Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 101
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Curr Opin Psychiatry ; 33(4): 312-318, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32452943

RESUMO

PURPOSE OF REVIEW: To inform readers about the increasingly popular Western dietary supplement, kratom (Mitragyna speciosa) and how the products are available in the Western world compared with traditional Southeast Asian use. Kratom has been traditionally used for increasing stamina of outdoor laborers (farmers), mood enhancement, pain, and opium addiction. Interestingly, kratom has been reported to have a paradoxical effect in that stimulant feelings, and sedative feelings can be obtained depending on the amount utilized. There are several biologically active alkaloids present in kratom. RECENT FINDINGS: Recent studies have been focused on the interactions of mitragynine, the most abundant alkaloid, and opioid-like effects. This has been driven by the harm that kratom products have produced in the Western world, in stark contrast to the lack of harm in Southeast Asian traditional use over centuries. Many users in the Western world ingest kratom for mood enhancement and/or to ween themselves from prescription or illicit opioids. Highly concentrated products and recreational use and misuse have resulted in individuals pushing doses to levels that have not been imagined or ever studied in animal, let alone humans. SUMMARY: Kratom, as a preparation and how it is utilized is different around the world.

2.
J Agric Food Chem ; 68(22): 6058-6064, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32392412

RESUMO

A field study was performed to investigate the development of cannabinoids in flowers of industrial hemp using three day-length-sensitive and two day-length-neutral varieties. Flower samples were analyzed for cannabinoids on a weekly basis from 2 to 4 weeks postanthesis to plant senescence. Results indicate that total THC, CBD, and CBG significantly increased as flowers matured, reaching the greatest concentration during 6 to 7 weeks postanthesis. After a plateau stage of varied length for different varieties, the peak concentrations declined as plants senesced. Total THC was above the 0.3% threshold from 4 weeks postanthesis to the end of the growing season for day-length-sensitive varieties, but this only occurred during 6 to 7 weeks postanthesis for day-length-neutral varieties. The CBD/THC ratio in flowers dynamically changed during the entire reproductive stage for all of the evaluated varieties. The current study provides vital information for successful cultivation of industrial hemp.

3.
Toxicol Lett ; 319: 148-154, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707106

RESUMO

In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC50) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (Ki) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC50, 2.2 and 4.2 µM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the Ki were found to be 1.1 and 2.8 µM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.


Assuntos
Alcaloides/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Medicamentosas , Mitragyna/química , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Isoenzimas/efeitos dos fármacos , Isoenzimas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo
4.
J Pharm Biomed Anal ; 180: 113019, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31838282

RESUMO

Corynantheidine, a minor alkaloid found in Mitragyna speciosa (Korth.) Havil, has been shown to bind to opioid receptors and act as a functional opioid antagonist, but its unique contribution to the overall properties of kratom remains relatively unexplored. The first validated bioanalytical method for the quantification of corynantheidine in rat plasma is described. The method was linear in the dynamic range from 1-500 ng/mL, requires a small plasma sample volume (25 µL), and a simple protein precipitation method for extraction of the analyte. The separation was achieved with Waters BEH C18 2.1 × 50 mm column and the 3-minute gradient of 10 mM ammonium acetate buffer (pH = 3.5) and acetonitrile as mobile phase. The method was validated in terms of accuracy, precision, selectivity, sensitivity, recovery, stability, and dilution integrity. It was applied to the analysis of the male Sprague Dawley rat plasma samples obtained during pharmacokinetic studies of corynantheidine administered both intravenously (I.V.) and orally (P.O.) (2.5 mg/kg and 20 mg/kg, respectively). The non-compartmental analysis performed in Certara Phoenix® yielded the following parameters: clearance 884.1 ±â€¯32.3 mL/h, apparent volume of distribution 8.0 ±â€¯1.2 L, exposure up to the last measured time point 640.3 ±â€¯24.0 h*ng/mL, and a mean residence time of 3.0 ±â€¯0.2 h with I.V. dose. The maximum observed concentration after a P.O. dose of 213.4 ±â€¯40.4 ng/mL was detected at 4.1 ±â€¯1.3 h with a mean residence time of 8.8 ±â€¯1.8 h. Absolute oral bioavailability was 49.9 ±â€¯16.4 %. Corynantheidine demonstrated adequate oral bioavailability, prolonged absorption and exposure, and an extensive extravascular distribution. In addition, imaging mass spectrometry analysis of the brain tissue was performed to evaluate the distribution of the compound in the brain. Corynantheidine was detected in the corpus callosum and some regions of the hippocampus.

