Potential pharmacokinetic interactions with concurrent use of herbal medicines and a ritonavir-boosted COVID-19 protease inhibitor in low and middle-income countries.

The COVID-19 pandemic sparked the development of novel anti-viral drugs that have shown to be effective in reducing both fatality and hospitalization rates in patients with elevated risk for COVID-19 related morbidity or mortality. Currently, nirmatrelvir/ritonavir (Paxlovid™) fixed-dose combination is recommended by the World Health Organization for treatment of COVID-19. The ritonavir component is an inhibitor of cytochrome P450 (CYP) 3A, which is used in this combination to achieve needed therapeutic concentrations of nirmatrelvir. Because of the critical pharmacokinetic effect of this mechanism of action for Paxlovid™, co-administration with needed medications that inhibit or induce CYP3A is contraindicated, reflecting concern for interactions with the potential to alter the efficacy or safety of co-administered drugs that are also metabolized by CYP3A. Some herbal medicines are known to interact with drug metabolizing enzymes and transporters, including but not limited to inhibition or induction of CYP3A and P-glycoprotein. As access to these COVID-19 medications has increased in low- and middle-income countries (LMICs), understanding the potential for herb-drug interactions within these regions is important. Many studies have evaluated the utility of herbal medicines for COVID-19 treatments, yet information on potential herb-drug interactions involving Paxlovid™, specifically with herbal medicines commonly used in LMICs, is lacking. This review presents data on regionally-relevant herbal medicine use (particularly those promoted as treatments for COVID-19) and mechanism of action data on herbal medicines to highlight the potential for herbal medicine interaction Herb-drug interaction mediated by ritonavir-boosted antiviral protease inhibitors This work highlights potential areas for future experimental studies and data collection, identifies herbal medicines for inclusion in future listings of regionally diverse potential HDIs and underscores areas for LMIC-focused provider-patient communication. This overview is presented to support governments and health protection entities as they prepare for an increase of availability and use of Paxlovid™.

Permeation of Phytochemicals of Selected Psychoactive Medicinal Plants across Excised Sheep Respiratory and Olfactory Epithelial Tissues.

The intranasal route of drug administration offers an opportunity to bypass the blood-brain barrier and deliver compounds directly into the brain. Scientific evidence exists for medicinal plants (e.g., Centella asiatica and Mesembryanthemum tortuosum) to treat central nervous system conditions such as anxiety and depression. The ex vivo permeation of selected phytochemicals (i.e., asiaticoside and mesembrine) has been measured across excised sheep nasal respiratory and olfactory tissue. Permeation studies were conducted on individual phytochemicals and C. asiatica and M. tortuosum crude extracts. Asiaticoside exhibited statistically significantly higher permeation across both tissues when applied alone as compared to the C. asiatica crude extract, while mesembrine permeation was similar when applied alone or as M. tortuosum crude extract. Permeation of all the phytocompounds was similar or slightly higher than that of the drug atenolol across the respiratory tissue. Permeation of all the phytocompounds was similar to or slightly lower than that of atenolol across the olfactory tissue. In general, the permeation was higher across the olfactory epithelial tissue than across the respiratory epithelial tissue and therefore showed potential for direct nose-to-brain delivery of the selected psychoactive phytochemicals.

Molecular mechanisms and associated cell signalling pathways underlying the anticancer properties of phytochemical compounds from Aloe species (Review).

Naturally occurring components from various species of Aloe have been used as traditional folk medicine since the ancient times. Over the last few decades, the therapeutic effects of extracts and phytochemical compounds obtained from Aloe vera have been proven in preclinical and clinical studies. Recently, compounds from other Aloe species apart from Aloe vera have been investigated for the treatment of different diseases, with a particular focus on cancer. In the present review, the effects of phytochemical compounds obtained from different Aloe species are discussed, with a specific focus on the effects on cell signalling in cancer and normal cells, and their selectivity and efficacy. This information will be useful for the application of Aloe-derived compounds as therapeutic agents, either alone or in combination with other standard drugs for cancer treatment.

Formulation of Medicated Chewing Gum Containing Sceletium tortuosum and Process Optimization Utilizing the SeDeM Diagram Expert System.

