Acute Oral Toxicological Profile of Croton membranaceus Mull. Arg. Aqueous Stem Extract, a Herbal Treatment for Benign Prostate Hyperplasia, in Male Sprague-Dawley Rats.

Croton membranaceus Mull. Arg. is a traditional medicinal plant frequently employed in Ghana for the treatment of benign prostatic hyperplasia and prostate cancer. The objective of this study was to determine the acute oral toxicity of the aqueous stem extract of Croton membranaceus (CMASE) in male Sprague-Dawley (S-D) rats. The acute toxicity of CMASE was evaluated using S-D rats randomly divided into four groups of five animals each. Three groups (low dose, median dose, and high dose) of rats received single oral doses of CMASE (1000, 2500, and 5000 mg/kg body weight, respectively) using an oral gavage. The control group was given distilled water. After 14 days of daily observations, hematological, biochemical, and histopathological analyses were conducted on the rats. From the results obtained, doses of CMASE up to 5000 mg/kg did not cause death or induce any clinical indications of toxicity during the study period. Also, the mean body weight and the hematological indices assessed were not significantly affected by the various doses of CMASE compared to the control group. However, serum uric acid and creatinine levels decreased significantly (p < 0.001) 14 days after the extract administration. Serum liver function enzyme levels, including alkaline phosphatase (ALP), alanine aminotransferases (ALT), and aspartate aminotransferases (AST), and serum proteins (total proteins and albumin) exhibited significant (p < 0.001) non dose-dependent changes (increases and decreases) in treated groups compared to the controls. Other biochemical indices, however, did not differ significantly between the treated groups and the controls. The gross pathological and histological analysis of the heart, liver, and kidney tissues did not reveal any significant changes in histoarchitecture. The oral LD50 of CMASE in rats was greater than 5000 mg/kg, indicating that the extract was relatively safe. It must, however, be used with care as a substitute for the roots.

Modulating Effects of the Hydroethanolic Leaf Extract of Persicaria lanigera R. Br. Soják (Polygonaceae) against Acute Inflammation.

Plant species have been used traditionally to treat numerous inflammatory disorders because of their known medicinal properties. This study aimed to assess the anti-inflammatory effect of aqueous ethanolic leaf extract of Persicaria lanigera using acute inflammatory models. The safety profile of the Persicaria lanigera extract was assessed using an acute toxicity model. The anti-inflammatory effect of the Persicaria lanigera leaf extract (100-600 mg·kg-1, p.o.) was studied in carrageenan-induced paw oedema, zymosan-induced knee joint arthritis, and histamine-induced paw oedema in Sprague-Dawley rats (n = 5). It was observed that the Persicaria lanigera leaf extract administered prophylactically significantly inhibited paw oedema from 99.01 ± 12.59 to 59.10 ± 4.94%, 56.08 ± 3.65%, and 48.62 ± 3.27% at 100 mg·kg-1, 300 mg·kg-1, and 600 mg·kg-1, while the standard drug, aspirin, showed 41.84 ± 9.25% in carrageenan-induced paw oedema, respectively. Furthermore, the extract decreased knee joint inflammation significantly from 62.43 ± 5.73% to 32.07 ± 2.98% and 24.33 ± 8.58% at 300 mg·kg-1 and 600 mg·kg-1 in zymosan-induced knee joint inflammation, respectively. In the histamine-induced paw oedema model, the extract significantly inhibited oedema to 61.53 ± 9.17%, 54.21 ± 9.38%, and 54.22 ± 9.37% at the same doses. Aqueous ethanolic leaf extract of Persicaria lanigera is safe and attenuates inflammation in acute inflammation models.

Antibacterial, Resistance Modulation, Anti-Biofilm Formation, and Efflux Pump Inhibition Properties of Loeseneriella africana (Willd.) N. Halle (Celastraceae) Stem Extract and Its Constituents.

