RESUMO
Tris(chloropropyl) phosphate (TCPP) is an organophosphorus flame retardant and plasticizer used in manufacturing and multiple consumer products. Commercial TCPP is a ubiquitous environmental contaminant and TCPP or its metabolites have been detected in human plasma and urine. In response to the demonstrated widespread human exposure and lack of toxicity data, the Division of the National Toxicology Program is investigating the chronic toxicity of TCPP following perinatal exposure in HSD:Sprague Dawley®SD® (HSD) rats (up to 20,000 ppm) and adult exposure in B6C3F1/N mice (females, up to 10,000 ppm; males up to 5000 ppm) to TCPP via feed. Systemic exposure and bioaccumulation were assessed by measuring plasma concentrations of tris(1-chloro-2-propyl)phosphate (TCIPP), the most abundant TCPP isomer. TCIPP concentrations in TCPP-exposed rats and mice ranged from 3.43 to 1180 ng/mL and increased with exposure concentration at all time points. No sex differences were observed in rats, but male mice had higher TCIPP concentrations than females. TCIPP did not bioaccumulate in rats or mice over the course of the study. Low TCIPP concentrations were seen in some control rats and mice that were attributed to background TCPP present during sample collection, preparation and/or analysis. Bis(2-chloroisopropyl) 1-carboxyethyl phosphate (BCPCP), a TCPP metabolite, was quantified in plasma from control and selected exposed animals. Results showed increases in BCPCP concentration that were proportional to exposure concentration in rats and mice at concentrations much higher than TCIPP, indicating that BCPCP might be a more suitable biomarker of TCPP exposure.
RESUMO
Microbial biotransformation of cannabidiol was assessed using 31 different microorganisms. Only Mucor ramannianus (ATCC 9628), Beauveria bassiana (ATCC 7195), and Absidia glauca (ATCC 22â752) were able to metabolize cannabidiol. M. ramannianus (ATCC 9628) yielded five metabolites, namely, 7,4â³ß-dihydroxycannabidiol (1: ), 6ß,4â³ß-dihydroxycannabidiol (2: ), 6ß,2â³ß-dihydroxycannabidiol (3: ), 6ß,3â³α-dihydroxycannabidiol (4: ), and 6ß,7,4â³ß-trihydroxycannabidiol (5: ). B. bassiana (ATCC 7195) metabolized cannabidiol to afford six metabolites identified as 7,3â³-dihydroxycannabidivarin (6: ), 7-hydroxycannabidivarin-3â³-carboxylic acid (7: ), 3â³-hydroxycannabidivarin (8: ), 4â³ß-hydroxycannabidiol (9: ), and cannabidivarin-3â³-carboxylic acid (10: ) along with compound 1: . Incubation of cannabidiol with A. glauca (ATCC 22â752) yielded three metabolites, 6α,3â³-dihyroxycannabidivarin (11: ), 6ß,3â³-dihyroxycannabidivarin (12: ), and compound 6: . All compounds were evaluated for their antimicrobial and antiprotozoal activity.
Assuntos
Beauveria , Canabidiol , Cannabis , Beauveria/metabolismo , Biotransformação , Canabidiol/metabolismo , Cannabis/metabolismo , Ácidos Carboxílicos/metabolismoRESUMO
Using gas chromatography (GC) in conjunction with electron impact mass spectrometry and retention-time comparison, 94 compounds, ranging from 2-methyl-2-propenal to octadecanoic acid, were identified in the interdigital secretions of male and female black wildebeests, Connochaetes gnou (also known as the white-tailed gnu). The constituents of these secretions belong to many different compound classes, including hydrocarbons, alcohols, aromatics and aliphatic carbonyl compounds including carboxylic acids as well as carboxylic acid esters. Relatively small quantitative differences were found between the male and female interdigital secretions. It was concluded that these compounds probably do not play a significant role in territorial marking or in chemical communication between males and females of the species, but they could be involved in preserving the remarkably strong attachment between members of social subgroups in black wildebeest populations.
