The effect of an anti-malarial herbal remedy, Maytenus senegalensis, on electrocardiograms of healthy Tanzanian volunteers.

BACKGROUND: The emergence of resistance to artemisinin-based combination therapy necessitates the search for new, more potent antiplasmodial compounds, including herbal remedies. The whole extract of Maytenus senegalensis has been scientifically investigated for potential biological activities both in vitro and in vivo, demonstrating strong antimalarial activity. However, there is a lack of data on the electrocardiographic effects of M. senegalensis in humans, which is a crucial aspect in the investigation of malaria treatment. Assessing the electrocardiographic effects of M. senegalensis is essential, as many anti-malarial drugs can inadvertently prolong the QT interval on electrocardiograms. Therefore, the study's objective was to evaluate the electrocardiographic effects of M. senegalensis in healthy adult volunteers. METHODS: This study is a secondary analysis of an open-label single-arm dose escalation. Twelve healthy eligible Tanzanian males, aged 18 to 45, were enrolled in four study dose groups. A single 12-lead electrocardiogram (ECG) was performed at baseline and on days 3, 7, 14, 28, and 56. RESULTS: No QTcF adverse events occurred with any drug dose. Only one volunteer who received the highest dose (800 mg) of M. senegalensis experienced a moderate transient change (△QTcF > 30 ms; specifically, the value was 37 ms) from baseline on day 28. There was no difference in maximum QTcF and maximum △QTcF between volunteers in all four study dose groups. CONCLUSIONS: A four-day regimen of 800 mg every 8 h of M. senegalensis did not impact the electrocardiographic parameters in healthy volunteers. This study suggests that M. senegalensis could be a valuable addition to malaria treatment, providing a safer alternative and potentially aiding in the battle against artemisinin-resistant malaria. The results of this study support both the traditional use and the modern therapeutic potential of M. senegalensis. They also set the stage for future research involving larger and more diverse populations to explore the safety profile of M. senegalensis in different demographic groups. This is especially important considering the potential use of M. senegalensis as a therapeutic agent and its widespread utilization as traditional medicine. Trial registration ClinicalTrials.gov, NCT04944966. Registered 30 June 2021-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04944966?term=kamaka&draw=2&rank=1.

Safety and Tolerability of an Antimalarial Herbal Remedy in Healthy Volunteers: An Open-Label, Single-Arm, Dose-Escalation Study on Maytenus senegalensis in Tanzania.

BACKGROUND: Though Maytenus senegalensis is one of the medicinal plants widely used in traditional medicine to treat infectious and inflammatory diseases in Africa, there is a lack of safety data regarding its use. Therefore, the study aimed to asselss the safety and tolerability of the antimalarial herbal remedy M. senegalensis. MATERIAL AND METHODS: The study design was an open-label, single-arm, dose-escalation. Twelve eligible male healthy Tanzanians aged 18 to 45 years were enrolled in four study dose groups. Volunteers' safety and tolerability post-investigational-product administration were monitored on days 0 to 7,14, and 56. RESULTS: There were no deaths or serious adverse events in any of the study groups, nor any adverse events that resulted in premature discontinuation. The significant mean changes observed in WBC (p = 0.003), Neutrophils (p = 0.02), Lymphocytes (p = 0.001), Eosinophils (p = 0.009), Alanine aminotransferase (p = 0.002), Creatinine (p = 0.03) and Total bilirubin (p = 0.004) laboratory parameters were not associated with any signs of toxicity or clinical symptoms. CONCLUSIONS: M. senegalensis was demonstrated to be safe and tolerable when administered at a dose of 800 mg every eight hours a day for four days. This study design may be adapted to evaluate other herbal remedies.