This study investigated the antibacterial, resistance modulation, biofilm inhibition, and efflux pump inhibition potentials of Loeseneriella africana stem extract and its constituents. The antimicrobial activity was investigated by the high-throughput spot culture growth inhibition (HT-SPOTi) and broth microdilution assays. The resistance modulation activity was investigated using the anti-biofilm formation and efflux pump inhibition assays. Purification of the extract was carried out by chromatographic methods, and the isolated compounds were characterized based on nuclear magnetic resonance, Fourier transform infrared and mass spectrometry spectral data and comparison with published literature. The whole extract, methanol, ethyl acetate, and pet-ether fractions of L. africana all showed antibacterial activity against the test bacteria with MICs ranging from 62.5 to 500.0 µg/mL The whole extract demonstrated resistance modulation effect through strong biofilm inhibition and efflux pump inhibition activities against S. aureus ATCC 25923, E. coli ATCC 25922 and P. aeruginosa ATCC 27853. Chromatographic fractionation of the ethyl acetate fraction resulted in the isolation of a triterpenoid (4S,4αS,6αR,6ßS,8αS,12αS,12ßR,14αS,14ßR)-4,4α,6ß,8α,11,11,12ß,14α-Octamethyloctadecahydropicene-1,3(2H,4H)-dione) and a phytosterol (ß-sitosterol). These compounds showed antibacterial activity against susceptible bacteria at a MIC range of 31-125 µg/mL and potentiated the antibacterial activity of amoxicillin (at » MIC of compounds) against E. coli and P. aeruginosa with modulation factors of 32 and 10, respectively. These compounds also demonstrated good anti-biofilm formation effect at a concentration range of 3-100 µg/mL, and bacterial efflux pump inhibition activity at ½ MIC and » MIC against E. coli and P. aeruginosa. Loeseneriella africana stem bark extracts and constituents elicit considerable antibacterial, resistance modulation, and biofilm and efflux pump inhibition activities. The results justify the indigenous uses of L. africana for managing microbial infections.

Evaluation of the anti-inflammatory and antioxidant potential of the stem bark extract and some constituents of Aidia genipiflora (DC.) dandy (rubiaceae).

Aidia genipiflora (DC.) Dandy (Rubiaceae) is used to treat various microbial and inflammatory conditions by traditional healers in West African countries. However, there is no information on anti-inflammatory potential of A. genipiflora. This work therefore provides information on the anti-inflammatory and the antioxidant activities of the stem bark extracts and some bioactive constituents of Aidia genipiflora. Method: The anti-inflammatory activities of the extracts and compounds from A. genipiflora were investigated using the carrageenan-induced footpad oedema assay and the egg albumin denaturation assay. The antioxidant activities of the extract and compounds were investigated using the DPPH radical scavenging assay and the phosphomolybdenum total antioxidant capacity assay. The whole extract of A. genipiflora was also investigated for its acute oral toxicity using the fixed-dose procedure described by the Organization for Economic Cooperation Development guidelines. Result: The whole extract showed no acute toxicity effect and the LD50 was estimated to be greater than 3000 mg/kg body weight. The whole extract, methanol, and ethyl acetate fractions (30, 100, and 300 mg/kg) showed in vivo anti-inflammatory activity with respective percentage inhibition of oedema of 45.11 ± 3.41, 31.12 ± 3.42 and 29.28 ± 3.58 (p < 0.001) at the highest dose of 300 mg/kg. Diclofenac, used as a reference drug, gave a % inhibition of 48.94 ± 3.58. The compounds isolated from A. genipiflora demonstrated in-vitro anti-inflammatory activity at the IC50 range (16-96 µg/mL) compared to diclofenac (IC50 of 74.48 µg/mL). Oleanonic acid (AG1) and D-mannitol (AG4) further demonstrated in vivo anti-inflammatory activity (ED50 = 20.61 ± 1.29; 23.51 ± 1.26 mg/kg respectively) which was less potent compared to diclofenac (ED50 = 12.50 ± 1.41 mg/kg) in the carrageenan-induced oedema assay. The whole extract, pet. ether, ethyl acetate, and methanol fractions of A. genipiflora exhibited DPPH scavenging activities with respective IC50 of 222.2, 169.7, 121.5, and 40.7 µg/mL. The whole extract of A. genipiflora exhibited considerable total antioxidant capacity with respective values of 248.5 mg/g of ascorbic acid equivalent. All the compounds exhibited low DPPH scavenging activity with IC50 (64-86 µg/mL), compared to ascorbic acid (IC50 of 3.13 ± 1.20 µg/mL). These results highlight the anti-inflammatory and antioxidant activities of Aidia genipiflora stem bark extract and its constituents as evidence to support its traditional uses.

Gestational iron supplementation reverses depressive-like behavior in post-partum Sprague Dawley rats: Evidence from behavioral and neurohistological studies.

Background: Postpartum depression is a mood disorder that affects about 9-20% of women after child birth. Reports suggest that gestational iron deficiency can cause a deficit in behavioral, cognitive and affective functions and can precipitate depressive symptoms in mothers during the postpartum period. The present study examined the effect of iron supplementation on depressive behavior during postpartum period in a rat model. Method: Female Sprague-Dawley rats were crossed. Pregnant rats received iron, fluoxetine, desferrioxamine or vehicle throughout the period of gestation. During the postpartum period, mothers from all groups were taken through the open field test (OFT), forced swim test (FST), novelty-induced hypophagia (NIH) and sacrificed for histological examination of the brains. Results: Results showed that rats treated with iron-chelating agent, desferrioxamine, and vehicle during gestation exhibited increased immobility scores in the FST, increased latency to feed and reduced feeding in the NIH with corresponding decreased number of neurons and dendritic branches in the cortex of the brain. These depression-related effects were attenuated by perinatal iron supplementation which showed decreased immobility scores in the FST comparable to rats treated with fluoxetine, a clinically effective antidepressant. Iron treatment also decreased latency to feeding while increasing feeding behavior in the NIH. Iron-treated dams had a higher number of neurons with dendritic connections in the frontal cortex compared to vehicle- and desferrioxamine-treated groups. Conclusion: The results suggest that, iron supplementation during gestation exerts an antidepressant-like effect in postpartum Sprague-Dawley rats, attenuates neuronal loss associated with depression and increases dendritic spine density.

