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There has been high interest in the use of traditional medicines for COVID-19 from early in the course of the pandemic. Significant advances in the science of ethnopharmacology have helped to introduce chemical entities identified from natural sources into modern medicine. However, the wider integration of natural products into the modern drug discovery process will require enhanced collaboration amongst the pharmaceutical industry, academic research units, regulatory bodies, ethics review committees and local, regional, continental and international organizations. Revisiting this topic holds promise of benefit for both the current and future pandemics.

Aim: Perceived knowledge, use and perceptions of pharmacogenomics (PGx) testing were assessed among healthcare practitioners in North Carolina. Materials & methods: A validated survey was distributed to various healthcare professionals and analyzed for differences among the groups. Results: The majority of the 744 survey respondents acknowledged the perceived benefits of PGx testing, but indicated either never or rarely using it. A substantial percentage of practitioners reported educational experiences but the majority had received no training. Among groups reporting using PGx testing, barriers to implementation were cost and insufficient training. Conclusion: The perceived cost of PGx testing and insufficiency or lack of training are major contributing factors to the infrequent use of PGx testing by healthcare providers in North Carolina.

Summary Introduction: Combretum species has been utilised for decades in African indigenous medical practices for the treatment of several parasitic infections. Objectives: This study aims at investigating the antileishmanial, antiplasmodial and antitrypanosomal properties of Combretum racemosum, Combretum platypterum and Combretum zenkeri. Methods: The leaf extracts of the plants were screened against two strains of Plasmodium falciparum using Plasmodium lactate dehydrogenase (pLDH) assay; promastigote and amastigote forms of Leishmania donovani; and Trypanosoma brucei brucei using Alamar Blue assay. Cytotoxicity screening were also carried out on African green monkey kidney cell line (Vero) and human monocytic leukemia (THP-1) cell lines. Results: C. racemosum was active against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of P. falciparum (IC50 of 25.6 and 26.7 µg/ml, respectively) and exerted significant antiprotozoal activities against T. brucei brucei (IC50 = 18.44 µg/ml). The extract of C. platypterum displayed a slightly lower antiplasmodial activity when compared to C. racemosum, while C. zenkeri was inactive against the parasites. In addition, the extracts failed to display significant inhibitory activity on the proliferation of L. donovani. Conclusions: This study supports the ethnomedicinal use of C. racemosum. Further research needs to be carried out to identify the antiprotozoal compounds in C. racemosum, as this could be explored for possible antiprotozoal drug development.

Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (-)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (C

The management of neuropsychiatric disorders relies heavily on pharmacotherapy. The use of herbal products as complimentary medicine, often concomitantly, is common among patients taking prescription neuropsychiatric drugs. Herb-drug interaction, a clinical consequence of this practice, may jeopardize the success of pharmacotherapy in neuropsychiatry. Besides the well-known ability of phytochemicals to inhibit and/or induce drug-metabolizing enzymes and transport proteins, several phytoconstituents are capable of exerting pharmacological effects on the central nervous system. The consequent pharmacokinetic and pharmacodynamic interactions with orthodox medications often result in deleterious clinical consequences. This study reviewed the relevant literature and identified 13 commonly used herbal products - celery, echinacea, ginkgo, ginseng, hydroxycut, kava, kratom, moringa, piperine, rhodiola, St John's wort, terminalia/commiphora ayurvedic mixture and valerian - which have shown clinically relevant interactions with prescription drugs used in the management of neuropsychiatric disorders. The clinical focus is aimed to provide easily accessible information that will be of interest to clinicians, researchers, and the drug-consuming public.

