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[PMID]: 29520812
[Au] Autor:Raffa RB; Pergolizzi JV; Taylor R; Ossipov MH; NEMA Research Group
[Ad] Address:University of Arizona College of Pharmacy, Tucson, AZ, USA.
[Ti] Title:Nature's first "atypical opioids": Kratom and mitragynines.
[So] Source:J Clin Pharm Ther;, 2018 Mar 08.
[Is] ISSN:1365-2710
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:WHAT IS KNOWN AND OBJECTIVE: Advances in pain research have led to an understanding that many pains are driven by more than one underlying (patho)physiologic cause (ie, they are "multimechanistic") and that better pain relief is obtained with fewer adverse effects when an analgesic is correspondingly multimechanistic. At least two of the more-modern analgesics combine opioid and non-opioid mechanisms, and have become known as "atypical opioids." Less well known is that just as Nature evolved opioids, it also evolved atypical opioids, presaging modern drug discovery efforts. COMMENT: Traditional (typical) opioids are extracts or analogs of substances derived from the poppy plant. They produce their analgesic and adverse effects primarily through a single, opioid mechanism (albeit with individual differences). Two most recent analgesics were developed to have both an opioid mechanism and, a second, non-opioid mechanism of action (inhibition of monoamine neurotransmitter reuptake). Little known is that Nature had already evolved a plant source of compounds with the same properties. WHAT IS NEW AND CONCLUSION: As debate about the use and abuse potential of kratom swirls, conflicting, often contradicting, opinions are expressed. A review of the basic pharmacology of kratom reveals the explanation for the bifurcation in viewpoints: kratom has both opioid and non-opioid properties. Fascinatingly, just as the poppy plant (Papaver) evolved the typical opioids, Mitragyna evolved the mitragynines-Nature's "atypical opioids."
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher
[do] DOI:10.1111/jcpt.12676

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[PMID]: 29459087
[Au] Autor:Basiliere S; Bryand K; Kerrigan S
[Ad] Address:Department of Forensic Science, Sam Houston State University, Huntsville, TX 77341, United States.
[Ti] Title:Identification of five Mitragyna alkaloids in urine using liquid chromatography-quadrupole/time of flight mass spectrometry.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1080:11-19, 2018 Mar 30.
[Is] ISSN:1873-376X
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Mitragyna speciosa (Kratom) is a psychoactive plant that has recently emerged as a recreational drug. Mitragyna alkaloids are not within the scope of traditional forensic toxicology screening methods, which may contribute to under-reporting. Solid phase extraction (SPE) and liquid chromatography-quadrupole/time of flight mass spectrometry (LC-Q/TOF-MS) were used to identify five alkaloids in urine. Target analytes included the two known psychoactive compounds, mitragynine and 7-hydroxymitragynine, in addition to speciociliatine, speciogynine, and paynantheine. Two deuterated internal standards (mitragynine-D and 7-hydroxymitragynine-D ) were employed. Using traditional reversed phase chromatography all compounds and isomers were separated in 10 min. The procedure was validated in accordance with the Scientific Working Group for Forensic Toxicology (SWGTOX) Standard Practices for Method Validation. Extraction efficiencies were 63-96% and limits of quantitation were 0.5-1 ng/mL. Precision, bias and matrix effects were all within acceptable thresholds, with the exception of 7-hydroxymitragynine, which is notably unstable and unsuitable for quantitative analysis. In this paper we present a simultaneous quantitative analytical method for mitragynine, speciociliatine, speciogynine and paynantheine, and a qualitative assay for 7-hydroxymitragynine in urine using high resolution mass spectrometry (HRMS).
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:In-Process

