The impact of catha edulis (vahl) forssk. ex endl. (celestraceae) (khat) on pharmacokinetics of clinically used drugs.

INTRODUCTION: Catha edulis (Vahl) Forssk. ex Endl. (Celestraceae) is used as a recreational drug on daily basis for its euphoric and psychostimulant effects. It is also chewed by individuals who are on medications, raising the possibility of drug-khat interaction. However, limited data are available in the literature, although clinically significant interactions are expected, as khat contains a complex mixture of pharmacologically active constituents. AREAS COVERED: It provides an overview of the phytochemistry, pharmacokinetics, pharmacodynamics, and pharmacogenetics of khat based on the literature mined from PubMed, Google Scholar, and Cochrane databases. It also presents a detailed account of drug-khat interactions with specific examples and their clinical significance. The interactions mainly occur at the pharmacokinetics level and particular attention is paid for the phases of absorption and cytochrome P450 enzyme-mediated metabolism. EXPERT OPINION: Despite the increasing trend of khat chewing with medications among the populace and the potential risk for the occurrence of clinically significant interactions, there is paucity of data in the literature demonstrating the magnitude of the risk. The available data, however, clearly demonstrate that the consequence of drug-khat interaction is dependent on genotype. Genotyping, where feasible, could be used to improve clinical outcome and minimize adverse reactions.

Arousal-Inducing Effect of Garcinia cambogia Peel Extract in Pentobarbital-Induced Sleep Test and Electroencephalographic Analysis.

Caffeine, a natural stimulant, is known to be effective for weight loss. On this basis, we screened the arousal-inducing effect of five dietary supplements with a weight loss effect (Garcinia cambogia, Coleus forskohlii, Camellia sinensis L., Irvingia gabonensis, and Malus pumila M.), of which the G. cambogia peel extract (GC) showed a significant arousal-inducing effect in the pentobarbital-induced sleep test in mice. This characteristic of GC was further evaluated by analysis of electroencephalogram and electromyogram in C57L/6N mice, and it was compared to that of the positive control, caffeine. Administration of GC (1500 mg/kg) significantly increased wakefulness and decreased non-rapid eye movement sleep, similar to that of caffeine (25 mg/kg), with GC and caffeine showing a significant increase in wakefulness at 2 and 6 h, respectively. Compared to that of caffeine, the shorter duration of efficacy of GC could be advantageous because of the lower possibility of sleep disturbance. Furthermore, the arousal-inducing effects of GC (1500 mg/kg) and caffeine (25 mg/kg) persisted throughout the chronic (3 weeks) administration study. This study, for the first time, revealed the arousal-inducing effect of GC. Our findings suggest that GC might be a promising natural stimulant with no side effects. In addition, it is preferential to take GC as a dietary supplement for weight loss during the daytime to avoid sleep disturbances owing to its arousal-inducing effect.

Biomedical analysis of New Psychoactive Substances (NPS) of natural origin.

New psychoactive substances (NPS) can be divided into two main groups: synthetic molecules and active principles of natural origin. With respect to this latter group, a wide range of alkaloids contained in plants, mainly from Asia and South America, can be included in the class of NPS of natural origin. The majority NPS of natural origin presents stimulant and/or hallucinogenic effects (e.g. Catha edulis and Ayahuasca, respectively) while few of them show sedative and relaxing properties (e.g. kratom). Few information is available in relation to the analytical identification of psychoactive principles contained in the plant material. Moreover, to our knowledge, scarce data are present in literature, about the characterization and quantification of the parent drug in biological matrices from intoxication and fatality cases. In addition, the metabolism of natural active principles has not been yet fully investigated for most of the psychoactive substances from plant material. Consequently, their identification is not frequently performed and produced metabolites are often unknown. To fill this gap, we reviewed the currently available analytical methodologies for the identification and quantification of NPS of natural origin in plant material and, whenever possible, in conventional and non-conventional biological matrices of intoxicated and dead subjects. The psychoactive principles contained in the following plants were investigated: Areca catechu, Argyreia nervosa, Ayahuasca, Catha edulis, Ipomoea violacea, Mandragora officinarum, Mitragyna speciosa, Pausinystalia yohimbe, Piper methisticum, Psilocybe, Rivea corymbosa, Salvia divinorum, Sceletium tortuosum, Lactuca virosa. From the results obtained, it can be evidenced that although several analytical methods for the simultaneous quantification of different molecules from the same plants have been developed and validated, a comprehensive method to detect active compounds from different natural specimens both in biological and non-biological matrices is still lacking.