Safety evaluation and bioassay-guided isolation of antimycobacterial compounds from Morella salicifolia root ethanolic extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Although the available medicines can cure almost all tuberculosis drug-susceptible patients some problems including the emergence of multi-drug resistant and extensively drug-resistant strains press for the need of new anti-TB medicines. Morella salicifolia is a common plant that is widely used in traditional medicine for managing HIV and AIDS-related conditions including tuberculosis but no studies have been done to evaluate its safety and efficacy. AIM OF THE STUDY: This study was designed to investigate the antimycobacterial activity and safety of M. salicifolia extract and its constituents. MATERIAL AND METHODS: Antimycobacterial activity of the crude extract was tested against non-pathogenic mycobacteria including Mycobacterium aurum (MA), Mycobacterium indicus pranii (MIP) and Mycobacterium madagascariense (MM) using the broth microdilution method. Bioassay-guided fractionation was employed to isolate the active compounds. Some of the isolated active compounds were tested for antimycobacterial activity against the standard and selected clinical isolates of M. tuberculosis. Safety of the crude extract was assessed using cytotoxicity assay and oral acute toxicity testing. RESULTS: The crude extract exhibited antimycobacterial activity against all the species used. The study led to isolation of six compounds; four pentacyclic triterpenoids; (3ß)-3-Hydroxyolean-12-en-28-oic acid (Oleanolic acid) (1), (2α,3ß)-2,3-Dihydroxyolean-12-en-28-oic acid (maslinic acid) (2), D-Friedoolean-14-ene-3ß,28-diol (taraxerol) (3), and D-Friedoolean-14-en-3ß-ol (myricadiol) (4), and two diarylheptanoids; (±)-myricanol (5) and myricanone (6). The six compounds exhibited activity against three nonpathogenic mycobacteria species. Compound 2, was the most active, with MICs of 17, 28 and 56 µg/ml against MM, standard a M. tuberculosis strain H37RV and rifampicin resistant M. tuberculosis clinical isolates, respectively. The crude extract did not show toxicity on peripheral blood mononuclear cells and it was safe in mice following acute oral toxicity test. CONCLUSION: The results from this study indicate that some isolated compounds in Morella salicifolia could form potential scaffolds for drug development efforts targeting M. tuberculosis. More studies are needed to further explore the potential of the plant extract and its secondary metabolites in the management of HIV and AIDS-related conditions using in-vivo models.

Two mosquito larvicidal arabinofuranosidetridecanol from Commiphora merkeri exudate.

Two new arabinofuranosidetridecanol, namely 1,2-tridecanediol-1-O-α-L-5'-acetylarabinofuranoside (1) and 1,2-tridecanediol-1-O-α-L-arabinofuranoside (2) together with known compound, 1,2-tridecanediol (3) were isolated from Commiphora merkeri exudate. Compound 1 showed larvicidal activity against Ae. aegypti (LC50 = 40.66 µg/mL), An. gambiae (LC50 = 22.86 µg/mL) and Cx. quinquefasciatus (LC50 = 15.88 µg/mL). Also, Compound 2 had larvicidal activity against Ae. aegypti (LC50 = 33.79 µg/mL), An. gambiae (LC50 = 31.99 µg/mL) and Cx. quinquefasciatus (LC50 = 17.70 µg/mL). There were no significant difference of larvae mortalities (≥ 95%) among the two compounds and among mosquito species except for compound 2 at 72 h for Cx. quinquefasciatus and An. gambiae. Compound 3 was not larvicidal active even after 72 h of exposure time. In addition, none of the compound was cytotoxic to brine shrimps. The two Arabinofuranosidetridecanol are potential against mosquito species and they could be safe in the environment.

Screening of Plants Used as Traditional Anticancer Remedies in Mkuranga and Same Districts, Tanzania, Using Brine Shrimp Toxicity Bioassay.

BACKGROUND: Inadequate specialized cancer hospitals and high costs are contributing factors that delay cancer patients from accessing health care services in Tanzania. Consequently, majority of patients are first seen by Traditional Health Practitioners (THPs) before they access specialized services. This study presents ethnomedical information and preliminary evaluation of 25 plant species claimed by THPs in Mkuranga and Same districts of Tanzania on use for treatment of cancer. Literature search and laboratory investigation results are presented to support evaluation. METHODS THIS STUDY WAS A SINGLE DISEASE ETHNOMEDICAL ENQUIRY FOCUSING ON PLANTS BEING USED FOR CANCER TREATMENT: Face-to-face interviews and questionnaires were administered to eight (8) THPs in Mkuranga and Same districts on the claimed plants and their use for management of cancer. Plants were selected based on being frequently mentioned and emphasis given by THPs. Literature search and brine shrimp toxicity (BST) of methanol : dichloromethane (1:1) extracts was used as surrogates to evaluate strength of the claims. RESULTS: This study reports 25 plant species used by the THPs in two districts of Tanzania. Eight plants (32%) have been reported in the literature to have activity against cancer cells. BST results revealed, 14 (56%) plants exhibited high toxicity against brine shrimps. The most active plants included Croton pseudopulchellus Pax (LC50 4.2 µg/ml), Dalbergia melanoxylon Guill. & Perr. (LC50 6.8 µg/ml), Loranthus micranthus Linn (LC50 4.0 µg/ml), Ochna mossambicensis Klotzsch (LC50 3.3 µg/ml), and Spirostachys africana Sond. (LC50 4.4 µg/ml); their toxicity was comparable to that of Catharanthus roseus (L) G. Don. (LC50 6.7 µg/ml), an established source of anticancer compounds. Nine other plants had LC50 values between (19.8 and 71.6) µg/ml, indicating also potential to yield anticancer. CONCLUSION: Literature search and BST results provide a strong support of the potential of the claimed plants to yield active anticancer compounds.