Sceletium tortuosum is one of the most promising medicinal plant species for treating anxiety and depression. Traditionally, aerial parts are chewed (masticatory herbal medicine) providing fast relief and rendering the masticatory route for delivery, ideal. This study intended formulating novel medicated chewing gum containing S. tortuosum to alleviate depression and anxiety. S. tortuosum extract was formulated into directly compressed medicated chewing gum (MCG) containing different Health-in-Gum® (HIG) bases through process optimization with the SeDeM Diagram Expert System. Physical properties of MCGs were characterized, and specialized drug release studies performed. According to the manufacturer, only HIG-03 was specifically developed for direct compression; however, the SeDeM System was successfully applied to all HIG-bases investigated. HIG-01 and HIG-04 are also considered useful in direct compression as no considerable differences in these MCG formulations' physical properties were recognized. Inclusion of a lubricant, however, is deemed essential, and MCG comprising HIG-01, most suited for direct compression. Dissolution experiments found only two alkaloids used as markers, mesembrine and mesembrenone, were released in quantifiable concentrations regardless formulation constituents. Novel directly compressed MCG-containing S. tortuosum extract was successfully formulated by which the biologically active phytochemicals of S. tortuosum can be scientifically delivered through the traditionally applied mastication method.

Physicochemical Stability of Enriched Phenolic Fractions of Cyclopia genistoides and ex vivo Bi-directional Permeability of Major Xanthones and Benzophenones.

Fractions of an ultrafiltered Cyclopia genistoides extract, respectively enriched in xanthones and benzophenones, were previously shown to inhibit mammalian α-glucosidase in vitro. The present study investigated ex vivo intestinal transport of these fractions, using excised porcine jejunal tissue, to determine whether the gut could be a predominant in vivo site of action. The major bioactive compounds, the xanthones (mangiferin, isomangiferin) and benzophenones (3-ß-D-glucopyranosyliriflophenone, 3-ß-D-glucopyranosyl-4-O-ß-D-glucopyranosyliriflophenone) exhibited poor permeation in the absorptive direction with a relatively high efflux ratio (efflux ratio > 1). The efflux ratio of 3-ß-D-glucopyranosyl-4-O-ß-D-glucopyranosyliriflophenone (3.05) was similar to rhodamine 123 (2.99), a known substrate of intestinal P-glycoprotein 1 efflux transporters. Low epithelial membrane transport rates, coupled with efflux mechanisms, would effectively concentrate these bioactive compounds at the target site (gut lumen). Storage stability testing and moisture sorption assays of the xanthone-enriched fraction, benzophenone-enriched fraction, and ultrafiltered Cyclopia genistoides extract were performed to determine their susceptibility to physical and chemical degradation during storage. Hygroscopicity of the powders, indicated by moisture uptake, decreased in the order: benzophenone-enriched fraction (22.7%) > ultrafiltered Cyclopia genistoides extract (14.0%) > xanthone-enriched fraction (10.7%). 3-ß-D-Glucopyranosylmaclurin, a minor benzophenone, was the least stable of the compounds, degrading faster in the benzophenone-enriched fraction than in ultrafiltered Cyclopia genistoides extract, suggesting that the ultrafiltered extract matrix may provide a degree of protection against chemical degradation. Compound degradation during 12 wk of storage at 40 °C in moisture-impermeable containers was best explained by first order reaction kinetics.

Artificial membranes in combination with selected natural oils for in vitro drug passive diffusion screening in Ussing type chamber apparatus applied to gastro-retentive systems.

This study aimed at developing an effective in vitro technique for the screening of drug passive diffusion utilising artificial membranes in combination with three selected oils (i.e. cognac, emu, and olive oil). Artificial membranes of varying chemical composition and characteristics have been investigated individually and in combination with the selected oils in terms of the passive diffusion of a fluorescent probe (i.e. Rhodamine 6G or R6G), in a diffusion apparatus as compared to excised pig intestinal tissues. In general, the permeation results showed that the rate and extent of R6G permeation were dependent on the membrane composition as well as the type of oil used. The apparent permeability coefficient (Papp) value for R6G across the cellulose nitrate membrane (0.197 × 10-7 ± 0.069 cm/s) was the closest to the Papp of R6G across the excised pig intestinal tissue (0.210 × 10-7 ± 0.080 cm/s). The cellulose acetate-nitrate mixture membrane impregnated with emu oil also produced a Papp value (0.191 × 10-7 ± 0.010 cm/s) that was relatively close to that of R6G across the excised pig intestinal tissue. The delivery of R6G from gastro-retentive matrix type tablets correlated with the release of R6G from the gastro-retentive tablets.