5.
J Ethnopharmacol ; 249: 112462, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816368

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kratom (Mitragyna speciosa) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid poly-drug users were using kratom to abstain from opioids. AIM OF THE STUDY: To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia. MATERIALS AND METHODS: A total of 204 opioid poly-drug users (142 current users vs. 62 former users) with current kratom use history were enrolled into this cross-sectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample. RESULTS: Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid poly-drug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21-4.11; p < 0.009). Similarly, there were no significant differences in the duration (OR: 1.1: 0.62-2.03; p < 0.708), daily quantity (OR: 1.5: 0.85-2.82; p < 0.154) or frequency of kratom use between current and former opioid poly-drug users (OR: 1.1: 0.62-2.06; p < 0.680). While both current and former opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81-10.18; p < 0.0001). In contrast, former opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04-3.50; p < 0.035). Results from the UPLC-MS/MS analysis indicated the major alkaloids present in the representative kratom street sample (of approximately 300 mL of brewed kratom) were mitragynine, followed by paynantheine, speciociliatine and speciogynine, as well as low levels of 7-hydroxymitragynine. CONCLUSIONS: Both current and former opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19 mg of mitragynine) to overcome opioid poly-drug use problems.

6.
J Med Chem ; 63(1): 433-439, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31834797

RESUMO

Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.

7.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121875, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790916

RESUMO

The nonpeptide small molecule, MES207, exhibits 17-fold preferential binding to the neuropeptide FF receptor 1 (NPFFR1) over NPFFR2 and shows antagonist functionality at NPFF receptors. In order to further the development of MES207 as a NPFFR1 probe, an UPLC-MS/MS bioanalytical method was developed and validated to quantify MES207 in rat plasma for a linearity range of 3-200 ng/mL. The method was applied in the analysis of the plasma, brain, and urine samples collected during pharmacokinetic studies in healthy male and female Sprague Dawley rats. The animals were dosed through oral gavage (50 mg/kg) and intravenously (2.5 mg/kg). Test samples were analyzed using the validated bioanalytical method to generate plasma concentration-time profiles. The results were further subjected to non-compartmental analysis using Phoenix 6.4®. MES207 exhibits a large volume of distribution (1.2 ±â€¯0.6 L), high clearance (0.8 ±â€¯0.1 L/h), and a poor oral bioavailability (1.7 ±â€¯0.4%). The compound also showed a multiple peak phenomenon with a very short absorption phase. It appears that gender does not significantly influence the differences in pharmacokinetic parameters of this NPFF probe.


Assuntos
Guanidinas/sangue , Guanidinas/farmacocinética , Piperidinas/sangue , Piperidinas/farmacocinética , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Feminino , Guanidinas/química , Limite de Detecção , Modelos Lineares , Masculino , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
8.
Nat Med ; 25(12): 1938-1947, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792461

RESUMO

B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.


Assuntos
Compostos de Anilina/farmacologia , Sulfonamidas/farmacologia , Trombocitopenia/tratamento farmacológico , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína bcl-X/genética , Compostos de Anilina/química , Animais , Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Proteólise , Sulfonamidas/química , Trombocitopenia/genética , Trombocitopenia/patologia , Proteína bcl-X/antagonistas & inibidores
9.
Front Pharmacol ; 10: 678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258480