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[PMID]: 29488268
[Au] Autor:Angkurawaranon C; Jiraporncharoen W; Likhitsathian S; Thaikla K; Kanato M; Perngparn U; Assanangkornchai S; Aramrattana A
[Ad] Address:Faculty of Medicine, Department of Family Medicine, Chiang Mai University, Chiang Mai, Thailand.
[Ti] Title:Trends in the use of illicit substances in Thailand: Results from national household surveys.
[So] Source:Drug Alcohol Rev;, 2018 Feb 27.
[Is] ISSN:1465-3362
[Cp] Country of publication:Australia
[La] Language:eng
[Ab] Abstract:INTRODUCTION AND AIMS: Thailand borders some of the world's largest methamphetamine and opioid producing countries and trafficking routes. Thailand's 'War on Drugs' campaign was launched in 2003. This study reports trends in illicit substance use in Thailand over the period 2001-2011. DESIGN AND METHODS: National Household surveys on illicit drug use were conducted in 2001, 2003, 2007, 2008 and 2011. A stratified multi-stage cluster random sampling technique was implemented for each survey. Provinces in four regions were systematically selected using a probability proportionate to the size of the targeted population. Participants were interviewed using structured questionnaires on their history of substance use. RESULTS: The prevalence of illicit drug use within the past drastically decreased from 4.5% in 2001 to 1.0% in 2003 (P < 0.05). Since 2003, the prevalence of illicit use within the past year varied between 1.0% and 1.3%. By 2011, it was estimated that 0.84% have used kratom (a substance derived from Mitragyna speciosa) within the past year. Around 0.20% and 0.19% reported using cannibis and yaba (metamphetamine tablet) within a year of the 2011 survey. Other types of illicit drugs were less commonly used in Thailand. DISCUSSION AND CONCLUSIONS: There was a decrease in prevalence of illicit drug use within the past year between 2001 and 2003 in Thailand. Since 2003, the past year prelavence of illicit drug use has remained relatively stable. From 2001 to 2011, cannabis, kratom and yaba have remained the three most commonly reported types of illicit drugs used in Thailand.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180228
[Lr] Last revision date:180228
[St] Status:Publisher
[do] DOI:10.1111/dar.12689

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[PMID]: 29255059
[Au] Autor:White CM
[Ad] Address:University of Connecticut School of Pharmacy, Storrs, CT charles.white@uconn.edu.
[Ti] Title:Pharmacologic and clinical assessment of kratom.
[So] Source:Am J Health Syst Pharm;75(5):261-267, 2018 Mar 01.
[Is] ISSN:1535-2900
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE: This article reviews the pharmacology, clinical utility, adverse effects, and abuse potential of kratom. SUMMARY: The leaves of contain the biologically active alkaloids of kratom. Kratom exerts opioid and α-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. There are no published human pharmacologic, pharmacokinetic, or drug interaction studies on kratom or mitragynine, making it virtually impossible to fully understand kratom's therapeutic potential and risks and the populations most likely to benefit or experience harm from its use. Kratom has been used to ameliorate opioid withdrawal symptoms but also induces withdrawal. Human pharmacologic, pharmacokinetic, and clinical data are of low quality, precluding any firm conclusions regarding safety and efficacy. Respiratory depression has not been commonly reported, but kratom does cause a host of adverse effects without clear guidance for how they should be treated. There are numerous assessments where people have been unable to stop using kratom therapy, and withdrawal signs and symptoms are problematic. Kratom does not appear in normal drug screens and, when taken with other substances of abuse, may not be recognized. Thirty-six deaths have been attributed to kratom, and the Food and Drug Administration issued a public health warning about the substance in November 2017. CONCLUSION: Kratom exerts opioid and α-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. Human pharmacologic, pharmacokinetic, and clinical data are of low quality, precluding any firm conclusions regarding safety and efficacy.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1712
[Cu] Class update date: 180223
[Lr] Last revision date:180223
[St] Status:In-Data-Review
[do] DOI:10.2146/ajhp161035

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[PMID]: 29248691
[Au] Autor:Swogger MT; Walsh Z
[Ad] Address:Department of Psychiatry, University of Rochester Medical 300 Center, Crittenden Blvd., Rochester, NY, USA. Electronic address: marc_swogger@urmc.rochester.edu.
[Ti] Title:Kratom use and mental health: A systematic review.
[So] Source:Drug Alcohol Depend;183:134-140, 2018 Feb 01.
[Is] ISSN:1879-0046
[Cp] Country of publication:Ireland
[La] Language:eng
[Ab] Abstract:BACKGROUND: Kratom (Mitragyna speciosa) is a psychoactive plant native to Southeastern Asia that is receiving increased international attention as a potential therapeutic agent. While much of the limited scientific research on kratom is focused on its analgesic potential, kratom use also has important risks and benefits in the domain of mental health. METHODS: We conducted a comprehensive systematic review of all studies on kratom use and mental health published between January 1960 and July 2017. RESULTS: Findings indicate kratom's potential as a harm reduction tool, most notably as a substitute for opioids among people who are addicted. Kratom also enhances mood and relieves anxiety among many users. For many, kratom's negative mental health effects - primarily withdrawal symptoms - appear to be mild relative to those of opioids. For some users, however, withdrawal is highly uncomfortable and maintaining abstinence becomes difficult. CONCLUSION: Results inform clinicians working in the mental health and substance use fields, policy-makers, and researchers about the mental health effects of this plant.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1712
[Cu] Class update date: 180207
[Lr] Last revision date:180207
[St] Status:In-Data-Review