Since the outbreak and subsequent declaration of COVID-19 as a global pandemic in March 2020, concerted efforts have been applied by the scientific community to curtail the spread of the disease and find a cure. While vaccines constitute a vital part of the public health strategy to reduce the burden of COVID-19, the management of this disease will continue to rely heavily on pharmacotherapy. This study aims to provide an updated review of pharmacological agents that have been developed and/or repurposed for the treatment of COVID-19. To this end, a comprehensive literature search was conducted using the PubMed, Google Scholar, and LitCovid databases. Relevant clinical studies on drugs used in the management of COVID-19 were identified and evaluated in terms of evidence of efficacy and safety. To date, the FDA has approved three therapies for the treatment of COVID-19 Emergency Use Authorization: convalescent plasma, remdesivir, and casirivimab/imdevimab (REGN-COV2). Drugs such as lopinavir/ritonavir, umifenovir, favipiravir, anakinra, chloroquine, hydroxychloroquine, tocilizumab, interferons, tissue plasminogen activator, intravenous immunoglobulins, and nafamosat have been used off-label with mixed therapeutic results. Adjunctive administration of corticosteroids is also very common. The clinical experience with these approved and repurposed drugs is limited, and data on efficacy for the new indication are not strong. Overall, the response of the global scientific community to the COVID-19 pandemic has been impressive, as evident from the volume of scientific literature elucidating the molecular biology and pathophysiology of SARS-CoV-2 and the approval of three new drugs for clinical management. Reviewed studies have shown mixed data on efficacy and safety of the currently utilized drugs. The lack of standard treatment for COVID-19 has made it difficult to interpret results from most of the published studies due to the risk of attribution error. The long-term effects of drugs can only be assessed after several years of clinical experience; therefore, the efficacy and safety of current COVID-19 therapeutics should continue to be rigorously monitored as part of post-marketing studies.

Ethnopharmacological relevance Rumex acetosa Linn belongs to Polygonaceae, the species is distributed worldwide (African, Asian, American and European countries). Rumex acetosa is used traditionally as vegetables and for its medicinal uses. Its diverse uses in traditional and cultural applications, have geared much research towards its phytochemical and pharmacological activities. This review intends to offer and give up-to-date knowledge cum research on its ethnopharmacology, chemical constituents, pharmacological activities, reactions with other drugs, and safety concerns, so that the medicinal uses and new research trends can be recognized. Methodology The literature related to the title i.e. R. acetosa Linn was effected by a search using the keywords like “Rumex acetosa, sorrel, garden sorrel and biological activity of R. acetosa” in “Google Scholar,” “PubMed,” “ScienceDirect” “Scopus” and “Web of Science” databases. Plant taxonomy was queried by the databases “The Plant List,” and Many publications' sites were queried like Springer, Elsevier, and dissertation search engines like Open-thesis, OATD, ProQuest and EthOs were put to use. Results This study argues the huge advantages that this plant species possesses and further highlights the up-to-date knowledge of chemistry, the invitro and invivo biological studies, phytochemistry and scientific basis for the use of the plant R. acetosa. Many cultures around the world uses the leaves and aerial parts as vegetables, other parts of this medicinal plant are employed in the management of a number of ailments such as constipation, diarrhea, jaundice, mild diabetes and as an analgesic, antihypertensive, against gallbladder, liver and skin disorders and inflammation. The phytochemistry of this wild vegetable showed that over 60 compounds were reportedly isolated, these includes anthraquinones, naphthalene, polyphenols and other compounds. Furthermore, this manuscript depicts the high level of oxalic acid in R. acetosa though cooking reduces oxalic acid concentration to negligible amount. Conclusions This review confirms the dangers that R. acetosa possesses when eaten uncooked in large quantity orally especially for some populace though there are strong evidences that it can serve as a functional food. It is clear that the medicinal value of its phytochemistry is yet to be explored fully. There are indications of enormous traditional uses, the pharmacological facts are satisfying though few, it is relieving that scientific evidences against oral diseases are obvious. There is need for more studies to validate these medicinal claims, this review tends to connect the research gap hence provide enough information for upcoming research on its use as a functional food.

Background The activity and haemolytic toxicity associated with primaquine has been linked to its reactive metabolites. The reactive metabolites are thought to be primarily formed through the action of cytochrome P450-mediated pathways. Human erythrocytes generally are not considered a significant contributor to drug biotransformation. As erythrocytes are the target of primaquine toxicity, the ability of erythrocytes to mediate the formation of reactive oxidative primaquine metabolites in the absence of hepatic enzymes, was evaluated. Methods Primaquine and its enantiomers were incubated separately with human red blood cells and haemoglobin. Post-incubation analysis was performed with UPLC–MS/MS to identify products of biotransformation. Results The major metabolite detected was identified as primaquine-5,6-orthoquinone, reflecting the pathway yielding putative active and haematotoxic metabolites of primaquine, which was formed by oxidative demethylation of 5-hydroxyprimaquine. Incubation of primaquine with haemoglobin in a cell-free system yielded similar results. It appears that the observed biotransformation is due to non-enzymatic processes, perhaps due to reactive oxygen species (ROS) present in erythrocytes or in the haemoglobin incubates. Conclusion This study presents new evidence that primaquine-5,6-orthoquinone, the metabolite of primaquine reflecting the oxidative biotransformation pathway, is generated in erythrocytes, probably by non-enzymatic means, and may not require transport from the liver or other tissues.