RESUMO

Sigma-1 receptors (S1R) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selective CM-304 and its analog the non-selective S1R/S2R antagonist AZ-66. Inhibition of thermal, induced chemical or inflammatory pain, as well as the allodynia resulting from chronic nerve constriction injury (CCI) and cisplatin exposure as models of neuropathic pain were assessed in male mice. Both sigma receptor antagonists dose-dependently (10-45 mg/kg, i.p.) reduced allodynia in the CCI and cisplatin neuropathic pain models, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg, i.p.), although AZ-66 demonstrated a much longer duration of action. Both CM-304 and AZ-66 produced antinociception in the writhing test [0.48 (0.09-1.82) and 2.31 (1.02-4.81) mg/kg, i.p., respectively] equivalent to morphine [1.75 (0.31-7.55) mg/kg, i.p.]. Likewise, pretreatment (i.p.) with either sigma-receptor antagonist dose-dependently produced antinociception in the formalin paw assay of inflammatory pain. However, CM-304 [17.5 (12.7-25.2) mg/kg, i.p.) and AZ-66 [11.6 (8.29-15.6) mg/kg, i.p.) were less efficacious than morphine [3.87 (2.85-5.18) mg/kg, i.p.] in the 55°C warm-water tail-withdrawal assay. While AZ-66 exhibited modest sedative effects in a rotarod assay and conditioned place aversion, CM-304 did not produce significant effects in the place conditioning assay. Overall, these results demonstrate the S1R selective antagonist CM-304 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, supporting the use of S1R antagonists as potential treatments for chronic pain.

10.
Psychopharmacology (Berl) ; 236(9): 2725-2734, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31098655

RESUMO

RATIONALE: Mitragyna speciosa (kratom) may hold promise as both an analgesic and treatment for opioid use disorder. Mitragynine, its primary alkaloid constituent, is an opioid receptor ligand. However, the extent to which the in vivo effects of mitragynine are mediated by opioid receptors, or whether mitragynine interacts with other opioid agonists, is not fully established. OBJECTIVES: The effects of mitragynine and the prototypical opioid agonist morphine were compared for their capacity to decrease operant responding for food delivery, and to increase response latency to a thermal stimulus. METHODS: Male and female Sprague-Dawley rats responded under a multiple cycle fixed ratio 10 schedule of food delivery and were tested on a hot plate (52 °C) immediately after each cycle. Morphine and mitragynine were administered alone, in combination with each other, and in combination with the opioid antagonist naltrexone. RESULTS: Morphine and mitragynine dose-dependently decreased schedule-controlled responding; the ED50 values were 7.3 and 31.5 mg/kg, respectively. Both drugs increased thermal antinociception; the ED50 value for morphine was 18.3. Further, doses of naltrexone that antagonized morphine did not antagonize mitragynine. Mitragynine (17.8 mg/kg) did not alter the rate-decreasing or antinociceptive effects of morphine. CONCLUSIONS: The antinociceptive effects of mitragynine and morphine occur at doses larger than those that disrupt learned behavior. Opioid receptors do not appear to mediate the disruptive effects of mitragynine on learned behavior. Mitragynine had lesser antinociceptive effects than morphine, and these did not appear to be mediated by opioid receptors. The pharmacology of mitragynine includes a substantial non-opioid mechanism.


Assuntos
Analgésicos/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Alcaloides de Triptamina e Secologanina/farmacologia , Analgésicos Opioides/farmacologia , Animais , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Mitragyna , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/agonistas
11.
Int J Drug Policy ; 70: 70-77, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31103778

RESUMO

Kratom (Mitragyna speciosa) is a tree-like plant indigenous to Southeast Asia. Its leaves, and the teas brewed from them have long been used by people in that region to stave off fatigue and to manage pain and opioid withdrawal. Evidence suggests kratom is being increasingly used by people in the United States and Europe for the self-management of opioid withdrawal and treatment of pain. Recent studies have confirmed that kratom and its chemical constituents have potentially useful pharmacological actions. However, there have also been increasing numbers of reports of adverse effects resulting from use of kratom products. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule I Controlled Substances, a move that triggered a massive response from pro-kratom advocates. The debate regarding the risks, and benefits and safety of kratom continues to intensify. Kratom proponents tout kratom as a safer and less addictive alternative to opioids for the management of pain and opioid addiction. The anti-kratom faction argues that kratom, itself, is a dangerous and addictive drug that ought to be banned. Given the widespread use of kratom and the extensive media attention it is receiving, it is important for physicians, scientists and policy makers to be knowledgeable about the subject. The purpose of this commentary is to update readers about recent developments and controversies in this rapidly evolving area. All of the authors are engaged in various aspects of kratom research and it is our intention to provide a fair and balanced overview that can form the basis for informed decisions on kratom policy. Our conclusions from these analyses are: (a) User reports and results of preclinical studies in animals strongly suggest that kratom and its main constituent alkaloid, mitragynine may have useful activity in alleviating pain and managing symptoms of opioid withdrawal, even though well-controlled clinical trials have yet to be done. (b) Even though kratom lacks many of the toxicities of classic opioids, there are legitimate concerns about the safety and lack of quality control of purported "kratom" products that are being sold in the US. (c) The issues regarding the safety and efficacy of kratom and its mitragynine constituent can only be resolved by additional research. Classification of the Mitragyna alkaloids as Schedule I controlled substances would substantially impede this important research on kratom.