Extract of Xylopia aethiopica and its kaurene diterpene, xylopic acid, improve learning and memory in mice.

Background: Cognitive dysfunction, presenting as learning and memory impairment, is a common manifestation in many chronic diseases of the nervous system. Some of these diseases include depression, epilepsy, and Alzheimer's disease. To date, few drugs or medicinal products have shown ability to improve learning and memory deficits. Neuroprotection is one of the mechanisms by which memory could be improved. The extract of Xylopia aethiopica and its kaurene derivative, xylopic acid, have previously demonstrated neuroprotective effects in animal models. The aim of the present study was to investigate the effect of an extract of Xylopia aethiopica fruit and xylopic acid, on learning and memory using murine models. Materials and methods: Unripe Xylopia aethiopica fruits were collected, dried, and extracted using 70% v/v ethanol. Xylopic acid was isolated from the fruits using petroleum ether, concentrated with ethyl acetate and then recrystallized with petroleum ether before purifying with ethanol (96%v/v). Institute of Cancer Research (ICR) mice received oral doses of the extract of Xylopia aethiopica (XAE; 30, 100 and 300 mg/kg), xylopic acid (XA; 30, 100 and mg/kg), citicoline (300 mg/kg), piracetam (300 mg/kg) or ketamine (30 mg/kg) and saline (vehicle). The animals were then taken through the Morris water maze test (MWM), spontaneous alternation Y-maze test (Y-maze), and novel object recognition test (NOR), to assess learning and memory. Results: In the NOR test, XAE (30, 100 and 300 mg/kg) and XA (30, 100 and 300 mg/kg) increased the percentage exploration and recognition index (p = 0.0005 and p < 0.0001, respectively) when compared to both vehicle and ketamine groups. Similarly, doses of XAE and XA as used in the NOR test increased the percentage alternation in the Y-maze test. Although XAE and XA treatments decreased the latencies to find hidden platform in the MWM test, it was not significantly different from the vehicle group. However, this decrease in latency differed significantly when compared to the ketamine group. Interestingly, both XAE and XA treatments increased the percentage frequency to the target quadrant in the probe trial of the MWM. It is noteworthy that in all the three models used, both the extract and xylopic acid performed better than piracetam and citicoline, the reference drugs. Conclusion: The ethanolic extract of Xylopia aethiopica fruit and xylopic acid improved exploratory learning and recognition memory, spatial working, recognition, and reference memories in the behavioral tests.

Glycine/NMDA Receptor Pathway Mediates the Rapid-onset Antidepressant Effect of Alkaloids From Trichilia Monadelpha.

INTRODUCTION: Major depressive disorder is often associated with suicidal tendencies, and this condition accentuates the need for rapid-acting antidepressants. We previously reported that Alkaloids (ALK) from Trichilia monadelpha possess antidepressant action in acute animal models of depression and that this effect is mediated through the monoamine and L-arginine-NO-cGMP pathways. This study investigated the possible rapid-onset antidepressant effect of ALK from T. monadelpha and its connection with the glycine/NMDA receptor pathway. METHODS: The onset of ALK action from T. monadelpha was evaluated using the Open Space Swim Test (OSST), a chronic model of depression. The modified forced swimming and tail suspension tests were used to assess the effect of the ALK on the glycine/NMDA receptor pathway. The Instutute of Cancer Research (ICR) mice were treated with either ALK (30-300 mg/kg, orally [PO]), imipramine (3-30 mg/kg, PO), fluoxetine (3-30 mg/kg, PO), or saline. To identify the role of glycine/NMDA receptor pathway in the effect of ALK, we pretreated mice with a partial agonist of the glycine/NMDA receptor, D-cycloserine (2.5 mg/kg, intraperitoneally [IP]), and an agonist of glycine/NMDA receptor, D-serine (600 mg/kg, IP), before ALK administration. RESULTS: ALK reversed immobility in mice after the second day of drug treatment in the OSST. In contrast, there was a delay in the effects induced by fluoxetine and imipramine. ALK also increased mean swimming and climbing scores in mice. ALK was more efficacious than imipramine and fluoxetine in reducing immobility and increasing distance traveled. It is noteworthy that ALK was less potent than fluoxetine and imipramine. D-cycloserine potentiated mobility observed in the ALK- and fluoxetine-treated mice. In contrast, D-serine decreased mobility in the ALK-treated mice. CONCLUSION: The study results suggest that ALK from T. monadelpha exhibits rapid antidepressant action in mice, and the glycine/NMDA receptor pathway possibly mediates the observed effect.