Evaluating the hematological and clinical-chemistry parameters of kratom (Mitragyna speciosa) users in Malaysia.

ETHNOPHARMACOLOGICAL RELEVANCE: Kratom (Mitragyna speciosa Korth.) from the Rubiaceae family is an indigenous tropical medicinal tree of Southeast Asia. Kratom leaves have been used for decades in Malaysia and Thailand in traditional context for its perceived vast medicinal value, and as a mild stimulant among manual labourers. Kratom consumption has been reported to cause side-effects in kratom users. AIM OF THE STUDY: To evaluate kratom's effects towards hematological and clinical-chemistry parameters among regular kratom users in Malaysia. METHODS: A total of 77 subjects (n=58 regular kratom users, and n=19 healthy controls) participated in this cross-sectional study. All the surveys were conducted through face-to-face interview to elicit subject's socio-demographic characteristics and kratom use history. A full-blood test was also administered. Laboratory analysis was conducted using GC-MS to determine mitragynine content in the acquired kratom samples in order to relate mitragynine consumption with possible alterations in the blood parameters of kratom users. RESULTS: Findings showed that there were no significant differences in the hematological and clinical-chemistry parameters of traditional kratom users and healthy controls, except for HDL and LDL cholesterol values; these were found to be above the normal reference range for the former. Similarly, long-term kratom consumption (>5 years), and quantity of daily kratom use (≥3 ½ glasses; mitragynine content 76.3-114.8mg) did not appear to alter the hematological and biochemical parameters of kratom users. CONCLUSION: These data suggest that even long-term and heavy kratom consumption did not significantly alter the hematological and clinical-chemistry parameters of kratom users in a traditional setting.

An amphetamine isomer whose efficacy and safety in humans has never been studied, ß-methylphenylethylamine (BMPEA), is found in multiple dietary supplements.

The amphetamine isomer ß-methylphenylethylamine (BMPEA) was first synthesized in the early 1930s, but its efficacy and safety in humans has not been studied. Recently, the United States Food and Drug Administration (FDA) detected BMPEA in dietary supplements labelled as containing Acacia rigidula. Over a year after the FDA reported its findings, we analyzed Acacia rigidula dietary supplements to determine if BMPEA had been removed. Supplements were analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry. Diluted methanolic extract from each supplement was run three times and each data set obtained was analyzed using Agilent MassHunter Qualitative Analysis. The presence of BMPEA was confirmed by accurate mass, retention time and mass spectra match against a reference standard. Quantification of BMPEA was determined using an eight-point calibration curve of spiked standard to a matrix blank. Twenty-one brands of Acacia rigidula supplements were analyzed. More than half (11/21; 52.4%) of the Acacia rigidula supplement brands contained BMPEA. The stimulant was present at quantities such that consumers following recommended maximum daily servings would consume a maximum of 93.7 mg of BMPEA per day. Consumers of Acacia rigidula supplements may be exposed to pharmacological dosages of an amphetamine isomer that lacks evidence of safety in humans. The FDA should immediately warn consumers about BMPEA and take aggressive enforcement action to eliminate BMPEA in dietary supplements. Copyright © 2015 John Wiley & Sons, Ltd.

Bioactivity-guided fractionation of physical fatigue-attenuating components from Rubus parvifolius L.

Alleviation of fatigue has been emerging as a serious issue that requires urgent attention. Health professionals and sports physiologists have been looking for active natural products and synthetic compounds to overcome fatigue in humans. This study was designed to define the anti-fatigue property of Rubus parvifolius L. (RPL) by characterization of active constituents using a mouse forced swimming test model. Four RPL fractions with different polarities containing anti-fatigue activity were sequentially isolated from the n-butanol RPL extract, followed by elution of 50% ethanol-water fraction from D101 macroporous resin chromatography to obtain nigaichigoside F1, suavissimoside R1 and coreanoside F1. Active constituents of the 50% ethanol-water eluate of RPL were total saponins. The fractions were examined based on the effect on weight-loaded swimming capacity of mice. Serum levels of urea nitrogen (SUN), triglyceride fatty acids (TG), lactate dehydrogenase (LDH), lactic acid (LA), ammonia and hepatic glycogen (HG) were also examined for potential mechanisms underlying the anti-fatigue effect of RPL extracts. During the experiment, two inflammatory markers, interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) in serum, were measured. We found that total saponins from RPL possess potent capabilities to alleviate mouse fatigue induced by forced swimming and that nigaichigoside F1 was responsible for the pharmacological effect. The underlying mechanisms include delays of SUN and LA accumulation, a decrease in TG level by increasing fat consumption, increases in HG and LDH so that lactic acid accumulation and ammonia in the muscle were reduced, and suppression of increased immune activation and inflammatory cytokine production. Our findings will be helpful for functional identification of novel anti-fatigue components from natural medicinal herbs.