In our continuing work on Vitex genus, the phytochemical investigation of leaves of Vitex grandifolia led to the isolation of two iridoids known in the literature as agnuside and bartsioside. The chemical structures were characterized by combined spectroscopic analysis. These compounds were isolated from this specie for the first time, this study give evidence to iridoids as chemotaxonomic marker and their constitutive presence has been reported in a number of genera in the family Lamiaceae. Iridoids have been isolated from nineteen species belonging to genus Vitex from Lamiaceae especially aucubin and agnuside. In addition to the utilization of morphological features of plants belonging to this genus, these compounds may be useful chemotaxonomic markers to aid taxonomic identification. This work evaluates and describes the distribution of iridoids in Vitex species to further establish this claim with structures of the iridoids found in this genus. Keywords: Iridoids, Agnuside, Chemotaxonomic markers, Lamiaceae

Background: Sexually transmitted gonorrhea, caused by the Gram-negative diplococcus Neisseria gonorrhoeae, continues to be a serious global health challenge despite efforts to eradicate it. Multidrug resistance among clinical N. gonorrhoeae isolates has limited treatment options, and attempts to develop vaccines have not been successful. Methods: A search of published literature was conducted, and information extracted to provide an update on the status of therapeutics and vaccine development for gonorrheal infection. Results: Recommended pharmacological treatment for gonorrhea has changed multiple times due to increasing acquisition of resistance to existing antibiotics by N. gonorrhoeae. Only broad-spectrum cephalosporin-based combination therapies are currently recommended for treatment of uncomplicated urogenital and anorectal gonococcal infections. With the reported emergence of ceftriaxone resistance, successful strategies addressing the global burden of gonorrhea must include vaccination. Century-old efforts at developing an effective vaccine against gonorrhea, leading to only four clinical trials, have not yielded any successful vaccine. Conclusions: While it is important to continue to explore new drugs for the treatment of gonorrhea, the historical trend of resistance acquisition suggests that any long-term strategy should include vaccine development. Advanced technologies in proteomics and in silico approaches to vaccine target identification may provide templates for future success.

Background: Besides its well-known role as a peripheral chemical mediator of immune, vascular, and cellular responses, histamine plays major roles in the central nervous system, particularly in the mediation of arousal and cognition-enhancement. These central effects are mediated by the histamine-3 auto receptors, the modulation of which is thought to be beneficial for the treatment of disorders that impair cognition or manifest with excessive daytime sleepiness. Methods: A database search of PubMed, Google Scholar, and clinicaltrials.gov was performed in June 2020. Full-text articles were screened and reviewed to provide an update on pitolisant and other histamine-3 receptor antagonists. Results: A new class of drugs—histamine-3 receptor antagonists—has emerged with the approval of pitolisant for the treatment of narcolepsy with or without cataplexy. At the recommended dose, pitolisant is well tolerated and effective. It has also been evaluated for potential therapeutic benefit in Parkinson disease, epilepsy, attention deficit hyperactivity disorder, Alzheimer’s disease, and dementia. Limited studies have shown pitolisant to lack abuse potential which will be a major advantage over existing drug options for narcolepsy. Several histamine-3 receptor antagonists are currently in development for a variety of clinical indications. Conclusions: Although limited clinical studies have been conducted on this new class of drugs, the reviewed literature showed promising results for future additions to the clinical indications of pitolisant, and the expansion of the list of approved drugs in this class for a variety of indications.

The antimalarial drug primaquine (PQ) causes methemoglobinemia and hemolysis in individuals with a genetic deficiency of glucose 6-phosphate dehydrogenase. Reactive oxygen species (ROS) generated by redox cycling of the metabolite primaquine-5,6-orthoquinone (POQ) in erythrocytes has been attributed to be responsible for the toxicity of PQ. Carboxyprimaquine (CPQ), the major human plasma metabolite of PQ, can also form the analogous carboxyprimaquine-5,6-orthoquinone (CPOQ) metabolite, which can also generate ROS in erythrocytes by redox cycling, thus contributing to the hematotoxicity of this drug. In order to study these pathways and characterize such effects in vivo, methods are needed for characterization and quantification of POQ and CPOQ in human erythrocytes. The purpose of this work was to develop a validated method for the quantitative determination of CPOQ and POQ metabolites in human erythrocytes, suitable for clinical studies of PQ metabolism. Several liquid-liquid extraction methods using different organic solvents had been investigated. The solvent mixture of water-methanol-acetonitrile (9:9:5, v/v) was shown to yield the best results for the two analytes. Chromatographic analysis of POQ and CPOQ in human erythrocytes was achieved on a high strength silica (HSS) column and gradient elution (water and acetonitrile, both containing 0.1% formic acid) by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Quantitative estimation of POQ and CPOQ was executed by monitoring ion pairs of m/z 260.23 > 175.03 and m/z 275.19 > 175.04, respectively. The method, which was validated for precision, accuracy, selectivity, and linearity, was successfully applied for the quantitative determination of POQ and CPOQ, the key metabolites of PQ in human erythrocytes in PQ clinical study.