Anti-plasmodial activity of Norcaesalpin D and extracts of four medicinal plants used traditionally for treatment of malaria.

BACKGROUND: Malaria is an old life-threatening parasitic disease that is still affecting many people, mainly children living in sub-Saharan Africa. Availability of effective antimalarial drugs played a significant role in the treatment and control of malaria. However, recent information on the emergence of P. falciparum parasites resistant to one of the artemisinin-based combination therapies suggests the need for discovery of new drug molecules. Therefore, this study aimed to evaluate the antiplasmodial activity of extracts, fractions and isolated compound from medicinal plants traditionally used in the treatment of malaria in Tanzania. METHODS: Dry powdered plant materials were extracted by cold macerations using different solvents. Norcaesalpin D was isolated by column chromatography from dichloromethane root extract of Caesalpinia bonducella and its structure was assigned based on the spectral data. Crude extracts, fractions and isolated compound were evaluated for antiplasmodial activity against chloroquine-sensitive P. falciparum (3D7), chloroquine-resistant P. falciparum (Dd2, K1) and artemisinin-resistant P. falciparum (IPC 5202 Battambang, IPC 4912 Mondolkiri) strains using the parasite lactate dehydrogenase assay. RESULTS: The results indicated that extracts of Erythrina schliebenii, Holarrhena pubescens, Dissotis melleri and C. bonducella exhibited antiplasmodial activity against Dd2 parasites. Ethanolic root extract of E. schliebenii had an IC50 of 1.87 µg/mL while methanolic and ethanolic root extracts of H. pubescens exhibited an IC50 = 2.05 µg/mL and IC50 = 2.43 µg/mL, respectively. Fractions from H. pubescens and C. bonducella roots were found to be highly active against K1, Dd2 and artemisinin-resistant parasites. Norcaesalpin D from C. bonducella root extract was active with IC50 of 0.98, 1.85 and 2.13 µg/mL against 3D7, Dd2 and IPC 4912-Mondolkiri parasites, respectively. CONCLUSIONS: Antiplasmodial activity of norcaesalpin D and extracts of E. schliebenii, H. pubescens, D. melleri and C. bonducella reported in this study requires further attention for the discovery of antimalarial lead compounds for future drug development.

Preparation and application of reversed phase Chromatorotor for the isolation of natural products by centrifugal preparative chromatography.

A method of preparation of rotors with a reversed phase (RP) solid silica gel sorbent layer has been developed for centrifugal preparative chromatography (CPC), also known as rotational planar chromatography (RPC). The rotors consist of binder free RP solid SiO2 layers of different thicknesses packed between two supported circular glass discs and can be used in any appropriate device for centrifugal chromatography, like Chromatotron and CycloGraph. Polar and /or semi-polar compounds with close R(f) values, as well as extracts and column fractions were separated and/or purified in a preparative and/or semi-preparative scale using the RP rotors, eluted with mixtures of aqueous-based solvents. We herein report three examples of its application, using RP Chromatorotors, for the isolation of the diastereoisomeric alkaloids banistenosides I and II from Banisteriopsis caapi, saponins III and IV from Fagonia cretica, and the sesquiterpenes artemisinin (V) and artemisinic acid (VI) from Artemisia annua.

Phytochemical, Antimicrobial and Antiplasmodial Investigations of Terminalia brownii.

Phytochemical investigation of the ethyl acetate-soluble fraction of stem bark extract of an African medicinal plant Terminalia brownii led to the isolation of a new oleanane-type triterpenoid, along with seven known triterpenoids, seven ellagic acid derivatives, and 3-O-ß-D-glucopyranosyl-ß-sitosterol. The new compound was identified using spectroscopic methods, notably 1D- and 2D NMR, as 3ß,24-O-ethylidenyl-2α,19α-dihydroxyolean-12-en-28-oic acid. The isolated compounds were evaluated for their antimicrobial and antiplasmodial activities. Two compounds with a galloyl group (4 and 6) were found to be active against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum, whereas three ellagic acid derivatives (5-7) were found active against three species of fungi and one species of bacteria.