Assessment of malaria diagnostic methods and treatments at a Ghanaian health facility.

INTRODUCTION: it has been more than a decade since the World Health Organization (WHO) recommended parasitological confirmation of malaria before treatment begins. Light microscopy and rapid diagnostic tests are currently being used for diagnosing malaria in routine clinical care settings. Many clinicians have however raised questions about the competencies of laboratory staff who perform these tests and the performance of these diagnostic methods. This study aimed at assessing the performance of microscopy and two rapid diagnostic test kits in the hands of routine laboratory staff compared to expert microscopy as well as assess the performance of clinical diagnosis. METHODS: this was a cross sectional study involving 799 participants of all ages who visited the out patient department of the University of Cape Coast Hospital with symptoms suggestive of malaria. RESULTS: when the different methods were compared to expert microscopy, the rapid diagnostic test kits had the highest sensitivities, Wondfo 94.83% (95% CI: 85.62-98.20) and CareStart 91.38 (95% CI: 81.02-97.14). Microscopy by laboratory staff had a sensitivity of 68.79 (95% CI: 55.46-80.46) whilst clinical diagnosis had the lowest sensitivity of 17.24 (95% CI: 8.59-29.43). Cohen´s kappa coefficient was used to measure the level of agreement of the methods with expert microscopy. Microscopy by laboratory staff, CareStart and Wondfo showed substantial measures of agreement (k = 0.737, 0.683, and 0.691 respectively). CONCLUSION: these findings suggest that clinical diagnosis is highly unreliable whilst rapid diagnostic tests and microscopy performed by routine laboratory staff could be trusted by clinicians as reliable diagnostic methods.

Analgesic Effect of Ziziphus abyssinica Involves Inhibition of Inflammatory Mediators and Modulation of KATP Channels, Opioidergic and Nitrergic Pathways.

The diversity offered by natural products has timelessly positioned them as a good source for novel therapeutics for the management of diverse medical conditions, including pain. This study evaluated hydro-ethanolic root bark extract of Ziziphus abyssinica (ZAE) as well as ß-amyrin and polpunonic acid isolated from the plant for analgesic property. The study also investigated the mechanism responsible for this action in the extract. The antinociceptive potential of ZAE (30, 100, and 300 mg/kg, p. o.) was assessed using the tail-immersion test (TIT), acetic acid-induced writhing test (AAT), and formalin test (FT). The extract's effect on acute and chronic musculoskeletal pain was also assessed by administering carrageenan unilaterally into the rat gastrocnemius muscles and measuring pain at 12 h and 10 days for acute and chronic pain respectively. The involvement of pro-inflammatory mediators (prostaglandin E2, bradykinin, TNF-α, and IL-1ß) was assessed. The possible pathways mediating the observed analgesic effect of ZAE were further assessed using the antagonists: naloxone, glibenclamide, NG-L-nitro-arginine methyl ester (L-NAME), atropine, nifedipine, and yohimbine in the FT. Also the analgesic effect of two triterpenoid compounds, ß-amyrin and polpunonic acid, previously isolated from the plant was assessed using the TIT. The anti-nociceptive activity of ZAE was demonstrated in the TIT by the significant (p < 0.05) increase in tail withdrawal threshold in ZAE-treated mice. ZAE also markedly reduced writhing and paw licking responses in both AAT and FT and significantly (p < 0.05) attenuated both acute and chronic musculoskeletal pain. ZAE also significantly reversed hyperalgesia induced by intraplantar injection of PGE2, bradykinin, TNF-α, and IL-1ß. Furthermore, data revealed the involvement of opioidergic, ATP-sensitive K+ channels and NO-cGMP pathways in the analgesic effect of ZAE. Both ß-amyrin and polpunonic acid exhibited analgesic activity in the tail suspension test. Our study demonstrates ZAE as an important source of new therapeutic agents for pain management.

The Anticonvulsant Effect of Hydroethanolic Leaf Extract of Calotropis procera (Ait) R. Br. (Apocynaceae).