Treatment of Skin Disorders with Aloe Materials.

The skin is the largest organ and functions as a barrier to protect the underlying tissues against the elements and pathogens, while also fulfilling many physiological roles and biochemical functions such as preventing excessive water loss. Skin disorders vary greatly in terms of origin, severity, symptoms and affect persons of all ages. Many plants have been used for medicinal purposes since ancient times including the treatment of skin disorders and diseases. Aloe represents one of the earliest medicinal plant species mentioned in antique scriptures and even in rock art dating back thousands of years. Different Aloe species and materials have been used in the prevention and treatment of skin related disorders. Aloe vera is the most commonly used Aloe species for medicinal purposes. Some of the most prominent skin related applications and disorders that Aloe materials have been investigated for are discussed in this paper, which include cosmetic, radiation, cancer, wound and antimicrobial applications. Both in vitro and in vivo studies are included in the discussions of this paper and comprehensive summaries of all these studies are given in tables in each section. Although some contradictory results were obtained among studies, certain Aloe materials have shown excellent efficacy and exhibited potential for the treatment of skin related disorders and cosmetic applications.

Capsaicin and Piperine as Functional Excipients for Improved Drug Delivery across Nasal Epithelial Models.

The fruit from various pepper plants has been employed for the seasoning of food, as perfuming agents, and also as traditional medicines. Phytochemicals isolated from different pepper species have been found to modulate the pharmacokinetics of orally administered drugs. This study investigated the possibility to apply capsaicin and piperine (extracted alkaloids) as modulators for drug delivery across the nasal epithelium. Both a nasal epithelial cell line (RPMI 2650) and excised sheep nasal tissue were used as models to investigate the effects of the selected pepper compounds on drug permeation. FITC-dextran 4400 (MW 4400 Da) was used as a large molecular weight marker compound for paracellular transport, while rhodamine 123 was used as a marker compound that is a substrate for P-glycoprotein-mediated efflux. From the permeation results, it was clear that capsaicin inhibited P-glycoprotein efflux to a larger extent, while piperine showed drug permeation enhancement via other mechanisms. The cell cytotoxicity studies indicated that capsaicin was noncytotoxic up to a concentration of 200 µM and piperine up to a concentration of 500 µM as indicated by cell viability above 80%. The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers indicated that some damage occurred after treatment with 200 µM capsaicin, but no changes were observed for piperine up to a concentration of 50 µM.

A sub-chronic Xysmalobium undulatum hepatotoxicity investigation in HepG2/C3A spheroid cultures compared to an in vivo model.

ETHNOPHARMACOLOGY RELEVANCE: Traditional herbal medicines are utilized by 27 million South Africans. Xysmalobium undulatum (Uzara) is one of the most widely used traditional medicinal plants in Southern Africa. A false belief in the safety of herbal medicine may result in liver injury. Herb-induced liver injury (HILI) range from asymptomatic elevation of liver enzymes, to cirrhosis and in certain instances even acute liver failure. Various in vitro and in vivo models are available for the pre-clinical assessment of drug and herbal hepatotoxicity. However, more reliable and readily available in vitro models are needed, which are capable of bridging the gap between existing models and real human exposure. Three-dimensional (3D) spheroid cultures offer higher physiological relevance, overcoming many of the shortcomings of traditional two-dimensional cell cultures. AIMS OF THIS STUDY: This study investigated the hepatotoxic and anti-prolific effects of the crude X. undulatum aqueous extract during a sub-chronic study (21 days), in both a 3D HepG2/C3A spheroid model and the Sprague Dawley rat model. METHODS: HepG2/C3A spheroids were treated with a known hepatotoxin, valproic acid, and crude X. undulatum aqueous extract for 21 days with continuous evaluation of cell viability and proliferation. This was done by evaluating cell spheroid growth, intracellular adenosine triphosphate (ATP) levels and extracellular adenylate kinase (AK). Sprague Dawley rats were treated with the same compounds over 21 days, with evaluation of in vivo toxicity effects on serum chemistry. RESULTS: The results from the in vitro study clearly indicated hepatotoxic effects and possible liver damage following treatment with valproic acid, with associated growth inhibition, loss of cell viability and increased cytotoxicity as indicated by reduced intracellular ATP levels and increased AK levels. These results were supported by the increased in vivo levels of AST, ALT and LDH following treatment of the Sprague Dawley rats with valproic acid, indicative of hepatic cellular damage that may result in hepatotoxicity. The in vitro 3D spheroid model was also able to predict the potential concentration dependant hepatotoxicity of the crude X. undulatum aqueous extract. Similarly, the results obtained from the in vivo Sprague Dawley model indicated moderate hepatotoxic potential. CONCLUSION: The data from both the 3D spheroid model and the Sprague Dawley model were able to indicate the potential concentration dependant hepatotoxicity of the crude X. undulatum aqueous extract. The results obtained from this study also confirmed the ability of the 3D spheroid model to effectively and reliably predict the long-term outcomes of possible hepatotoxicity.