Medicinal plants exploration has become an important tool in the discovery of bioactive natural substances capable of inhibiting the mechanisms of microbial and protozoal activity. The aim of this study was to determine the antimicrobial and antiprotozoal activities of medicinal plants extracts used for the treatment of various illnesses in southwestern Nigeria. Twenty-four medicinal plant extracts were screened for antimicrobial activity against three fungal and six bacterial strains; and antiprotozoal activities against chloroquine-sensitive strains of Plasmodium falciparum (antiplasmodial assay), a culture of Leishmania donovani promastigotes and axenic amastigotes (antileishmanial activity) and two-days old culture of Trypanosoma brucei brucei (antitrypanosomal assay). Five extracts exhibited strong antifungal activity against Cryptococcus neoformans, with Ricinodendron heudelotii (Baill.) Heckel, Terminalia ivorensis A.Chev and Macaranga barteri Mull. Arg, having an IC50 of 31.73, 32.10 and 75.63 μg/mL, respectively. Ten of the extracts were active against T. brucei, with Eleusine indica displaying the most significant activity (IC50 and IC90 of 8.26 and 10.14 μg/mL). None of the extracts displayed any significant antiplasmodial and antileishmanial activities. In addition, none of the extracts displayed cytotoxicity on transformed human monocytic (THP1) cells. The study revealed that M. barteri had the broadest spectrum of activity, with activity against C. neoformans, P. aeruginosa, vancomycin resistant Enterococci faecalis (VRE) and T. brucei. M. barteri could be exploited for broad spectrum antimicrobial and antitrypanosomal activity, while Eleusine indica could be subjected to bioassay guided fractionation and isolation of antitrypanosomal constituents. This study suggests that the evaluated plants are potential sources of novel anti-infective agents.

Ethnopharmacological relevance The disease burden of protozoal infections is enormous in West Africa and other developing regions of the world. Malaria is one of the most important parasitic disease in tropical areas caused by protozoans of the genus Plasmodium and more than a third of the world's population (about two billion people) lives in malaria-endemic areas. Leishmaniasis and trypanosomiasis are other parasitic protozoan infections caused by protozoan of the genus Leishmania and Trypanosoma respectively. The development of resistance to available antiprotozoal drugs has necessitated the search for new and effective compounds. Plant-based products with long history of traditional use in treating infectious diseases can be explored in this regard. Aim of the study To evaluate in vitro the antiplasmodial, antileishmanial and anti-trypanosomal activities of fractions of 18 medicinal plants belonging to 14 different families. Materials and methods Fractions (hexane, chloroform and methanol) of eighteen medicinal plants belonging to fourteen families, with historical use as traditional antiprotozoal therapy were screened in vitro for activity against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum , Leishmania donovani (promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells) and Trypanosoma brucei brucei , using standard procedures. Results The methanol fraction of Corchorus walcottii showed selective antileshimanial activity against intracellular L. donovani amastigotes with an IC 50 average of 5.94 µg/ml. Methanol fraction of Cassia obtusifolia , methanol and chloroform fractions of Corchorus walcotti and methanol fraction of Vitex grandifolia exhibited activity against T. brucei brucei blood stage trypamastigotes with IC 50 values of 5.88, 5.73, 7.29 and 8.73 (µg/ml) respectively. Methanol fractions of Crotalaria mucronata and Pseudocedrela kotschyi, with the chloroform fraction of Launaea taraxacifolia showed >50% growth inhibition against chloroquine-sensitive (D6) strain of P. falciparum with values as 60%, 73% and 52%. At concentrations of 15.8667 µg/mL, the most active fractions antimalarial activity was exhibited by methanol extracts of Pseudocedrela kotschyi (IC 50 = 29.7 µg/mL (D6) S.I = 1 µg/ml (W2) S.I = 1.3) and Crotalaria mucronata (IC 50 = 46.45 µg/mL (D6) S.I > 1.0, 46.86 µg/mL (W2) S.I = 1.0) and chloroform extract of Launaea taraxicifolia (IC 50 = 21.55 µg/mL (D6) S.I >2.2, 18.0 µg/mL (W2) S.I >2.6). Conclusion The results showed that the methanol extracts of Pseudocedrela kotschyi and, Crotalaria mucronata with chloroform extract of Launaea taraxicifolia may contain useful antimalarial leads. Cassia obtusifolia, Corchorus walcottii and Vitex grandifolia may be promising candidates for isolation of antiprotozoal compounds which could serve as new lead structures for development of new drugs against these neglected tropical (leshmanasis and trypanosomiasis) diseases and may provide scientific support for the traditional use of these plants against protozoal related treatments.