Assuntos
Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Mitragyna/efeitos adversos , Extratos Vegetais/efeitos adversos , Extratos Vegetais/uso terapêutico , Alcaloides de Triptamina e Secologanina/efeitos adversos , Animais , Humanos , Extratos Vegetais/farmacologia , Folhas de Planta/efeitos adversos , Alcaloides de Triptamina e Secologanina/farmacologia , Alcaloides de Triptamina e Secologanina/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico
12.
Drug Test Anal ; 11(8): 1162-1171, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30997725

RESUMO

Kratom (Mitragyna speciosa) is a psychoactive plant popular in the United States for the self-treatment of pain and opioid addiction. For standardization and quality control of raw and commercial kratom products, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of ten key alkaloids, namely: corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine, mitragynine, mitraphylline, paynantheine, speciociliatine, and speciogynine. Chromatographic separation of diastereomers, or alkaloids sharing same ion transitions, was achieved on an Acquity BEH C18 column with a gradient elution using a mobile phase containing acetonitrile and aqueous ammonium acetate buffer (10mM, pH 3.5). The developed method was linear over a concentration range of 1-200 ng/mL for each alkaloid. The total analysis time per sample was 22.5 minutes. The analytical method was validated for accuracy, precision, robustness, and stability. After successful validation, the method was applied for the quantification of kratom alkaloids in alkaloid-rich fractions, ethanolic extracts, lyophilized teas, and commercial products. Mitragynine (0.7%-38.7% w/w), paynantheine (0.3%-12.8% w/w), speciociliatine (0.4%-12.3% w/w), and speciogynine (0.1%-5.3% w/w) were the major alkaloids in the analyzed kratom products/extracts. Minor kratom alkaloids (corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine) were also quantified (0.01%-2.8% w/w) in the analyzed products; however mitraphylline was below the lower limit of quantification in all analyses.


Assuntos
Alcaloides/análise , Mitragyna/química , Extratos Vegetais/química , Folhas de Planta/química , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Espectrometria de Massas em Tandem/métodos
13.
Eur J Med Chem ; 165: 250-257, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30685525

RESUMO

Sigma receptors (σRs) are considered to be a significant and valid target for developing new medications to address several diseases. Their potential involvement in numerous central nervous system disorders, neuropathic pain, addiction, and cancer has been extensively reported. In particular, the σ2R has been identified as potential target for the development of pharmaceutical agents intended to treat the negative effects associated with drugs of abuse. As a continuation of our previous efforts to develop new selective σ2R ligands, a series of benzimidazolone derivatives were designed, synthesized, and characterized. The newly synthesized ligands were evaluated through in vitro radioligand binding assays to determine their affinity and selectivity towards both σ1 and σ2 receptors. Several derivatives displayed high affinity for the σ2R (Ki = 0.66-68.5 nM) and varied from preferring to selective, compared to σ1R (σ1/σ2 = 5.8-1139). Among them, compound 1-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-3-propyl-1,3-dihydrobenzimidazol-2-one dihydrochloride (14) displayed the ability to produce a dose-dependent reduction in the convulsive effects of cocaine in a rodent model after injecting 10 mg/kg (i.p.). These preliminary results support the use of selective σ2R ligands in the development of useful pharmacological tools or potential pharmacotherapies for cocaine toxicity.