Assuntos
Antílopes/fisiologia , Feromônios/análise , Animais , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Caracteres Sexuais , Comportamento Social , Especificidade da Espécie , TerritorialidadeRESUMO
PURPOSE: We aimed to assess intranasal (IN) epinephrine effects on cerebrospinal fluid (CSF) absorption, nasal mucosa quality, plasma epinephrine pharmacokinetics (PK), and cardiovascular changes in dogs. METHODS: CSF epinephrine concentration was measured and nasal mucosa quality was evaluated after IN epinephrine 4 mg and one or two 4 mg doses (21 min apart), respectively. Maximum plasma concentration [Cmax], time to Cmax [Tmax], area under the curve from 0 to 120 min [AUC0-120], and cardiovascular effects were evaluated after epinephrine IN (4 and 5 mg) and intramuscular (IM; 0.3 mg). Clinical observations were assessed. RESULTS: After epinephrine IN, there were no changes in CSF epinephrine or nasal mucosa. Cmax, Tmax, and AUC1-120 were similar following epinephrine IN and IM. Epinephrine IN versus IM increased plasma epinephrine at 1 min (mean ± SEM, 1.15 ± 0.48 for 4 mg IN and 1.7 ± 0.72 for 5 mg IN versus 0.47 ± 0.11 ng/mL for 0.3 mg IM). Epinephrine IN and IM produced similar heart rate and ECG results. Clinical observations included salivation and vomiting. CONCLUSIONS: Epinephrine IN did not alter CSF epinephrine or nasal tissue and had similar cardiovascular effects as epinephrine IM. Epinephrine IN rapidly increased plasma epinephrine concentration versus epinephrine IM.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Epinefrina/administração & dosagem , Mucosa Nasal/efeitos dos fármacos , Administração Intranasal/efeitos adversos , Anafilaxia/tratamento farmacológico , Animais , Área Sob a Curva , Cães , Avaliação Pré-Clínica de Medicamentos , Epinefrina/sangue , Epinefrina/líquido cefalorraquidiano , Epinefrina/farmacocinética , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Injeções Intramusculares , Masculino , Modelos Animais , Mucosa Nasal/diagnóstico por imagemRESUMO
BACKGROUND: Histamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine. METHODS: Dogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (Cmax), area under plasma concentration-time curve from 1 to 90 min (AUC1-90), and time to reach Cmax (Tmax) were measured. Clinical observations were documented. RESULTS: In the 12 dogs in this study, nasal congestion occurred at 5-10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in Cmax and AUC1-90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower Tmax versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30-60 min after administration) in the saline group. Clinical observations included salivation and emesis. CONCLUSION: IN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.
Assuntos
Administração Intranasal/métodos , Resistência das Vias Respiratórias/efeitos dos fármacos , Epinefrina/administração & dosagem , Epinefrina/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Resistência das Vias Respiratórias/fisiologia , Animais , Cães , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Frequência Cardíaca/fisiologia , Histamina/toxicidadeRESUMO
Epinephrine is the standard of care for the treatment of severe allergy and anaphylaxis. Epinephrine is most often administered through the intramuscular (IM) route via autoinjector. The current study aimed to evaluate an alternative method of epinephrine treatment through intranasal (IN) delivery in dogs. The pharmacokinetic (PK) parameters of maximum plasma concentration (Cmax ), time to reach maximum plasma concentration (Tmax ), and area under the plasma concentration-time curve from 0 to 90 minutes (AUC0-90 ) were observed after IN epinephrine (2, 3, 4, 5, 10, and 20 mg) and IM epinephrine via autoinjector (0.15 and 0.3 mg) for 90 minutes. Heart rate effects were measured after IN (2 and 5 mg) and IM (0.15 and 0.3 mg) epinephrine administration. IN epinephrine (5 mg) demonstrated significantly greater plasma epinephrine concentration at 1 minute as compared with IM epinephrine (0.3 mg) (1.68 ± 0.65 ng/mL vs 0.21 ± 0.08 ng/mL, P = .03). There were no significant differences in Cmax , Tmax , and AUC0-90 between 2-mg IN and 0.15-mg IM epinephrine or between 5-mg IN and 0.3-mg IM epinephrine. IN epinephrine reduced heart rate increases, as compared to IM epinephrine. IN and IM epinephrine were both well-tolerated. Overall, IN epinephrine demonstrated advantages over IM epinephrine, including the rapid increase in plasma epinephrine and lack of increased heart rate over time.