A number of currently used drugs have been obtained from medicinal plants which are a major source of drugs. These drugs are either used in their pure form or modified to a semisynthetic drug. Drug discovery through natural product research has been fruitful over the years. Traditionally, Calotropis procera is used extensively in the management of epilepsy. This study is conducted to explore the anticonvulsant effect of a hydroethanolic leaf extract of Calotropis procera (CPE) in murine models. This effect was evaluated using picrotoxin-induced convulsions, strychnine-induced convulsions, and isoniazid- and pilocarpine-induced status epilepticus in mice of both sexes. The results showed that CPE (100-300 mg/kg) exhibited an anticonvulsant effect against strychnine-induced clonic seizures by significantly reducing the duration (p = 0.0068) and frequency (p = 0.0016) of convulsions. The extract (100-300 mg/kg) caused a profound dose-dependent delay in the onset of clonic convulsions induced by picrotoxin (p < 0.0001) and tonic convulsions (p < 0.0001) in mice. The duration of convulsions was reduced significantly also for both clonic and tonic (p < 0.0001) seizures as well. CPE (100-300 mg/kg), showed a profound anticonvulsant effect and reduced mortality in the pilocarpine-induced convulsions. ED50 (~0.1007) determined demonstrated that the extract was less potent than diazepam in reducing the duration and onset of convulsions but had comparable efficacies. Flumazenil-a GABAA receptor antagonist-did not reverse the onset or duration of convulsions produced by the extract in the picrotoxin-induced seizure model. In isoniazid-induced seizure, CPE (300 mg kg1, p.o.) significantly (p < 0.001) delayed the onset of seizure in mice and prolonged latency to death in animals. Overall, the hydroethanolic leaf extract of Calotropis procera possesses anticonvulsant properties.

Neuropharmacological Assessment of the Hydroethanolic Leaf Extract of Calotropis procera (Ait). R. Br. (Apocynaceae) in Mice.

BACKGROUND: Calotropis procera has been widely used traditionally for its analgesic and anti-inflammatory effects. It is also reportedly used in ethnomedicine for mental health disorders including epilepsy even in the absence of supporting scientific data. Thus, the potential of the plant to affect neurological functions was evaluated. METHODS: Irwin's test was performed to determine the effect of the oral administration of the extract (30-3000 mg kg-1) on gross behaviour and physiological function. The activity meter, rotarod, pentylenetetrazol- (PTZ-) induced convulsion, pentobarbitone-induced sleep test, and the tail immersion tests were used to evaluate the spontaneous activity, neuromuscular function, convulsive threshold, sedation, and analgesic effects of the Calotropis procera extract (30-1000 mg/kg), respectively, in mice. RESULTS: Calotropis procera extract (CPE) exhibited significant (p < 0.0001) anticonvulsant and analgesic effects. There was a significant increase in withdrawal latency of the CPE-treated animals in the tail immersion test for analgesia (p < 0.0001), while latency and duration of PTZ-induced convulsions were positively modulated. Calotropis procera extract showed significant (p < 0.0001) central nervous system depressant effects in pentobarbitone-induced hypnosis at 100-1000 mg/kg and spontaneous activity test (30-1000 mg/kg). The extract also depicted impaired motor coordination at 100-1000 mg/kg dose levels. LD50 was estimated to be above 1000 mg kg-1. CONCLUSIONS: Calotropis procera extract has significant central nervous system depressant and analgesic effects in mice.

Evidence of an antidepressant-like effect of xylopic acid mediated by serotonergic mechanisms.

BACKGROUND: Depression causes significant debilitating symptoms and economic burden. Current management is challenged by slow onset of action and modest efficacies of antidepressants; thus, the search for newer antidepressants remains relevant. We evaluated the antidepressant effects of a kaurene diterpene, xylopic acid (XA), in zebrafish and mouse models. METHODS: The chronic unpredictable stress (CUS) protocol in zebrafish and the tail suspension test (TST), forced swim test (FST), lipopolysaccharide-induced depression-like behaviour test (LID) and repeated open space swimming test (OSST) in mice were used. We further examined the impact of depleting monoamines on XA's antidepressant effects. The contribution of glutamatergic and nitrergic pathways on the antidepressant effect of XA in mice and XA's effects on 5-HT receptors and monoamine oxidase (MAO) enzymes were also evaluated. Finally, XA's influence on neuroprotection was evaluated by measuring BDNF and oxidative stress enzymes in whole brain. XA doses (1-10 µM) in zebrafish and (10, 30, 100 mg kg-1) in mice exerted potent antidepressant-like potential in FST, TST, LID and showed fast-onset antidepressant-like property in the OSST. RESULTS: The antidepressant-like properties in mice were reversed by blocking synthesis/release of serotonin but not noradrenaline using p-chlorophenylalanine and α-methyl-p-tyrosine, respectively. This antidepressant-like effect was potentiated by D-cycloserine and Nω-Nitro-L-arginine methyl ester (L-NAME) but not by D-serine and L-arginine. XA also evoked partial agonist-like effects on 5-hydroxytrptamine receptors on the rat fundus but it did not have MAO inhibition effect. It also increased BDNF, glutathione and antioxidant enzymes. CONCLUSION: Therefore, xylopic acid possesses antidepressant-like effects largely mediated by serotonergic and neuroprotective mechanisms.