Background: Sexually transmitted gonorrhea, caused by the Gram-negative diplococcus Neisseria gonorrhoeae, continues to be a serious global health challenge despite efforts to eradicate it. Multidrug resistance among clinical N. gonorrhoeae isolates has limited treatment options, and attempts to develop vaccines have not been successful. Methods: A search of published literature was conducted, and information extracted to provide an update on the status of therapeutics and vaccine development for gonorrheal infection. Results: Recommended pharmacological treatment for gonorrhea has changed multiple times due to increasing acquisition of resistance to existing antibiotics by N. gonorrhoeae. Only broad-spectrum cephalosporin-based combination therapies are currently recommended for treatment of uncomplicated urogenital and anorectal gonococcal infections. With the reported emergence of ceftriaxone resistance, successful strategies addressing the global burden of gonorrhea must include vaccination. Century-old efforts at developing an effective vaccine against gonorrhea, leading to only four clinical trials, have not yielded any successful vaccine. Conclusions: While it is important to continue to explore new drugs for the treatment of gonorrhea, the historical trend of resistance acquisition suggests that any long-term strategy should include vaccine development. Advanced technologies in proteomics and in silico approaches to vaccine target identification may provide templates for future success.

Heavy metals are known to disrupt important physiological processes in living cells, and have been responsible for various pathological conditions with possible contributions to cancer development. Food contamination have been identified as one of the ways humans are exposed to heavy metals. In developing countries like Nigeria, the regulatory framework for enforcing compliance with globally acceptable exposure to deleterious contaminants is poor. In the current study, thirteen samples of cured meat products of diverse origin marketed in South-west Nigeria were evaluated for lead, cadmium, chromium and nickel contents using the atomic absorption spectroscopy technique. All the samples analysed contained cadmium between 0.35 and 1.20 ppm, levels considered higher than acceptable limits in consumable products. Lead, chromium and nickel were not detected in any of the samples. As known cumulative poisons, there is the need for stringent regulatory control of these heavy metals in cured meat products imported into or produced indigenously in the country in order to minimize the risks to public health.

Poor oral bioavailability is the single most important challenge in drug delivery. Prominent among the factors responsible for this is metabolic activity of the intestinal and hepatic cytochrome P450 (CYP450) enzymes. In preliminary studies, it was demonstrated that 8-arm-PEG was able to inhibit the felodipine metabolism. Therefore, this report investigated the oral bioavailability-enhancing property of 8-arm-PEG employing detailed in vitro, in vivo, and in silico evaluations. The in vitro metabolism of felodipine by cytochrome P450 3A4-expressed human liver microsomes (HLM) was optimized yielding a typical Michaelis-Menten plot through the application of Enzyme Kinetic Module software from where the enzyme kinetic parameters were determined. In vitro investigation of 8-arm-poly(ethylene glycol) against CYP3A4-catalyzed felodipine metabolism employing human liver microsomes compared closely with naringenin, a typical grapefruit flavonoid, yielding IC50 values of 7.22 and 121.97 μM, respectively. The investigated potential of 8-arm-poly(ethylene glycol) in oral drug delivery yielded satisfactory in vitro drug release results. The in vivo studies of the effects of 8-arm-poly(ethylene glycol) on the oral bioavailability of felodipine as performed in the Large White pig model showed a >100% increase in plasma felodipine levels compared to controls, with no apparent effect on systemic felodipine clearance. The outcome of this research presents a novel CYP3A4 inhibitor, 8-arm-poly(ethylene glycol) for oral bioavailability enhancement.