Assuntos
Broncodilatadores/administração & dosagem , Epinefrina/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Administração Intranasal , Animais , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Broncodilatadores/farmacocinética , Cães , Epinefrina/efeitos adversos , Epinefrina/sangue , Epinefrina/farmacocinética , Feminino , Injeções Intramusculares , MasculinoRESUMO
Photooxygenation of Δ8 tetrahydrocannabinol (Δ8-THC), Δ9 tetrahydrocannabinol (Δ9-THC), Δ9 tetrahydrocannabinolic acid (Δ9-THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides. Testing these compounds for their modulatory effect on cannabinoid receptors CB1 and CB2 led to the identification of 7 and 21 as CB1 partial agonists with Ki values of 0.043 µM and 0.048 µM, respectively and 23 as a cannabinoid with high binding affinity for CB2 with Ki value of 0.0095 µM, but much less affinity towards CB1 (Ki 0.467 µM). The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC50 values ranging from 4.2 to 8.5 µg/mL. Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Canabinoides/farmacologia , Oxigênio Singlete/química , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Bactérias/efeitos dos fármacos , Canabinoides/síntese química , Canabinoides/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Humanos , Leishmania major/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Processos Fotoquímicos , Plasmodium falciparum/efeitos dos fármacos , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistasRESUMO
Nine oxygenated cannabinoids were isolated from a high potency Cannabis sativa L. variety. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR, HRMS and GC-MS. These minor compounds include four hexahydrocannabinols, four tetrahydrocannabinols, and one hydroxylated cannabinol, namely 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol, Δ(9)-THC aldehyde A, 8-oxo-Δ(9)-THC, 10aα-hydroxy-10-oxo-Δ(8)-THC, 9α-hydroxy-10-oxo-Δ(6a,10a)-THC, and 1'S-hydroxycannabinol, respectively. The latter compound showed moderate anti-MRSa (IC50 10.0 µg/mL), moderate antileishmanial (IC50 14.0 µg/mL) and mild antimalarial activity against Plasmodium falciparum (D6 clone) and P. falciparum (W2 clone) with IC50 values of 3.4 and 2.3 µg/mL, respectively.
Assuntos
Canabinoides/química , Canabinoides/farmacologia , Cannabis/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oxirredução , Plasmodium falciparum/efeitos dos fármacosRESUMO
Seven new naturally occurring hydroxylated cannabinoids (1-7), along with the known cannabiripsol (8), have been isolated from the aerial parts of high-potency Cannabis sativa. The structures of the new compounds were determined by 1D and 2D NMR spectroscopic analysis, GC-MS, and HRESIMS as 8α-hydroxy-Δ(9)-tetrahydrocannabinol (1), 8ß-hydroxy-Δ(9)-tetrahydrocannabinol (2), 10α-hydroxy-Δ(8)-tetrahydrocannabinol (3), 10ß-hydroxy-Δ(8)-tetrahydrocannabinol (4), 10α-hydroxy-Δ(9,11)-hexahydrocannabinol (5), 9ß,10ß-epoxyhexahydrocannabinol (6), and 11-acetoxy-Δ(9)-tetrahydrocannabinolic acid A (7). The binding affinity of isolated compounds 1-8, Δ(9)-tetrahydrocannabinol, and Δ(8)-tetrahydrocannabinol toward CB1 and CB2 receptors as well as their behavioral effects in a mouse tetrad assay were studied. The results indicated that compound 3, with the highest affinity to the CB1 receptors, exerted the most potent cannabimimetic-like actions in the tetrad assay, while compound 4 showed partial cannabimimetic actions. Compound 2, on the other hand, displayed a dose-dependent hypolocomotive effect only.
