Toxicity and Safety Implications of Herbal Medicines Used in Africa

The use of herbal medicines has seen a great upsurge globally. In developing countries, many patronize them largely due to cultural acceptability, availability and cost. In developed countries, they are used because they are natural and therefore assumed to be safer than allopathic medicines. In recent times, however, there has been a growing concern about their safety. This has created a situation of ambivalence in discussions regarding their use. Some medicinal plants are intrinsically toxic by virtue of their constituents and can cause adverse reactions if inappropriately used. Other factors such as herb-drug interactions, lack of adherence to good manufacturing practice (GMP), poor regulatory measures and adulteration may also lead to adverse events in their use. Many in vivo tests on aqueous extracts largely support the safety of herbal medicines, whereas most in vitro tests on isolated single cells mostly with extracts other than aqueous ones show contrary results and thus continue the debate on herbal medicine safety. It is expected that toxicity studies concerning herbal medicine should reflect their traditional use to allow for rational discussions regarding their safety for their beneficial use. While various attempts continue to establish the safety of various herbal medicines in man, their cautious and responsible use is required

Semi-synthetic analogues of cryptolepine as a potential source of sustainable drugs for the treatment of malaria, human African trypanosomiasis, and cancer

The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer.UK Medical Research Council (MRC) and a Medicines for Malaria Venture Grant.http://www.frontiersin.org/Pharmacologyhj2022BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

Isobolographic analysis of co-administration of two plant-derived antiplasmodial drug candidates, cryptolepine and xylopic acid, in Plasmodium berghei

Abstract Background Increasing resistance to current anti-malarial therapies requires a renewed effort in searching for alternative therapies to combat this challenge, and combination therapy is the preferred approach to address this. The present study confirms the anti-plasmodial effects of two compounds, cryptolepine and xylopic acid and the relationship that exists in their combined administration determined. Methods Anti-plasmodial effect of cryptolepine (CYP) (3, 10, 30 mg kg−1) and xylopic acid (XA) (3, 10, 30 mg kg−1) was evaluated in Plasmodium berghei-infected male mice after a 6-day drug treatment. The respective doses which produced 50% chemosuppression (ED50) was determined by iterative fitting of the log-dose responses of both drugs. CYP and XA were then co-administered in a fixed dose combination of their ED50s (1:1) as well as different fractions of these combinations (1/2, 1/4, 1/8, 1/16 and 1/32) to find the experimental ED50 (Zexp). The nature of interaction between cryptolepine and xylopic acid was determined by constructing an isobologram to compare the Zexp with the theoretical ED50 (Zadd). Additionally, the effect of cryptolepine/xylopic acid co-administration on vital organs associated with malarial parasiticidal action was assessed. Results The Zadd and Zexp were determined to be 12.75 ± 0.33 and 2.60 ± 0.41, respectively, with an interaction index of 0.2041. The Zexp was significantly (P < 0.001) below the additive isobole indicating that co-administration of cryptolepine and xylopic acid yielded a synergistic anti-plasmodial effect. This observed synergistic antiplasmodial effect did not have any significant deleterious effect on the kidney, liver and spleen. However, the testis were affected at high doses. Conclusion The co-administration of cryptolepine and xylopic acid produces synergistic anti-malarial effect with minimal toxicity

Development of GABA_A Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

Recent studies have demonstrated that subtype-selective GABA_A receptor modulators are able to relax precontracted human airway smooth muscle <i>ex vivo</i> and reduce airway hyper-responsiveness in mice upon aerosol administration. Our goal in this study was to investigate systemic administration of subtype-selective GABA_A receptor modulators to alleviate bronchoconstriction in a mouse model of asthma. Expression of GABA_A receptor subunits was identified in mouse lungs, and the effects of α4-subunit-selective GABA_AR modulators, XHE-III-74EE and its metabolite XHE-III-74A, were investigated in a murine model of asthma (ovalbumin sensitized and challenged BALB/c mice). We observed that chronic treatment with XHE-III-74EE significantly reduced airway hyper-responsiveness. In addition, acute treatment with XHE-III-74A but not XHE-III-74EE decreased airway eosinophilia. Immune suppressive activity was also shown in activated human T-cells with a reduction in IL-2 expression and intracellular calcium concentrations [Ca²⁺]_i in the presence of GABA or XHE-III-74A, whereas XHE-III-74EE showed only partial reduction of [Ca²⁺]_i and no inhibition of IL-2 secretion. However, both compounds significantly relaxed precontracted tracheal rings <i>ex vivo</i>. Overall, we conclude that the systemic delivery of a α4-subunit-selective GABA_AR modulator shows good potential for a novel asthma therapy; however, the pharmacokinetic properties of this class of drug candidates have to be improved to enable better beneficial systemic pharmacodynamic effects

Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABA_A Receptor Modulators

We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α₄β₃γ₂ GABA_AR selective compound <b>1</b> and acidic α₅β₃γ₂ selective GABA_AR positive allosteric modulator compound <b>2</b> relaxed airway smooth muscle <i>ex vivo</i> and attenuated airway hyperresponsiveness (AHR) in a murine model of asthma. Importantly, compound <b>2</b> relaxed acetylcholine contracted human tracheal airway smooth muscle strips. Oral treatment of compounds <b>1</b> and <b>2</b> decreased eosinophils in bronchoalveolar lavage fluid in ovalbumin sensitized and challenged mice, thus exhibiting anti-inflammatory properties. Additionally, compound <b>1</b> reduced the number of lung CD4⁺ T lymphocytes and directly modulated their transmembrane currents by acting on GABA_ARs. Excellent pharmacokinetic properties were observed, including long plasma half-life (up to 15 h), oral availability, and extremely low brain distribution. In conclusion, we report the selective targeting of GABA_ARs expressed outside the brain and demonstrate reduction of AHR and airway inflammation with two novel orally available GABA_AR ligands