Toxicity and anti-prolific properties of Xysmalobium undulatum water extract during short-term exposure to two-dimensional and three-dimensional spheroid cell cultures.

Xysmalobium undulatum (Uzara) is one of the most widely used indigenous traditional herbal remedies in Southern Africa. Commercially available Uzara plant material was used to prepare a crude aqueous extract, of which the toxicity potential was investigated in the hepatic HepG2/C3A cell line in both traditional two-dimensional (2D) and rotating three-dimensional (3D) spheroid cell cultures. These cultures were treated over a period of 4 days at concentrations of 200, 350, 500, and 750 mg/kg plant extract to protein content. Basic physiological parameters of the cell cultures were measured during exposure, including cell proliferation, glucose uptake, intracellular adenosine triphosphate levels, and adenylate kinase release. The results indicated that all physiological parameters monitored were affected in a dose dependent manner, with the highest concentration of Uzara crude water extract (750 mg/kg) resulting in toxicity. Anti-proliferating effects of Uzara crude water extract were observed in both the 2D and 3D cell cultures, with the most pronounced effects at concentrations of 350, 500, and 750 mg/kg. Discrepancies between results obtained from the 2D and 3D cell culture models may be attributed to the type of repair system that is initiated upon exposure, depending on where cells are within the cell cycle. DNA repair systems differ in cells within the G1 phase and non-diving cells, (i.e. cells found predominantly in in vitro 3D and the in vivo situation).

Absorptive and Secretory Transport of Selected Artemisinin Derivatives Across Caco-2 Cell Monolayers.

BACKGROUND: Malaria continues to be a major health concern and affects more than 200 million people a year. Drugs currently used for treatment of malaria are increasingly rendered ineffectual by the ongoing emergence of parasite resistance. For any new drugs, however, knowledge of their membrane permeability is an essential pre-requisite for eventual use. Treatment failure and emergence of resistance can occur as a result of reduced availability of the drug at the desired site of action. Cellbased permeability assays such as Caco-2 cell monolayers serve as a model for predicting drug absorption and efflux, and provide an estimate of drug bioavailability. OBJECTIVE: Here we have studied the bi-directional transport of new anti-malarial compounds, artemisone and artemiside, as well as reference compounds, namely the known anti-malarial drug artemether, and caffeine and atenolol. METHODS: The Caco-2 cell monolayer model was used to assess the membrane permeation properties of these compounds, and to identify if they are subject to P-gp associated efflux, in the presence and absence of verapamil. The effect of piperine on the transport of the compounds that were identified to be P-gp substrates was also assessed. Samples withdrawn from the acceptor chambers at pre-determined time intervals were analysed by means of high-performance liquid chromatography (HPLC). RESULTS: Transport results in terms of the absorptive direction revealed that artemisone and artemether had low absorption rates relative to the reference compounds. It was further demonstrated that artemisone is slightly effluxed, and although both artemether and artemiside were susceptible to P-gp mediated efflux, it appears that other efflux proteins may also be involved. CONCLUSION: The low permeability of anti-malarial drugs must be borne in mind during development of effective dosage regimens of new drugs.

The In Vitro and In Vivo Effects of Hypoxis hemerocallidea on Indinavir Pharmacokinetics: Modulation of Efflux.