Background Primaquine (PQ), an 8-aminoquinoline, is the only drug approved by the United States Food and Drug Administration for radical cure and prevention of relapse in Plasmodium vivax infections. Knowledge of the metabolism of PQ is critical for understanding the therapeutic efficacy and hemolytic toxicity of this drug. Recent in vitro studies with primary human hepatocytes have been useful for developing the ultra high-performance liquid chromatography coupled with high-resolution mass spectrometric (UHPLC-QToF-MS) methods for simultaneous determination of PQ and its metabolites generated through phase I and phase II pathways for drug metabolism. Methods These methods were further optimized and applied for phenotyping PQ metabolites from plasma and urine from healthy human volunteers treated with single 45 mg dose of PQ. Identity of the metabolites was predicted by MetaboLynx using LC–MS/MS fragmentation patterns. Selected metabolites were confirmed with appropriate standards. Results Besides PQ and carboxy PQ (cPQ), the major plasma metabolite, thirty-four additional metabolites were identified in human plasma and urine. Based on these metabolites, PQ is viewed as metabolized in humans via three pathways. Pathway 1 involves direct glucuronide/glucose/carbamate/acetate conjugation of PQ. Pathway 2 involves hydroxylation (likely cytochrome P450-mediated) at different positions on the quinoline ring, with mono-, di-, or even tri-hydroxylations possible, and subsequent glucuronide conjugation of the hydroxylated metabolites. Pathway 3 involves the monoamine oxidase catalyzed oxidative deamination of PQ resulting in formation of PQ-aldehyde, PQ alcohol and cPQ, which are further metabolized through additional phase I hydroxylations and/or phase II glucuronide conjugations. Conclusion This approach and these findings augment our understanding and provide comprehensive view of pathways for PQ metabolism in humans. These will advance the clinical studies of PQ metabolism in different populations for different therapeutic regimens and an understanding of the role these play in PQ efficacy and safety outcomes, and their possible relation to metabolizing enzyme polymorphisms. Electronic supplementary material The online version of this article (10.1186/s12936-018-2433-z) contains supplementary material, which is available to authorized users.

Background: Over the last ten years, a new class of drugs, known as the direct-acting oral anticoagulants (DOACs), have emerged at the forefront of anticoagulation therapy. Like the older generation anticoagulants, DOACs require specific reversal agents in cases of life-threatening bleeding or the need for high-risk surgery. Methods: Published literature was searched, and information extracted to provide an update on DOACS and their reversal agents. Results: The DOACs include the direct thrombin inhibitor—dabigatran, and the factor Xa inhibitors—rivaroxaban, apixaban, edoxaban, and betrixaban. These DOACs all have a rapid onset of action and each has a predictable therapeutic response requiring no monitoring, unlike the older anticoagulants, such as warfarin. Two reversal agents have been approved within the last five years: idarucizumab for the reversal of dabigatran, and andexanet alfa for the reversal of rivaroxaban and apixaban. Additionally, ciraparantag, a potential “universal” reversal agent, is currently under clinical development. Conclusions: A new generation of anticoagulants, the DOACs, and their reversal agents, are gaining prominence in clinical practice, having demonstrated superior efficacy and safety profiles. They are poised to replace traditional anticoagulants including warfarin.