Assuntos
Canabinoides/isolamento & purificação , Cannabis/química , Analgésicos , Animais , Canabinoides/química , Relação Dose-Resposta a Droga , Dronabinol/análogos & derivados , Cromatografia Gasosa-Espectrometria de Massas , Camundongos , Mississippi , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismoRESUMO
Cannabis has been around for thousands of years and has been used recreationally, medicinally, and for fiber. Over 500 compounds have been isolated from Cannabis sativa with approximately 105 being cannabinoids. Of those 105 compounds, Δ9-tetrahydrocannabinol has been determined as the primary constituent, which is also responsible for the psychoactivity associated with Cannabis. Cannabinoid receptors belong to the large superfamily of G protein-coupled receptors. Targeting the cannabinoid receptors has the potential to treat a variety of conditions such as pain, neurodegeneration, appetite, immune function, anxiety, cancer, and others. Developing in vitro bioassays to determine binding and functional activity of compounds has the ability to lead researchers to develop a safe and effective drug that may target the cannabinoid receptors. Using radioligand binding and functional bioassays, a structure-activity relationship for major and minor cannabinoids was developed.
RESUMO
Cannabisol (1), a unique dimer of Δ9-tetrahydrocannabinol (Δ9-THC) with a methylene bridge, was isolated from Cannabis sativa. This is the first example of a C-bridged dimeric cannabinoid. The structure of 1 was unambiguously deduced by HRESIMS, GCMS, and NMR spectroscopy. A plausible biogenesis of 1 is described.
RESUMO
The University of Mississippi has a contract with the National Institute on Drug Abuse (NIDA) to carry out a variety of research activities dealing with cannabis, including the Potency Monitoring (PM) program, which provides analytical potency data on cannabis preparations confiscated in the United States. This report provides data on 46,211 samples seized and analyzed by gas chromatography-flame ionization detection (GC-FID) during 1993-2008. The data showed an upward trend in the mean Δ(9)-tetrahydrocannabinol (Δ(9)-THC) content of all confiscated cannabis preparations, which increased from 3.4% in 1993 to 8.8% in 2008. Hashish potencies did not increase consistently during this period; however, the mean yearly potency varied from 2.5-9.2% (1993-2003) to 12.0-29.3% (2004-2008). Hash oil potencies also varied considerably during this period (16.8 ± 16.3%). The increase in cannabis preparation potency is mainly due to the increase in the potency of nondomestic versus domestic samples.
Assuntos
Canabinoides/química , Cannabis/química , Dronabinol/química , Ionização de Chama , Drogas Ilícitas/química , Óleos de Plantas/químicaRESUMO
Microbial metabolism of cannflavin A (1) and B (2), two biologically active flavonoids isolated from Cannabis sativa L., produced five metabolites (3-7). Incubation of 1 and 2 with Mucor ramannianus (ATCC 9628) and Beauveria bassiana (ATCC 13144), respectively, yielded 6''S,7''-dihydroxycannflavin A (3), 6''S,7''-dihydroxycannflavin A 7-sulfate (4) and 6''S,7''-dihydroxycannflavin A 4'-O-alpha-L-rhamnopyranoside (5), and cannflavin B 7-O-beta-D-4'''-O-methylglucopyranoside (6) and cannflavin B 7-sulfate (7), respectively. All compounds were evaluated for antimicrobial and antiprotozoal activity.