Hypoxis hemerocallidea (African potato) is a popular medicinal plant that has been used traditionally for the treatment of various disorders. Some HIV/AIDS patients use this traditional medicine together with their antiretroviral therapy. This study aimed to determine the impact of selected H. hemerocallidea materials (i.e., a commercial product, an aqueous extract, and biomass reference plant material) on the bidirectional permeability of indinavir across Caco-2 cell monolayers as well as the bioavailability of indinavir during an acute, single administration study in Sprague-Dawley rats. All of the selected H. hemerocallidea test materials demonstrated inhibition effects on indinavir efflux across Caco-2 cell monolayers, albeit to different extents. An increase in the bioavailability of indinavir was obtained in vivo when administered concomitantly with the H. hemerocallidea materials, albeit not statistically significantly. The change in bioavailability directly correlated with the in vitro permeability results. It can therefore be concluded that the change in permeability and bioavailability of indinavir was caused by efflux inhibition and this effect was dependent on the type of H. hemerocallidea material investigated, which was found to be in the following order: commercial product > aqueous extract > reference plant material. The clinical significance of the combined effect of efflux and metabolism inhibition by H. hemerocallidea should be determined in another in vivo model that expresses the cytochrome P450 3A4 enzyme.

Potential Herb-Drug Pharmacokinetic Interactions between African Wild Olive Leaf Extract and Selected Antihypertensive Drugs.

The African wild olive (Olea europaea subsp. africana) is traditionally used as a hypotensive agent. Herb-drug interactions may result from the concurrent use of herbal medicines and conventional prescription drugs. This aspect was investigated by determining the effect of the extract on the in vitro intestinal epithelial permeation of selected hypotensive drugs using the Caco-2 cell culture model. The phytochemical profiles of leaf extracts of African wild olive from different localities in South Africa were compared, since efficacy is determined by the chemical composition. Extracts were analysed using ultra-performance liquid chromatography. The oleuropein concentration varied considerably from below the detection limit (4.94 µg/mL) to 59.4 mg/g dry weight. Chemometric models constructed from the aligned chromatographic data indicated only quantitative differences between the profiles. The leaf extract was found to increase the permeability of propranolol in the absorptive direction (Papp = 8.93 × 10-6 cm/s) across Caco-2 cell monolayers, but considerably decreased transport in the secretory direction (Papp = 3.68 × 10-6 cm/s). The permeation of diltiazem was enhanced by the extract in both the absorptive (Papp = 7.33 × 10-6 cm/s) as well as in the secretory direction (Papp = 7.16 × 10-6 cm/s), but a decrease in the efflux ratio was observed. The extract therefore caused a net increase in the transport of both drugs in the absorptive direction due to an inhibition effect on their efflux. This suggests a potential increase in the blood levels of these drugs when taken simultaneously with African wild olive leaf extract, indicating potential adverse effects that must be verified in vivo.

Recent developments in our understanding of the implications of traditional African medicine on drug metabolism.

INTRODUCTION: The use of traditional herbal medicines has become increasingly popular globally, but in some countries, it is the main or sometimes even the only healthcare service available in the most rural areas. This is especially true for Africa where herbal medicines form a key component of traditional medicinal practices and there is access to a diversity of medicinal plants. Although many benefits have been derived from the use of traditional herbal medicines, many concerns are associated with their use of which herb-drug interactions have been identified to have a rising impact on patient treatment outcome. One type of pharmacokinetic interaction involves the modulation of drug metabolizing enzymes, which may result in enhanced or reduced bioavailability of co-administered drugs. Areas covered: This review highlights the current information available on drug metabolism-associated information with regards to traditional African medicines related to some of the most prevalent diseases burdening the African continent. Expert opinion: It is clear from previous studies that enzyme modulation by traditional African medicines plays a significant role in the pharmacokinetics of some co-administered drugs, but more research is needed to provide detailed information on these interactions, specifically for treatment of prevalent diseases such as tuberculosis and hypertension.

Topical Delivery of Withania somnifera Crude Extracts in Niosomes and Solid Lipid Nanoparticles.