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice.

BACKGROUND: Evidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect. METHODS: Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg-1), artesunate (ART: 1, 2, 4, 8, 16 mg kg-1), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg-1) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED50s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Bodyweight and 30-day survival post-treatment were additionally recorded. RESULTS: ED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg-1, respectively. The Zadd, Zexp, and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Zexp for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss. CONCLUSION: Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.

Antiplasmodial and Antipyretic Activity and Safety Evaluation of the Methanolic Leaf Extract of Murraya exotica (L.).

BACKGROUND: The increasing mortality and morbidity of malaria in Africa coupled with the recent reports of antimalarial drug resistance reinforces the need for novel antimalarial agents from natural plant products with folkloric use for the disease. Murraya exotica (L.) (Rutaceae) is widely used as an ornamental plant used indigenously to treat fever, cough, and infectious wounds and eliminate pain from injury and trauma. This study was conducted to evaluate extracts of the leaves of Murraya exotica (L.) (Rutaceae) for its safety and antipyretic and antimalarial activity in rodent models. METHOD: In this study, the Peters 4-day suppressive and curative test in Plasmodium berghei-infected mice was used to demonstrate the antiplasmodial activity of the methanolic leaf extract of Murraya exotica (L.) (MEE). The study also evaluated the subacute toxicity study and the antipyretic activity of MEE on baker's yeast-induced hyperthermia in rodent models. RESULTS: Murraya exotica (L.) extract demonstrated curative antimalarial activity, with a percentage suppression of 45.84, 64.32 ± 0.33, 56.74 ± 2.16, and 64.61 ± 0.67 at doses of 50, 100, 300, and 600 mg/kg, respectively. In the Peters 4-day suppressive test, MEE at dose 600 mg/kg had the highest chemosuppression (76.02 ± 1.38%) compared with artesunate (2 mg/kg, p.o.) (82.56 ± 0.97%). Subacute oral toxicity studies in Sprague-Dawley rats documented no deaths, with no significant changes in clinical signs, organ weights, and hematological and biochemical parameters. The LD50 of MEE was estimated to be above 1000 mg/kg in Sprague-Dawley rats. All doses of MEE and paracetamol reduced pyrexia in 1 h and 2 h after their administration. The percentage reduction of rectal temperature (T R ) for the positive control (paracetamol, 150 mg/kg, p.o.) was 44.36% while the Murraya exotica extract at doses 50 mg/kg, 100 mg/kg, 300 mg/kg, and 600 mg/kg recorded 67.74%, 40.78%, 66.42%, and 59.42%, respectively. Murraya exotica at dose 100 mg/kg exhibited significant reduction (p < 0.05) in baker's yeast-induced pyrexia. CONCLUSIONS: The findings in this study show the antipyretic, curative, and suppressive antiplasmodial activity as well as the safety of the methanolic leaf extract of Murraya exotica (L.) supporting its traditional use for malaria and fever.

Anti-inflammatory, anti-nociceptive and antipyretic activity of young and old leaves of Vernonia amygdalina.

BACKGROUND: Both young and old leaves of Vernonia amygdalina (VA) are traditionally used to treat inflammation, pain and fever. However, the efficacy of young and old leaves for treating these ailments have not been compared till date. AIM: To ascertain the effect of young and old leaves of VA in managing inflammation, pain and fever. METHODS: Both quantitative and qualitative phytochemical screening of ethanol extracts of young (EthYL) and old (EthOL) leaves of VA were performed. The anti-inflammatory activity of orally administered EthYL and EthOL (50-200 mg/kg) and Diclofenac (10 mg/kg) were evaluated in carrageenan-induced inflammation model in rats. Antipyretic activity of EthYL, EthOL and Aspirin (25 mg/kg) were assessed in the Baker's yeast-induced pyrexia model. Anti-allodynic effect of both extracts were evaluated by inserting inflamed paws of rats in cold water. Antinociceptive property of the extracts were assessed using tail withdrawal and formalin-induced nociception test. Histopathological examination of the paws was performed, in addition to formalin test to understand the possible mechanism of action of the extracts. Negative control rats received 2 ml/kg normal saline in all tests. RESULTS: The amount of flavonoids, alkaloids, tannins, and phenolics were significantly (p < 0.05) higher in EthOL than EthYL, while saponins were significantly higher (p < 0.05) in EthYL than EthOL. The antioxidant ability and total antioxidant capacity were significantly (p < 0.05) higher in EthYL than EthOL. However, this was significantly (p < 0.05) lower than the anti-oxidant activity of Ascorbic acid. A dose-dependent increase in anti-inflammatory, antipyretic and antinociceptive properties were observed in both EthYL and EthOL, similar to the standard drugs. Mast cell degranulation accompanied by vasodilatation and high leukocytosis were observed in the negative control, but were markedly low in extract treated groups. Both extracts mediated their analgesic effect through opioidergic and nitric oxide pathways with EthYL additionally implicating the muscarinic cholinergic system. CONCLUSION: Although both EthYL and EthOL alleviate inflammation, pyrexia and nociception, EthYL of VA was found to be more potent than EthOL.