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[PMID]: 29248450
[Au] Autor:Singh D; Müller CP; Murugaiyah V; Hamid SBS; Vicknasingam BK; Avery B; Chear NJY; Mansor SM
[Ad] Address:Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. Electronic address: darshan@usm.my.
[Ti] Title:Evaluating the hematological and clinical-chemistry parameters of kratom (Mitragyna speciosa) users in Malaysia.
[So] Source:J Ethnopharmacol;214:197-206, 2018 Mar 25.
[Is] ISSN:1872-7573
[Cp] Country of publication:Ireland
[La] Language:eng
[Ab] Abstract: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.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180115
[Lr] Last revision date:180115
[St] Status:In-Process

  7 / 247 MEDLINE  
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[PMID]: 29076424
[Au] Autor:Kong WM; Chik Z; Mohamed Z; Alshawsh MA
[Ad] Address:Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur. Malaysia.
[Ti] Title:Physicochemical Characterization of Mitragyna speciosa Alkaloid Extract and Mitragynine Using In Vitro High Throughput Assays.
[So] Source:Comb Chem High Throughput Screen;, 2017 Oct 26.
[Is] ISSN:1875-5402
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Mitragynine, a major active alkaloid of Mitragyna speciosa, acts as an agonist on µ-opioid receptors, producing effects similar to morphine and other opioids. It has been traditionally utilized to alleviate opiate withdrawal symptoms. Besides consideration about potency and selectivity, a good drug must possess a suitable pharmacokinetic profile, with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile, in order to have a high chance of success in clinical trials. The purity of mitragynine in a Mitragyna speciosa alkaloid extract (MSAE) was determined using Ultra-Fast Liquid Chromatography (UFLC). In vitro high throughput ADME-Tox studies such as aqueous solubility, plasma protein binding, metabolic stability, permeability and cytotoxicity tests were carried out to analyze the physicochemical properties of MSAE and mitragynine. The UFLC quantification revealed that the purity of mitragynine in the MSAE was 40.9%. MSAE and mitragynine are highly soluble in aqueous solution at pH 4.0 but less soluble at pH 7.4. A parallel artificial membrane permeability assay demonstrated that it is extensively absorbed through the semi-permeable membrane at pH 7.4 but very poorly at pH 4.0. Both are relatively highly bound to plasma proteins (> 85 % bound) and are metabolically stable to liver microsomes (> 84 % remained unchanged). In comparison to MSAE, mitragynine showed higher cytotoxicity against WRL 68, HepG2 and Clone 9 hepatocytes after 72 h treatment. The obtained ADME and cytotoxicity data demonstrated that both MSAE and mitragynine have poor bioavailability and have the potential to be significantly cytotoxic.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1710
[Cu] Class update date: 171027
[Lr] Last revision date:171027
[St] Status:Publisher
[do] DOI:10.2174/1386207320666171026121820

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[PMID]: 29071751
[Au] Autor:Manda VK; Avula B; Dale OR; Ali Z; Khan IA; Walker LA; Khan SI
[Ad] Address:National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, Oxford, MS, 38677, USA.
[Ti] Title:PXR mediated induction of CYP3A4, CYP1A2, and P-gp by Mitragyna speciosa and its alkaloids.
[So] Source:Phytother Res;, 2017 Oct 26.
[Is] ISSN:1099-1573
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Kratom (Mitragyna speciosa), a native herb of Southeast Asia, is widely known for its psychoactive properties. Recent increase in the use of kratom as a recreational drug has increased the risk of its interaction with conventional drugs if taken concomitantly. A few reports are available related to the effects of kratom on the activity of cytochrome P450 enzymes (CYPs), but there are no reports of its effects on pregnane X receptor (PXR), a transcription factor that regulates the expression of CYPs and P-glycoprotein (P-gp). This study was carried out to evaluate the effects of a methanolic extract of kratom leaves, an alkaloid rich fraction and its 5 indole and 4 oxindole alkaloids on PXR activation and the resulting changes in the mRNA expression of PXR target genes (CYP3A4, CYP1A2, and P-gp). A significant activation of PXR was observed by the extract (3-fold), alkaloidal fraction (4-fold) and all 9 alkaloids (4- to 6-fold) that was associated with an increased mRNA expression which resulted into an increase in the activity of CYP3A4, CYP1A2, and P-gp. These results indicate that high consumption of Mitragyna speciosa extract along with the conventional drugs may lead to potential herb-drug interactions due to its effects on PXR.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1710
[Cu] Class update date: 171026
[Lr] Last revision date:171026
[St] Status:Publisher
[do] DOI:10.1002/ptr.5942