Analgesic, anti-inflammatory, and CNS depressant activities of new constituents of Nepeta clarkei.

Two new pentacyclic triterpenes named kirmanoic acid (1) and kurramanoic acid (2) have been isolated from the chloroform-soluble portion of the whole plant of Nepeta clarkei Hook. The structures of the two new compounds were assigned on the basis of their ¹H and ¹³C NMR spectra including two-dimensional NMR techniques such as COSY, HMQC, and HMBC experiments. Kirmanoic acid (1) was investigated for analgesic, anti-inflammatory, and CNS depressant activities. Interestingly kirmanoic acid (1) showed strong analgesic activity than standard drug in acetic induced writhing and formalin tests. Similarly kirmanoic acid (1) also showed strong anti-inflammatory activity than its standard drug. The gross behavioral study of kirmanoic acid (1) revealed that it exhibited mild CNS stimulant and muscle relaxant in the mice. Compound 1 showed a slight increase in Locomotor activity and possesses the antidepressant effect.

Analgesic activity of Heliopsis longipes and its effect on the nervous system.

Heliopsis longipes S.F. Blake (Asteraceae: Heliantheae) (chilcuague) is used in Mexican traditional medicine against parasites and to alleviate tooth and muscle pains. Its biocide effect has already been experimentally demonstrated; however, its analgesic action and its action on the nervous system (NS) have not been investigated yet. The objectives of this study were to evaluate the analgesic action of affinin and the H. longipes root ethanol extract, as well as their effects on the NS using an animal model. The ethanol extract was obtained by maceration, and affinin was purified from it through chromatographic techniques. Chemical and thermal analgesia were used to assess their analgesic proprieties. Irwin's test was used to evaluate their stimulating or depressing effects. The ethanol extract and affinin displayed analgesic action similar to ketorolac and stimulating effect comparable to caffeine on the nervous system of adult mice.

[General anesthesia during short operations in patients using the herbal psychogenic stimulant CAT (Catha edulis)].

The specific features of general anesthesia during short inpatient operations were performed in 85 patients who were regular CAT users owing to their national habits. According to the herbal psychogenic stimulant CAT dependence, the patients were divided into 3 groups. The findings indicate that propofol (2 mg/kg) in combination with isoflurane and premedication as diatepam (0.1-0.15 mg/kg) and fentanyl (1 mg/kg) is the anesthesia of choice in all group patients. Ketamine in combination with isoflurane may be used in the controls and Group 1 patients with mild CAT dependence. In patients with moderate and severe CAT dependence, ketamine should be considered to be contraindicated due to the development of adverse psychomotor and somatic reactions requiring monitoring and drug correction in an intensive care unit. The results of the study have been introduced into practice on choosing the modes of anesthesia at the Revolution Hospital, Republic of Yemen.

Capillary electrophoresis for caffeine and pyroglutamate determination in coffees study of the in vivo effect on learning and locomotor activity in mice.

In a preliminary study pyroglutamate showed to be over 10 times increased in some lyophilised coffees with respect to brewed or filtered coffees, and probably that increase is related to some stage of the industrial process. Pyroglutamate is known to have a number of remarkable cognitive enhancing effects, which could be also related to the properties of coffee traditionally associated to caffeine. Pyroglutamate improves memory and learning and has anti-anxiety effects in rats. Therefore, a method has been developed and validated for the simultaneous determination of caffeine and pyroglutamate in coffee by capillary electrophoresis. Separation conditions employed MECK conditions with 50 mM borate buffer at pH 9.5 with 130 mM SDS. The applied potential was 10 kV and detection was performed at 200 nm. Afterwards, 10 soluble coffees from the market were measured and caffeine and pyroglutamate levels were compared. Those coffees with higher pyroglutamate with or without caffeine were preliminarily tested for sedative/stimulant properties and cognition enhancing effects in mice. The most relevant finding was a partial reversal of scopolamine-induced amnesia in the passive avoidance paradigm after oral administration of one coffee.

Separation and determination of strychnine and brucine in Strychnos nux-vomica L. and its preparation by nonaqueous capillary electrophoresis.