In vitro activity of Erythrophleum ivorense extract against the promastigote stage of cutaneous Leishmania parasite, a member of Leishmania (Mundinia) enriettii complex isolates from Ghana.

BACKGROUND: Cutaneous leishmaniasis causes physical disfigurement and impairment on affected individuals, however, little attention has been paid to it eradication. The situation of this neglected disease is complicated with the expansion of the non-human pathogenic Leishmania enriettii complex causing infection in humans. We have previously shown that the extract from Erythrophleum ivorense has leishmanicidal activity against promastigote stages of the L. enriettii complex isolate from Ghana and L eishmania donovani. The extract of E. ivorense has shown to have anti-inflammatory, wound-healing ability, antiallergic, antimalarial and antischistosomal activity. However, the concentration threshold of E. ivorense extract required for leishmanicidal activity against the emerging human pathogenic L. enriettii complex isolates is not clear. AIM: To test for the concentration threshold of E. ivorense extract required to obtain ideal leishmanicidal activity against the promastigote stage of human pathogenic L. enriettii complex isolates from Ghana. METHOD: The ethanolic leaf extract of E. ivorense was serially diluted and tested against the promastigote stage of the L. enriettii complex. Parasite inhibition was measured at 590 nm using a spectrophotometer after staining parasites with trypan blue. To select the threshold concentration for maximum inhibition of the promastigote stage of the L. enriettii complex, the concentration cut-off statistic was used. RESULTS: The MIC of E. ivorense extract for L. enriettii promastigote inhibition was 62.3 µg ml-1. The highest promastigote inhibition was observed at 72 h. CONCLUSION: We show that a MIC of 62.3 µg ml-1 of E. ivorense leaf extract exhibits an ideal leishmanicidal activity against the promastigote stage of L. enriettii complex isolates.

DNA Damage Protecting Activity and Antioxidant Potential of Launaea taraxacifolia Leaves Extract.

BACKGROUND: The leaf extract of Launaea taraxacifolia commonly known as African Lettuce is used locally to treat dyslipidemia and liver diseases, which are associated with oxidative stress. Methanol extract from L. taraxacifolia leaves was tested for its antioxidant activity and its ability to protect DNA from oxidative damage. MATERIALS AND METHODS: In vitro antioxidant potential of the leaf extract was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide (NO), and hydroxyl (OH) radical scavenging assays. Ferric reducing power, total antioxidant capacity (TAC), metal chelating, and anti-lipid peroxidation ability of the extract were also examined using gallic acid, ascorbic acid, citric acid, and ethylenediaminetetraacetic acid as standards. RESULTS: L. taraxacifolia leaves extract showed antioxidant activity with IC50 values of 16.18 µg/ml (DPPH), 123.3 µg/ml (NO), 128.2 µg/ml (OH radical), 97.94 µg/ml (metal chelating), 80.28 µg/ml (TAC), and 23 µg/ml (anti-lipid peroxidation activity). L. taraxacifolia leaves extract exhibited a strong capability for DNA damage protection at 20 mg/ml concentration. CONCLUSION: These findings suggest that the methanolic leaf extract of L. taraxacifolia could be used as a natural antioxidant and also as a preventive therapy against diseases such as arteriosclerosis associated with DNA damage.

An isobolographic analysis of the anti-nociceptive effect of geraniin in combination with morphine or diclofenac.