Assuntos
Benzimidazóis/metabolismo , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Ligantes , Receptores sigma/metabolismo , Animais , Benzimidazóis/química , Humanos , Ligação Proteica , Ensaio Radioligante , Convulsões/prevenção & controle , Relação Estrutura-Atividade , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
14.
Planta Med ; 85(4): 340-346, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30452072

RESUMO

Kratom (Mitragyna speciosa) has been examined for its opioid activity, especially for the treatment of opioid withdrawal and pain. Mitragynine, the most abundant alkaloid in kratom, is thought to be the major psychoactive alkaloid. An HPLC method was developed for the quantification of mitragynine in kratom leaf extracts. In addition, a multiple reaction mode based UPLC-MS/MS method was developed and validated for the quantification of mitragynine in rat plasma. Pharmacokinetic studies were performed by comparing a single intravenous dose of mitragynine (5 mg/kg, mitragynine hydrochloride) to a single oral dose of mitragynine (20 mg/kg, mitragynine hydrochloride), lyophilized kratom tea, and the organic fraction of the lyophilized kratom tea at an equivalent mitragynine dose of 20 mg/kg in rats. After intravenous administration, mitragynine exhibited a biexponential decrease in the concentration-time profile, indicating the fast distribution of mitragynine from the systemic circulation or central compartment to the peripheral compartments. Mitragynine hydrochloride, lyophilized kratom tea, and the lyophilized kratom tea organic fraction were dosed orally and the absolute oral bioavailability of mitragynine in rats was found to be 1.5- and 1.8-fold higher than that of mitragynine dosed alone. The results provide evidence that an equivalent oral dose of the traditional preparation (lyophilized kratom tea) and formulated/manufactured products (organic fraction) of kratom leaves provide better systemic exposure of mitragynine than that of mitragynine dosed alone.


Assuntos
Mitragyna/química , Extratos Vegetais/farmacocinética , Folhas de Planta/química , Alcaloides de Triptamina e Secologanina/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Trânsito Gastrointestinal , Injeções Intravenosas , Masculino , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Alcaloides de Triptamina e Secologanina/administração & dosagem , Alcaloides de Triptamina e Secologanina/sangue , Alcaloides de Triptamina e Secologanina/isolamento & purificação
15.
Addict Biol ; 24(5): 874-885, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29949228

RESUMO

Kratom, derived from the plant Mitragyna speciosa, is receiving increased attention as an alternative to traditional opiates and as a replacement therapy for opiate dependence. Mitragynine (MG) and 7-hydroxymitragynine (7-HMG) are major psychoactive constituents of kratom. While MG and 7-HMG share behavioral and analgesic properties with morphine, their reinforcing effects have not been examined to date. 7-HMG, but not MG, substituted for morphine self-administration in a dose-dependent manner in the rat self-administration paradigm. Following the substitution procedure, re-assessment of morphine self-administration revealed a significant increase following 7-HMG and a significant decrease following MG substitution. In a separate cohort, 7-HMG, but not MG, engendered and maintained intravenous self-administration in a dose-dependent manner. The effects of pretreatment with nalxonaxine (NLXZ), a µ1 opiate receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7-HMG and morphine self-administration were also examined. Both NLXZ and NTI reduced 7-HMG self-administration, whereas only NLXZ decreased morphine intake. The present results are the first to demonstrate that 7-HMG is readily self-administered, and the reinforcing effects of 7-HMG are mediated in part by µ and δ opiate receptors. In addition, prior exposure to 7-HMG increased subsequent morphine intake whereas prior exposure to MG decreased morphine intake. The present findings indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal, whereas 7-HMG should be considered a kratom constituent with high abuse potential that may also increase the intake of other opiates.