An easy, rapid method for simultaneous determination of strychnine and brucine in Strychnos nux-vomica L. and its preparation was developed by nonaqueous capillary electrophoresis (NACE) without pretreatment for the first time. Optimum separation was achieved with a fused-silica capillary column (50 cmx75 microm i.d.) and a running buffer containing 30 mM ammonium acetate, 1.0% acetic acid and 15% acetonitrile (ACN) in methanol medium. The applied voltage was 30.0 kV. The analytes were detected by UV at 214 nm. The effects of concentration of ammonium acetate, acetic acid and organic modifier on electrophoretic behavior of the analytes were studied. The established method with sophoridine as internal standard was linear in the range of 5-1000 mg/mL for both strychnine and brucine. The extracts of Strychnos nux-vomica and its preparation could be directly injected for determination with recoveries ranging from 94.5 to 104%.

Chromatographic separation of (-)-ephedrine and (+)-pseudoephedrine in the traditional Chinese medicinal preparation Jiketing granule.

(-)-Ephedrine (EP) and (+)-Pseudoephedrine (PEP) in Jiketing granule were separated by TLC, RP-HPLC, GC, HPLC-MS, and the chromatographic phenomenon was interpreted by the topological indices. The observed chromatographic separations of investigated components were compared. This comparison indicated that simply methods as C18 RP-HPLC and GC are the more effective techniques, and more suitable than others for this preparation, for the separation of two alkaloids.

Coffee, decaffeinated coffee, tea and cancer of the colon and rectum: a review of epidemiological studies, 1990-2003.

The literature from 1990 to 2003 on the relation between coffee, decaffeinated coffee, tea and colorectal cancer risk has been reviewed. For the relation with coffee, three cohort (517 total cases) and nine case-control studies (7555 cases) analysed colon cancer; three cohort (307 cases) and four case-control studies (2704 cases) rectal cancer; six case-control studies (854 cases) colorectal cancer. For colon cancer most case-control studies found risk estimates below unity; the results are less clear for cohort studies. No relation emerged for rectal cancer. A meta-analysis, including five cohort and twelve case-control studies, reported a pooled relative risk of 0.76 (significant). Any methodological artefact is unlikely to account for the consistent inverse association in different countries and settings. Plausible biological explanations include coffee-related reductions of cholesterol, bile acids and neutral sterol secretion in the colon; antimutagenic properties of selected coffee components; increased colonic motility. Decaffeinated coffee was not related to either colon or rectal cancer in three case-control studies. No overall association between tea and either colon or rectal cancer risk emerged in seven cohort (1756 total cases of colon, 759 of rectal and 60 of colorectal cancer) and 12 case-control studies (8058 cases of colon, 4865 of rectal, 604 of colorectal cancer).

Plants and the central nervous system.

This review article draws the attention to the many species of plants possessing activity on the central nervous system (CNS). In fact, they cover the whole spectrum of central activity such as psychoanaleptic, psycholeptic and psychodysleptic effects, and several of these plants are currently used in therapeutics to treat human ailments. Among the psychoanaleptic (stimulant) plants, those utilized by human beings to reduce body weight [Ephedra spp. (Ma Huang), Paullinia spp. (guaraná), Catha edulis Forssk. (khat)] and plants used to improve general health conditions (plant adaptogens) were scrutinized. Many species of hallucinogenic (psychodysleptic) plants are used by humans throughout the world to achieve states of mind distortions; among those, a few have been used for therapeutic purposes, such as Cannabis sativa L., Tabernanthe iboga Baill. and the mixture of Psychotria viridis Ruiz and Pav. and Banisteriopsis caapi (Spruce ex Griseb.) C.V. Morton. Plants showing central psycholeptic activities, such as analgesic or anxiolytic actions (Passiflora incarnata L., Valeriana spp. and Piper methysticum G. Forst.), were also analysed.Finally, the use of crude or semipurified extracts of such plants instead of the active substances seemingly responsible for their therapeutic effect is discussed.

[Separation of alkaloids in tea by high-speed counter-current chromatography].

Alkaloids extracted from the green tea were separated by high-speed counter-current chromatography. A series of experiments have been performed to investigate effects of different solvent system. A system of CHCl3-CH3OH-NaH2PO4(23 mmol/L) = (4:3:2) was selected, in which the upper phase was used as the stationary phase, and the lower phase as mobile phase. When acidity of solvent system is pH 5.6, three chemical components are very efficiently isolated by one injection of 50 mg sample mixture. Analyzing the eluted fractions by TLC, we know that one is caffeine, and the other is theophylline. In comparing the separation results by high-speed counter-current chromatography with those by TLC, the advantages of this method is verified. It should find wide applications of this technology for the separation of crude mixture of plant components.