Aqueous decoction of Hypoxis hemerocallidea Fisch.C.A. Mey. (Hypoxidaceae) (Hypoxis) is widely consumed in Southern Africa by people living with HIV/AIDS, some of whom are on ARV and other medications.The aim of this study was to investigate the potential of the crude aqueous extracts of Hypoxis to inhibit major forms of CYP450 and transport proteins.Corms of Hypoxis were water-extracted and incubated (in graded concentrations: 1-100 µg/mL) with human liver microsomes (20 min) to monitor the effects on phenacetin O-deethylation, coumarin 7-hydroxylation, bupropion hydroxylation, paclitaxel 6α-hydroxylation, diclofenac 4'-hydroxylation, S-mephenytoin 4'-hydroxylation, bufuralol 1'-hydroxylation, chlorzoxazone 6-hydroxylation, midazolam 1'-hydroxylation and testosterone 6β-hydroxylation as markers for the metabolic activities of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4/5, respectively. The generation of metabolites were monitored and quantified with the aid of LC-MS/MS. The potential of the extracts to inhibit human ATP-binding cassette transporter activity was assessed using recombinant MDCKII and LLC-PK1 cells over-expressing human breast cancer resistant protein and human P-glycoprotein , respectively (with Ko143 and cyclosporin A as positive controls). Similar assessment was performed with human organic anion transporting polypeptide (OATP1B1 and OATP1B3) using recombinant HEK293 cells over-expressing OATP1B1 and OATP1B3, respectively (with rifamycin and 10 µM atorvastatin as positive controls).Extracts of Hypoxis inhibited the production of the metabolites of the substrates of the following enzymes (as compared to controls) with the indicated IC50 values (µg/mL): CYP1A2 (120.6), CYP2A6 (210.8), CYP2B6 (98.5), CYP2C8 (195.2), CYP2C9 (156) and CYP3A4/5 (185.4). The inhibition of the uptake activity of OATP1B1 and OATP1B3 were also observed with IC50 values of 93.4 and 244.8 μg/mL, respectively.Extract concentrations higher than the estimated IC50 values are achievable in the gastrointestinal tract when traditional doses of Hypoxis are considered. This may have profound effects on presystemic metabolism of the drug substrates. If absorbed, systemic inhibition of metabolic enzymes/transporters by Hypoxis may be expected.The result suggests that there is the potential for HDI between Hypoxis and the substrates of the affected enzymes/transporters, if sufficient in vivo concentration of Hypoxis extracts is attained.

Background: Although warfarin remains the anticoagulant drug of choice in a wide range of patients, its narrow therapeutic window makes patients susceptible to a high risk of bleeding complications or failure to prevent clotting. This has necessitated therapeutic monitoring in warfarinised patients. Factors that could be responsible for the fluctuating responses to warfarin vary from pharmacogenetic to concomitant morbidity, diet and medication. In order to assess the quality of management of warfarin treatment in a local primary-care setting, the current study evaluated warfarin utilisation and monitoring records in two hospitals with different patient groups. Methods: A retrospective study was undertaken in the specialised warfarin clinics at Wesfleur and Gugulethu hospitals (Western Cape, South Africa) covering all warfarin-related therapy records over a 12-month period. Data extracted from the patients’ folders included age, gender, race, weight, address, concurrent chronic illnesses, treatment and medication, indication for warfarin and INR history. Results: A total of 119 patients’ folders were analysed. Attendance at the clinics reflects the demographics and racial distribution of the host location of the hospitals. While all the patients were maintained above the minimum international normalised ratio (INR) value of 2, about 50% had at least one record of INR above the cut-off value of 3.5. However, over a third of the patients (32.2%) had at least one record of INR greater than 3.5 in Gugulethu Hospital, compared to over half (58.3%) in Wesfleur Hospital. In total, atrial fibrillation was the most common indication for warfarinisation while hypertension was the most common concurrent chronic condition in warfarinised patients. All patients who received quinolone antibiotics had INR values above the cut-off point of 3.5 within the same month of the initiation of antibiotic therapy, suggesting drug-induced warfarin potentiation. Other co-medications, including beta-lactam antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and anti-ulcer drugs appeared to alter warfarin responses as measured by recorded INR values. Conclusion: The study found inter-individual variability in the response to warfarin therapy, which cut across racial classifications. It also confirms the possible influence of concomitant morbidity on patient response to anticoagulant therapy.