16.
J Pharmacol Exp Ther ; 368(2): 272-281, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30530624

RESUMO

Sigma-2 receptors, recently identified as TMEM97, have been implicated in cancer and neurodegenerative disease. Structurally distinct sigma-2 receptor ligands induce cell death in tumor cells, linking sigma-2 receptors to apoptotic pathways. Recently, we reported that sigma-2 receptors can also stimulate glycolytic hallmarks, effects consistent with a prosurvival function and upregulation in cancer cells. Both apoptotic and metabolically stimulative effects were observed with compounds related to the canonical sigma-2 antagonist SN79. Here we investigate a series of 6-substituted SN79 analogs to assess the structural determinants governing these divergent effects. Substitutions on the benzoxazolone ring of the core SN79 structure resulted in high-affinity sigma-2 receptor ligands (K i = 0.56-17.9 nM), with replacement of the heterocyclic oxygen by N-methyl (producing N-methylbenzimidazolones) generally decreasing sigma-1 affinity and a sulfur substitution (producing benzothiazolones) imparting high affinity at both subtypes, lowering subtype selectivity. Substitution at the 6-position with COCH3, NO2, NH2, or F resulted in ligands that were not cytotoxic. Five of these ligands induced an increase in metabolic activity, as measured by increased reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) in human SK-N-SH neuroblastoma cells, further supporting a role for sigma-2 receptors in metabolism. Substitution with 6-isothiocyanate resulted in ligands that were sigma-2 selective and that irreversibly bound to the sigma-2 receptor, but not to the sigma-1 receptor. These ligands induced cell death upon both acute and continuous treatment (EC50 = 7.6-32.8 µM), suggesting that irreversible receptor binding plays a role in cytotoxicity. These ligands will be useful for further study of these divergent roles of sigma-2 receptors.


Assuntos
Benzoxazóis/metabolismo , Citotoxinas/metabolismo , Piperazinas/metabolismo , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Animais , Benzoxazóis/química , Linhagem Celular Tumoral , Citotoxinas/química , Relação Dose-Resposta a Droga , Humanos , Piperazinas/química , Ligação Proteica/fisiologia , Ratos , Relação Estrutura-Atividade
17.
Xenobiotica ; 49(11): 1279-1288, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30547698

RESUMO

1. Mitragynine is the major indole-based alkaloid of Mitragyna speciosa (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment and as a means of self-treating opioid addiction. 2. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine. 3. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6, Met8 and Met11) was catalyzed by the CYP3A4. 4. In summary, mitragynine was extensively metabolized in HLM primarily to O-demethylated and mono-oxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.


Assuntos
Mitragyna/química , Alcaloides de Triptamina e Secologanina/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Glutationa/metabolismo , Humanos , Hidrólise , Metabolômica/métodos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Alcaloides de Triptamina e Secologanina/metabolismo , Espectrometria de Massas em Tandem
18.
J Ethnopharmacol ; 233: 34-40, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30594604

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Mitragyna speciosa (Korth.) or kratom have been traditionally used in Malaysia and Thailand mainly to enhance work productivity, as a folk remedy for treating common ailments, and as a mood enhancer. AIM OF THE STUDY: This present study sought to investigate kratom use motives among regular kratom users in Malaysia. MATERIALS AND METHODS: A total of 116 regular kratom users were recruited for this cross-sectional survey. The Drinking Motives Questionnaire (DMQ) was administered to measure kratom use motives. RESULTS: Our results indicate that heavy (>3 glasses daily, each glass contains 48.24-50.4 mg of mitragynine) kratom use was associated with coping (t87.09 =3.544, p < 0.001), and enhancement (t114 =2.180, p = 003). Single subjects had higher mean scores on the coping domain, relative to married subject (t113.89 =3.029, p < 0.003), while those earning more than RM1500 per month had higher mean scores on the enhancement domain, compare to those earning less than RM1500 per month (t107 =2.151, p < 0.034). Higher scores on the coping domain was significantly associated with higher (>3 glasses daily) kratom consumption (p < 0.0045). CONCLUSIONS: Coping was associated with high (>3 glasses daily) kratom consumption among regular kratom users in traditional, rural settings.


Assuntos
Mitragyna , Motivação , Preparações de Plantas , Adaptação Psicológica , Adolescente , Adulto , Alcaloides/análise , Humanos , Malásia , Masculino , Folhas de Planta , Preparações de Plantas/química , Inquéritos e Questionários , Tailândia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA