent antihistaminic-antiserotonin compound, cyproheptadine, is without effect on carrageenin-induced edema.