BACKGROUND: Withania somnifera is a medicinal plant native to India and is known to have anticancer properties. It has been investigated for its anti-melanoma properties, and since melanoma presents on the skin, it is prudent to probe the use of W. somnifera in topical formulations. To enhance topical drug delivery and to allow for controlled release, the use of niosomes and solid lipid nanoparticles (SLNs) as delivery vesicles were explored. OBJECTIVE: The objective of this study is to determine the stability and topical delivery of W. somnifera crude extracts encapsulated in niosomes and SLNs. MATERIALS AND METHODS: Water, ethanol, and 50% ethanol crude extracts of W. somnifera were prepared using 24 h soxhlet extraction which were each encapsulated in niosomes and SLNs. Franz cell diffusion studies were conducted with the encapsulated extracts to determine the release and skin penetration of the phytomolecules, withaferin A, and withanolide A. RESULTS: The niosome and SLN formulations had average sizes ranging from 165.9 ± 9.4 to 304.6 ± 52.4 nm with the 50% ethanol extract formulations having the largest size. A small particle size seemed to have correlated with a low encapsulation efficiency (EE) of withaferin A, but a high EE of withanolide A. There was a significant difference (P < 0.05) between the amount of withaferin A and withanolide A that were released from each of the formulations, but only the SLN formulations managed to deliver withaferin A to the stratum corneum-epidermis and epidermis-dermis layers of the skin. CONCLUSION: SLNs and niosomes were able to encapsulate crude extracts of W. somnifera and release the marker compounds, withaferin A, and withanolide A, for delivery to certain layers in the skin. SUMMARY: Withania somnifera crude extracts were prepared using ethanol, water, and 50% ethanol as solvents. These three extracts were then incorporated into niosomes and solid lipid nanoparticles (SLNs) for use in skin diffusion studies, thus resulting in six formulations (ethanol niosome, water niosome, 50% ethanol niosome, ethanol SLN, water SLN, and 50% ethanol SLN). The diffusion of two marker compounds (withaferin A and withanolide A) from the formulations into the skin was then determined. Abbreviations used: API: Active pharmaceutical ingredient, ANOVA: Analysis of variance, ED: Epidermis-dermis, HPLC: High-performance liquid chromatography, HLB: Hydrophilic-lipophilic balance, NMR: Nuclear magnetic resonance spectroscopy, PDI: Polydispersity index, SLN: Solid lipid nanoparticle, SD: Standard deviation, SCE: Stratum corneum-epidermis, TEM: Transmission electron microscopy.

In vitro wound healing and cytotoxic activity of the gel and whole-leaf materials from selected aloe species.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe vera is one of the most important medicinal plants in the world with applications in the cosmetic industry and also in the tonic or health drink product market. Different parts of Aloe ferox and Aloe marlothii are used as traditional medicines for different applications. Although wound healing has been shown for certain aloe gel materials (e.g. A. vera ) previously, there are conflicting reports on this medicinal application of aloe leaf gel materials. AIM OF THE STUDY: The present study aimed at determining the wound healing properties of the gel and whole-leaf materials of Aloe vera, Aloe ferox and Aloe marlothii, as well as their cytotoxic effects on normal human keratinocyte cells (HaCaT). MATERIALS AND METHODS: Nuclear magnetic resonance spectroscopy was used to chemically fingerprint the aloe gel and whole-leaf materials by identifying characteristic marker molecules of aloe gel and whole-leaf materials. An MTT assay was performed to determine the cytotoxicity of the various aloe whole-leaf and gel materials on HaCaT cells. Wound healing and in vitro cell migration were investigated with HaCaT cells by means of the CytoSelect™ assay kit. RESULTS: The in vitro wound healing assay suggested that all the aloe gel and whole-leaf materials examined, exhibited faster wound healing activity than the untreated control group. After 48h, all the aloe gel and whole-leaf materials almost completely caused full wound closure, displaying 98.07% (A. marlothii whole-leaf), 98.00% (A. vera gel), 97.20% (A. marlothii gel), 96.00% (A. vera whole-leaf), 94.00% (A. ferox gel) and 81.30% (A. ferox whole-leaf) wound closure, respectively. It was noteworthy that the gel materials of all the three aloe species exhibited significantly faster (p<0.05) wound healing actions when compared to their respective whole-leaf materials at 32h. CONCLUSION: The gel and whole-leaf materials of A. vera, A. ferox and A. marlothii have shown the ability to heal wounds at a faster rate and to a larger extent than untreated keratinocytes. The MTT assay results suggested that the gel and whole-leaf materials of all the selected Aloe species showed negligible toxicity towards the HaCaT cells.

Isolation and in vitro permeation of phenylpropylamino alkaloids from Khat (Catha edulis) across oral and intestinal mucosal tissues.