Assuntos
Anti-Infecciosos/isolamento & purificação , Antiprotozoários/isolamento & purificação , Beauveria/metabolismo , Cannabis/química , Flavonas/isolamento & purificação , Flavonas/metabolismo , Mucor/metabolismo , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Antiprotozoários/química , Antiprotozoários/metabolismo , Flavonas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade ParasitáriaRESUMO
The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Delta(9)-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Delta(9)-THC and Delta(8)-THC showed a U-shaped dose response with only Delta(9)-THC showing significant antidepressant-like effects at 2.5 mg/kg (p<0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200mg/kg, respectively (p<0.01). The antidepressant-like action of Delta(9)-THC and CBC was further confirmed in the TST. Delta(9)-THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p<0.05) while CBC resulted in a significant dose-dependent decrease in immobility at 40 and 80 mg/kg doses (p<0.01). Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.
Assuntos
Antidepressivos/farmacologia , Canabinoides/farmacologia , Cannabis/química , Depressão/tratamento farmacológico , Dronabinol/farmacologia , Animais , Antidepressivos/administração & dosagem , Canabidiol/administração & dosagem , Canabidiol/farmacologia , Canabinoides/administração & dosagem , Catalepsia/induzido quimicamente , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/análogos & derivados , Elevação dos Membros Posteriores , Hipotermia/induzido quimicamente , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Camundongos , Distribuição Aleatória , NataçãoRESUMO
The double-edged sword of antibiotic use in the fight against disease has saved countless lives at the cost of an escalation in pathogenic bacteria with increased resistance to multiple antibiotic classes. Reduction of resistance is a complicated multi-step endeavor that requires a sustained international effort of reduced utilization, infection control and development of effective and economical antimicrobial agents. The carbapenems are beta-lactam antibiotics that are stable to most beta-lactamases. They have potent bactericidal activity against a wide range of Gram-positive and Gram-negative aerobic bacteria as well as against anaerobic bacteria, while being safe, efficacious and tolerable. The use of carbapenems in hospitals has therefore been restricted to the empirical treatment of critical patients with a variety of serious infections, e.g., nosocomial pneumonia, septicemia, meningitis and cystic fibrosis. This article reviews patents claiming carbapenem antibacterial agents published from 2004-2008.
Assuntos
Antibacterianos/síntese química , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Carbapenêmicos/síntese química , Carbapenêmicos/uso terapêutico , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Infecções Bacterianas/microbiologia , Carbapenêmicos/efeitos adversos , Carbapenêmicos/farmacocinética , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Patentes como Assunto , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
Nine dihydroartemisinin acetal dimers (6-14) with diversely functionalized linker units were synthesized and tested for in vitro antiprotozoal, anticancer and antimicrobial activity. Compounds 6, 7 and 11 [IC(50): 3.0-6.7 nM (D6) and 4.2-5.9 nM (W2)] were appreciably more active than artemisinin (1) [IC(50): 32.9 nM (D6) and 42.5 nM (W2)] against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of the malaria parasite, Plasmodium falciparum. Compounds 10, 13 and 14 displayed enhanced anticancer activity in a number of cell lines compared to the control drug, doxorubicin. The antifungal activity of 7 and 12 against Cryptococcus neoformans (IC(50): 0.16 and 0.55 microM, respectively) was also higher compared to the control drug, amphotericin B. The antileishmanial and antibacterial activities were marginal. A number of dihydroartemisinin acetal monomers (15-17) and a trimer (18) were isolated as byproducts from the dimer synthesis and were also tested for biological activity.
Assuntos
Acetais/síntese química , Acetais/farmacologia , Antifúngicos/síntese química , Antineoplásicos/síntese química , Antiprotozoários/síntese química , Artemisininas/síntese química , Artemisininas/farmacologia , Acetais/química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Artemisininas/química , Linhagem Celular Tumoral , Cryptococcus neoformans/efeitos dos fármacos , Dimerização , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Plasmodium falciparum/efeitos dos fármacos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Naturally occurring cannabinoids (phytocannabinoids) are biosynthetically related terpenophenolic compounds uniquely produced by the highly variable plant, Cannabis sativa L. Natural and synthetic cannabinoids have been extensively studied since the discovery that the psychotropic effects of cannabis are mainly due to Delta(9)-THC. However, cannabinoids exert pharmacological actions on other biological systems such as the cardiovascular, immune and endocrine systems. Most of these effects have been attributed to the ability of these compounds to interact with the cannabinoid CB1 and CB2 receptors. The FDA approval of Marinol, a product containing synthetic Delta(9)-THC (dronabinol), in 1985 for the control of nausea and vomiting in cancer patients receiving chemotherapy, and in 1992 as an appetite stimulant for AIDS patients, has further intensified the research interest in these compounds. This article reviews patents (2003-2007) that describe methods for isolation of cannabinoids from cannabis, chemical and chromatographic methods for their purification, synthesis, and potential therapeutic applications of these compounds.