Antiparasitic and anticancer carvotacetone derivatives of Sphaeranthus bullatus.

The CH2Cl2-MeOH (1:1) extract of the aerial parts of Sphaeranthus bullatus, an annual herb native to tropical East Africa, showed activity against chloroquine sensitive D6 (IC50 9.7 microg/mL) and chloroquine resistant W2 (IC50 15.0 microg/mL) strains of Plasmodium falciparum. Seventeen secondary metabolites were isolated from the extract through conventional chromatographic techniques and identified using various spectroscopic methods. The compounds were evaluated for their in vitro antiplasmodial, antileishmanial and anticancer activities revealing activity of four carvotacetone derivatives, namely 3-acetoxy-7-hydroxy-5-tigloyloxycarvotacetone (1), 3,7-dihydroxy-5-tigloyloxycarvotacetone (2), 3-acetoxy-5,7-dihydroxycarvotacetone (3) and 3,5,7-trihydroxy-carvotacetone (4); with antiplasmodial IC50 values of 1.40, 0.79, 0.60 and 3.40 microg/mL, respectively, against chloroquine sensitive D6 strains of P. falciparum; antiplasmodial activity of IC50 2.00, 0.90, 0.68 and 2.80 microg/mL, respectively, against chloroquine resistant W2 strains of P. falciparum; antileishmanial IC50 values of 0.70, 3.00, 0.70 and 17.00 microg/mL, respectively, against the parasite L. donovanii promastigotes, and anticancer activity against human SK-MEL, KB, BT-549 and SK-OV-3 tumor cells, with IC50 values between <1.1 - 5.3 microg/mL for 1-3. In addition, cytotoxic effects of the active compounds were evaluated against monkey kidney fibroblasts (VERO) and pig kidney epithelial cells (LLC-PK11). The structures of carvotacetone derivatives were determined by 1D and 2D NMR spectroscopy; the absolute stereochemical configuration of 3-acetoxy-7-hydroxy-5-tigloyloxycarvotacetone (1) was determined as 3R, 4R, 5S by circular dichroism, specific rotation, 1H NMR and 2D NMR ROESY and NOESY experiments.

Antimicrobial and antiparasitic abietane diterpenoids from the roots of Clerodendrum eriophyllum.

Chromatographic separation of the roots of a Kenyan medicinal plant, Clerodendrum eriophyllum, led to the isolation of ten abietane diterpenoids (1-10), one of which (1) was isolated for the first time from a natural source. Using spectroscopic data, the structure of 1 was determined to be 12-hydroxy-8,12-abietadiene-3,11,14-trione. Circular dichroism (CD) spectra showed that the stereochemistry of compounds 1, 3, and 6-8 belongs to the normal series of abietane diterpenes, which confirmed the absolute stereochemistry of the isolated compounds. Compounds 1-10 were evaluated for their in vitro antiplasmodial, antileishmanial, antifungal and antibacterial activities. Compounds 3 and 7 exhibited potent antifungal activity (IC50/MIC 0.58/1.25 and 0.96/2.5 microg/mL, respectively) against C. neoformans, whereas 3, 6 and 7 showed strong antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus with IC50/MIC values between 1.33-1.75/2.5-5 and 0.96-1.56/2.5 microg/mL, respectively. In addition, compounds 3 and 9 exhibited potent antileishmanial activity (IC50 0.08 and 0.20 microg/mL, respectively) against L. donovani, while 3 and 7 displayed weak antimalarial activity against Plasmodium falciparum, but 9 was inactive.

Antiparasitic activity of some xanthones and biflavonoids from the root bark of Garcinia livingstonei.

A new biflavanoid, ent-naringeninyl-(I-3alpha,II-8)-4'-O-methylnaringenin (6), along with five known xanthones and two known biflavonoids, was isolated from the root bark of Garcinia livingstonei collected in Tanzania. The absolute configuration of 6 was established by CD spectroscopy. This compound showed moderate activity against P. falciparum (IC(50) 6.7 microM). Antitrypanosomal activity (IC(50) 0.87 microM) was observed for 1,4,5-trihydroxy-3-(3-methylbut-2-enyl)-9H-xanthen-9-one (3). The dimeric xanthone garcilivin A (4) showed a higher and nonselective antiparasitic activity and cytotoxicity (IC(50) 2.0 microM against MRC-5 cells) than its diastereoisomer garcilivin C (5) (IC(50) 52.3 microM).