ETHNOPHARMACOLOGICAL RELEVANCE: Khat, the leaves of Catha edulis, is used as a "natural amphetamine-like" stimulant in eastern and southern Africa, as well as in the Arabian Peninsula. Leaves are masticated to elicit a state of euphoria. Although the psychostimulatory effects of the leaves are attributed to the presence of phenylpropylamino alkaloids (i.e. cathinone, cathine and norephedrine), the extent of permeation of these alkaloids across the oral and intestinal mucosa has not been established. MATERIALS AND METHODS: Cathinone was isolated in the form of the oxalate salt from young buds, following acid-base extraction. High performance countercurrent chromatography (HPCCC) was used to isolate cathine and norephedrine, following borohydride reduction of a mixture of the three alkaloids. The in vitro permeability of these three alkaloids in their pure form, as well as in a crude extract, was evaluated across Caco-2 cell monolayers and across excised porcine intestinal, sublingual and buccal tissues. RESULTS: The purities of the isolated cathine and norephedrine were in excess of 90%, thereby proving that HPCCC can be applied for efficient separation of these alkaloids from extracts of Khat. The apparent permeability (Papp) coefficients for the Khat alkaloids in their pure form were all above 1.0×10-6cm/s, indicating that the transport of the three alkaloids across the selected biological membranes is comparable to that of the highly permeable reference compound, caffeine. Although readily transported across the various membranes, the alkaloids were transported to a lesser extent when present in a leaf extract, suggesting that other phytochemicals present in the extract influence their permeation. CONCLUSIONS: These results provide evidence that chewing of Khat contributes to the buccal and sublingual absorption of the psychoactive alkaloids in the bloodstream directly across the oral mucosal membranes. In addition, it confirms that these metabolites will be readily absorbed from the gastrointestinal tract when swallowed.

Evaluation of Isolated Fractions of Aloe vera Gel Materials on Indinavir Pharmacokinetics: In vitro and in vivo Studies.

Aloe vera is a plant with a long history of traditional medicinal use and is consumed in different products, sometimes in conjunction with prescribed medicines. A. vera gel has shown the ability to modulate drug absorption in vitro. The aim of this study was to fractionate the precipitated polysaccharide component of A. vera gel based on molecular weight and to compare their interactions with indinavir pharmacokinetics. Crude polysaccharides were precipitated from a solution of A. vera gel and was fractionated by means of centrifugal filtration through membranes with different molecular weight cut-off values (i.e. 300 KDa, 100 KDa and 30 KDa). Marker molecules were quantified in the aloe leaf materials by means of nuclear magnetic resonance spectroscopy and the average molecular weight was determined by means of gel filtration chromatography linked to multi-angle-laser-light scattering and refractive index detection. The effect of the aloe leaf materials on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers as well as indinavir metabolism in LS180 cells was measured. The bioavailability of indinavir in the presence and absence of the aloe leaf materials was determined in Sprague-Dawley rats. All the aloe leaf materials investigated in this study reduced the TEER of Caco-2 cell monolayers, inhibited indinavir metabolism in LS 180 cells to different extents and changed the bioavailability parameters of indinavir in rats compared to that of indinavir alone. These indinavir pharmacokinetic modulation effects were not dependent on the presence of aloverose and also not on the average molecular weight of the isolated fractions.

Combining Chemical Permeation Enhancers for Synergistic Effects.

Currently, macromolecular drugs such as proteins are mainly administered by means of injections due to their low intestinal epithelial permeability and poor stability in the gastrointestinal tract. This study investigated binary combinations of chemical drug absorption enhancers to determine if synergistic drug absorption enhancement effects exist. Aloe vera, Aloe ferox and Aloe marlothii leaf gel materials, as well as with N-trimethyl chitosan chloride (TMC), were combined in different ratios and their effects on the transepithelial electrical resistance (TEER), as well as the transport of FITC-dextran across Caco-2 cell monolayers, were measured. The isobole method was applied to determine the type of interaction that exists between the absorption enhancers combinations. The TEER results showed synergism existed for the combinations between A. vera and A. marlothii, A. marlothii and A. ferox as well as A. vera and TMC. Antagonism interactions also occurred and can probably be explained by chemical reactions between the chemical permeation enhancers, such as complex formation. In terms of FITC-dextran transport, synergism was found for combinations between A. vera and A. marlothii, A. marlothii and A. ferox, A. vera and TMC, A. ferox and TMC and A. marlothii and TMC, whereas antagonism was observed for A. vera and A. ferox. The combinations where synergism was obtained have the potential to be used as effective drug absorption enhancers at lower concentrations compared to the single components.