BACKGROUND: Geraniin, a dehydroellagitannin, is a major component of the aqueous extract of the aerial parts of Phyllanthus muellerianus (Kuntze) Exell. (Euphorbiaceae). Several Phyllanthus species are traditionally used for painful disorders. The anti-nociceptive effects of the aqueous extract of the aerial parts of P. muellerianus and of geraniin have been scientifically established. The aim of the paper is to determine whether a combination of geraniin and diclofenac or geraniin and morphine leads to better anti-nociceptive effects. METHODS: The nature of the interactions of morphine and diclofenac with geraniin was evaluated by undertaking the isobolographic analysis. Mice were treated with geraniin (3-30 mg/kg), morphine (1-10 mg/kg), and diclofenac (10-100 mg/kg) to obtain the ED50 values of the agents in the formalin test. Dose-response curves were then obtained and analyzed after the co-administration of geraniin with morphine or diclofenac in fixed ratio (1:1) combinations based on specific fractions (1/2, 1/4, and 1/8) of their respective ED50 values for the formalin test. RESULTS: Geraniin was less potent than morphine but more potent than diclofenac in the formalin-induced nociception. The isobolographic analysis of geraniin/morphine (G/M) and geraniin/diclofenac combinations (G/D) at different fractions revealed the potentiation of their anti-nociceptive effects. The degrees of potentiation, which were calculated as interaction indices, showed synergism for both combinations in both phase I (G/M: 0.040, G/D: 0.017) and phase II (G/M: 0.004, G/D: 0.002) of the formalin test. CONCLUSIONS: The present study demonstrates synergism for the co-administration of geraniin with both morphine and diclofenac.

Possible mechanisms involved in the anti-nociceptive effects of hydro-ethanolic leaf extract of Ziziphus abyssinica.

CONTEXT: Various parts of Ziziphus abyssinica Hochst ex. A. Rich (Rhamnaceae) have been used in Ghanaian and African traditional medicine as an analgesic. However, there are little scientific data to support the anti-nociceptive effects of the hydro-ethanolic leaf extract of Ziziphus abyssinica (EthE) as well as the possible mechanisms involved in its anti-nociceptive effects. PURPOSE: To predict possible nociceptive pathways involved in the anti-nociceptive effects of EthE. MATERIALS AND METHODS: The effect of EthE (30, 100 and 300 mg/kg) on intraplantar injection of pain mediators such as interleukin-1ß, tumour necrosis factor-α, prostaglandin E2 and bradykinin was evaluated in male Sprague Dawley rats using Randall-Selitto test for 5 h. The effect of specific antagonists to the opioidergic, adenosinergic, ATP-sensitive K+ channels, nitric oxide, serotonergic, muscarinic, adrenergic and voltage-gated calcium channel on the anti-nociceptive effect of EthE (100 mg/kg) was evaluated using the formalin test in male imprinting control region (ICR) mice for 1 h. RESULTS: Pretreatment of the rats with EthE significantly reversed the hypernociception induced by intraplantar injection of TNF-α (F4,120 = 10.86, p < 0.0001), IL-1ß (F4,120 = 14.71, p < 0.0001), bradykinin (F4,80 = 12.52, p < 0.0001) and prostaglandin E2 (F5,144 = 6.165, p = 0.0001). The anti-nociceptive effect exhibited by EthE in the formalin test was reversed by systemic administration of NG-l-nitro-arginine methyl ester, naloxone, theophylline and glibenclamide. CONCLUSIONS: EthE inhibits hypernociception induced by TNF-α, IL-1ß, bradykinin and prostaglandin E2. EthE exhibited anti-nociceptive effects possibly mediated through opioidergic, adenosinergic, ATP-sensitive potassium channels and nitric oxide cyclic GMP pathways.

Hydro-ethanolic leaf extract of Ziziphus abyssinica Hochst Ex A. Rich (Rhamnaceae) exhibits anti-nociceptive effects in murine models.

BACKGROUND: Despite substantial advances in pain research and treatment, millions of people continue to suffer from pain and this has been attributed mainly to the unavailability of effective and safer analgesics. The use of plants as medicines is still widespread and plants constitute a large source of novel phytocompounds that might become leads for the discovery of newer, effective and safer alternatives. Various parts of Ziziphus abyssinica have been used in folk medicine in several African countries as painkillers. However, there is no report on the possible anti-nociceptive effects of this plant especially the leaves, hence the need for this current study. METHODS: The possible anti-nociceptive activity of hydro-ethanolic leaf extract of Ziziphus abyssinica (EthE) was assessed in rodents using chemical (acetic acid, formalin and glutamate), thermal (tail-immersion test) and mechanical/inflammatory (carrageenan) models of nociception. RESULTS: EthE (30-300 mg/kg, p.o.) dose-dependently and significantly inhibited chemical-induced nociception with a maximum inhibition of 86.29 ± 2.27%, 76.34 ± 5.67%, 84.97 ± 5.35%, and 82.81 ± 5.97% respectively for acetic acid, formalin (phase 1), formalin (phase 2) and glutamate tests at its highest dose. EthE also dose-dependently and significantly increased reaction times in both tail-immersion and carrageenan-induced hypernociceptive tests. The activities of the extract in the various models were comparable with the effect of morphine hydrochloride and diclofenac sodium used as standard analgesic drugs. CONCLUSION: Oral administration of hydro-ethanolic leaf extract of Ziziphus abyssinica ameliorates nocifensive behaviours associated with chemical-, thermal- and mechanical/inflammatory - induced nociceptive pain.