Background There has been some evidence to suggest that the addition of chloroquine (CQ) or quinine (QN) to 8-aminoquinoline (8-AQ) treatment regimens may increase the therapeutic efficacy of the 8-AQ and simultaneously mitigate against its haemolytic toxicity. However, both CQ and QN are considered effective, although perhaps moderate inhibitors of CYP2D6, an enzyme now regarded as necessary for primaquine (PQ) pharmacologic activity. An understanding of the influence of CQ and QN on the metabolism of PQ may shed light on the potential mechanisms of the beneficial interaction. Methods Differential metabolism of PQ enantiomers by recombinant human CYP2D6, monoamine oxidase A (MAO), and cryopreserved human hepatocytes in the presence/absence of CQ and QN. Results Both CQ and QN significantly inhibited the activity of CYP2D6. PQ depletion by MAO and human hepatocytes was not affected significantly by the presence of CQ and QN. CYP2D6-mediated hydroxylation was largely suppressed by both CQ and QN. The formation of the primary deaminated metabolites, including carboxyprimaquine (CPQ) and cyclized side chain derivative from the aldehyde (m/z 241), was not sensitive to the presence of CQ and QN. However, the appearance of the glucuronides of CPQ and PQ alcohol were significantly suppressed. CQ and QN also inhibited the appearance of the m/z 257 metabolite with a similar pattern, suggesting that it may be derived from the CPQ conjugate. The apparent quinone-imine of CPQ (m/z 289) was only partially suppressed by both QN and CQ, but with a differential pattern of inhibition for the two drugs. The m/z 274 (quinone-imine of a ring-hydroxylated PQ metabolite) and m/z 422 (an apparent glucose conjugate of PQ) metabolites in hepatocytes were strongly suppressed by both QN and CQ, perhaps a reflection of the 2D6 inhibition by these drugs. The formation of the carbamoyl glucuronide of PQ (m/z 480) was not affected by CQ/QN. Conclusion The metabolite-specific interactions in the current studies seem at variance with earlier reports of the dependence of PQ on CYP2D6 metabolism, and enhanced PQ anti-malarial activity/reduced toxicity in the presence of CQ/QN. These results suggest a complex picture in which CQ/QN may shift metabolite pathway balances towards a profile that retains efficacy, while reducing the formation or availability of toxic metabolites to erythrocytes. Alternatively, these drugs may alter transport or distribution of PQ metabolites in a fashion that reduces toxicity while maintaining efficacy against the parasite.

Polymorphic expression of metabolic enzymes have been identified as one of the key factors responsible for the interindividual/ethnic/racial variability in drug metabolism and effect. In Nigeria, there is a disproportionately high incidence of sickle‐cell disease (SCD), a condition characterized by painful crisis frequently triggered by malaria. Proguanil, a substrate of the polymorphic CYP2C19, is a chemoprophylactic antimalarial drug widely used among SCD patients in Nigeria. This study aimed to conduct a comparative CYP2C19 phenotyping among SCD patients and healthy controls and to compare the results with those previously reported. One hundred seventy‐seven unrelated subjects comprising 131 SCD patients and 46 non‐SCD volunteers were phenotyped. This was carried out by collecting pooled urine samples over 8 h following PG administration. Proguanil and its major CYP2C19‐dependent metabolites were measured by high‐performance liquid chromatography. Metabolic ratios (MRs) were computed and employed in classifying subjects into poor or extensive metabolizers. Among SCD group, 130 (99.2%) were extensive metabolizers (EMs) and 1 (0.8%) was poor metabolizer (PM) of PG, while 95.7 and 4.3% non‐SCDs were EMs and PMs, respectively. MRs ranged from 0.02 to 8.70 for SCD EMs and from 0.22 to 8.33 for non‐SCD EMs. Two non‐SCDs with MRs of 18.18 and 25.76 and the SCD with MR of 16.77 regarded as PMs had earlier been genotyped as CYP2C19*2/*2. Poor metabolizers of proguanil in SCD patients are reported for the first time. Regardless of clinical significance, a difference in metabolic disposition of proguanil and CYP2C19 by SCDs and non‐SCDs was established.

States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.

Individual or whole parts of Persea Americana, Caesalpinia bonduc and Caesalpinia pulcherrima have been traditionally used for the treatment of various infectious diseases in West Africa. Methanolic extracts and fractions of these plants were screened for in vitro activity against L. donovani (promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells), T. brucei, Plasmodium falciparum (chloroquine sensitive and chloroquine resistant strains) and selected pathogenic microbes. With IC50 values less than 10 µg/mL, the extracts exhibited selective antileishmanial activity against, L. donovani Amastigote, and less potent effects against L. donovani Promastigote, L. donovani Amastigote + THP, and T. brucei blood stage trypamastigotes. Fractions of P. Americana and C. pulcherrima showed strong activities against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. With IC50 values ranging from 3.6 to 12 µg/mL, all fractions of C. pulcherrima exhibited significant antimicrobial activity especially against C. glabrata, C. krusei, S. aureus and P. aeruginosa (IC50 < 8 – 81 µg/mL). Crude extracts of P. Americana showed activity against C. glabrata, S. aureus and P. aeruginosa (IC50 22 – 86 µg/mL). These findings are important scientific support for traditional uses of these plants in infectious diseases and provide a strong basis for further studies towards anti-infective drug discovery from the plants. Acknowledgements: This work was in part supported by USAID/HED grant 153 – 6200BF A-15 – 01 to Prof A. Falodun, University of Benin.