  9 / 247 MEDLINE  
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[PMID]: 28966251
[Au] Autor:Matsunaga T; Morikawa Y; Kamase K; Horinouchi M; Sasajima Y; Suenami K; Sato K; Takekoshi Y; Endo S; El-Kabbani O; Ikari A
[Ad] Address:Laboratory of Biochemistry, Gifu Pharmaceutical University.
[Ti] Title:Enhancement of Endothelial Barrier Permeability by Mitragynine.
[So] Source:Biol Pharm Bull;40(10):1779-1783, 2017.
[Is] ISSN:1347-5215
[Cp] Country of publication:Japan
[La] Language:eng
[Ab] Abstract:Persistent inhalation of mitragynine (MG), a major alkaloid in the leaves of Mitragyna speciosa, causes various systemic adverse effects such as seizure, diarrhea and arthralgias, but its toxicity to endothelial cells and effects on barrier function of the cells are poorly understood. In this study, we compared toxicities of MG and mitraphylline, another constituent of the leaves, against human aortic endothelial (HAE), bronchial BEAS-2B, neuronal SK-N-SH, hepatic HepG2, kidney HEK293, gastric MKN45, colon DLD1, lung A549, breast MCF7 and prostate LNCaP cells, and found that MG, but not mitraphylline, shows higher toxicity to HAE cells compared to the other cells. Forty-eight-hours incubation of HAE cells with a high concentration of MG (60 µM) provoked apoptotic cell death, which was probably due to signaling through enhanced reactive oxygen species (ROS) generation and resultant caspase activation. Treatment of the cells with MG at sublethal concentrations less than 20 µM significantly lowered transendothelial electrical resistance and elevated paracellular permeability, without affecting the cell viability. In addition, the MG-elicited lowering of the resistance was abolished by a ROS inhibitor N-acetyl-L-cysteine and augmented by H O and 9,10-phenanthrenequinone, which generates ROS through its redox cycle. These results suggest the contribution of ROS generation to the increase in endothelial barrier permeability.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1710
[Cu] Class update date: 171002
[Lr] Last revision date:171002
[St] Status:In-Process
[do] DOI:10.1248/bpb.b17-00117

  10 / 247 MEDLINE  
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[PMID]: 28950813
[Au] Autor:Chin KY; Mark-Lee WF
[Ad] Address:Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia. Cheras, Kuala Lumpur. Malaysia.
[Ti] Title:A Review on the Antinociceptive Effects of Mitragyna speciosa and Its Derivatives in Animal Model.
[So] Source:Curr Drug Targets;, 2017 Sep 25.
[Is] ISSN:1873-5592
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Mitragyna speciosa is a tropical plant with narcotic effects. The antinociceptive effects of its crude extracts, bioactive compounds and structurally modified derivatives have been examined in rodent models. This review aims to summarize the evidence on the antinociceptive effects of M. speciosa and its derivatives and explore whether they can offer an alternative to morphine in pain management. Methanolic and alkaloid extracts of M. speciosa were shown to attenuate the nociceptive response in rodents. Mitragynine and 7-hydroxymitragynine offered better antinociceptive effects than crude extracts. Structurally modified derivatives of 7-hydroxymitragynine, such as MGM-9, MGM-15, MGM-16, demonstrated superior antinociceptive effects compared to morphine. M. speciosa and its derivatives mainly act on the opioid receptor, but receptor subtypes specificity differs between each compounds. The tolerance and adverse side effects of M. speciosa and its derivatives are similar with morphine. The affinity of MGM-9 on kappa-opioid receptor could potentially limit the effects of drug dependence. In conclusion, M speciosa derivatives can offer alternatives to morphine in controlling chronic pain. Structural modification of mitragynine and 7-hydroxymitragynine can generate compounds with higher potency and lesser side-effects. Human clinical trials are required to validate the use of these compounds in clinical setting.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1709
[Cu] Class update date: 170927
[Lr] Last revision date:170927
[St] Status:Publisher
[do] DOI:10.2174/1389450118666170925154025


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