Assuntos
Canabinoides/síntese química , Canabinoides/uso terapêutico , Descoberta de Drogas/métodos , Psicotrópicos/uso terapêutico , Animais , Estimulantes do Apetite/farmacologia , Estimulantes do Apetite/uso terapêutico , Canabinoides/química , Canabinoides/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Humanos , Psicotrópicos/síntese química , Psicotrópicos/farmacologia , Receptores de Canabinoides/classificação , Receptores de Canabinoides/fisiologia , Relação Estrutura-AtividadeRESUMO
Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anticancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were >1,000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the antioxidant L-NAC, the iron chelator desferroxamine and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity, whereas inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage, iron/heme and cysteine/methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ER-stress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases (SERCA). A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity.
Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Heme/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Artemisia/química , Biomarcadores/metabolismo , Western Blotting , Cálcio/metabolismo , Ciclo Celular/efeitos dos fármacos , Dimerização , Retículo Endoplasmático/metabolismo , Inibidores Enzimáticos/farmacologia , Perfilação da Expressão Gênica , Humanos , Lisina/análogos & derivados , Lisina/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Tapsigargina/farmacologiaRESUMO
Nine new cannabinoids (1-9) were isolated from a high-potency variety of Cannabis sativa. Their structures were identified as (+/-)-4-acetoxycannabichromene (1), (+/-)-3''-hydroxy-Delta((4'',5''))-cannabichromene (2), (-)-7-hydroxycannabichromane (3), (-)-7R-cannabicoumarononic acid A (4), 5-acetyl-4-hydroxycannabigerol (5), 4-acetoxy-2-geranyl-5-hydroxy-3-n-pentylphenol (6), 8-hydroxycannabinol (7), 8-hydroxycannabinolic acid A (8), and 2-geranyl-5-hydroxy-3-n-pentyl-1,4-benzoquinone (9) through 1D and 2D NMR spectroscopy, GC-MS, and HRESIMS. The known sterol beta-sitosterol-3-O-beta-d-glucopyranosyl-6'-acetate was isolated for the first time from cannabis. Compounds 6 and 7 displayed significant antibacterial and antifungal activities, respectively, while 5 displayed strong antileishmanial activity.
Assuntos
Canabinoides/isolamento & purificação , Canabinoides/farmacologia , Cannabis/química , Plantas Medicinais/química , Animais , Antibacterianos , Antifúngicos , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida/efeitos dos fármacos , Canabinoides/química , Chlorocebus aethiops , Escherichia coli/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Leishmania donovani/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Plasmodium falciparum/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
Twelve artemisinin acetal dimers were synthesized and tested for antitumor activity in the National Cancer Institute (NCI) in vitro human tumor 60 cell line assay, producing a mean GI(50) concentration between 8.7 (least active) and 0.019 microM (most active). The significant activity of the compounds in this preliminary screen led to additional in vitro antitumor and antiangiogenesis studies. Several active dimers were also evaluated in the in vivo NCI hollow fiber assay followed by a preliminary xenograft study. The title compounds were found to be active against solid tumor-derived cell lines and showed good correlation with other artemisinin-based molecules in the NCI database. The dimers were also evaluated for their antimalarial and antileishmanial activities. The antimalarial activity ranged from 0.3 to 32 nM (IC(50)), compared to 9.9 nM for artemisinin.