RESUMO
The terminal elimination half-life of delta 1-tetrahydrocannabinol (delta 1-THC) was investigated in eight men who were heavy users of marijuana. A stable isotope assay, following smoking deuterium-labeled delta 1-THC, was used to determine plasma concentrations. In two additional users plasma levels were followed after administration of unlabeled delta 1-THC. The subjects were asked to smoke a "loading dose" of 56 mg delta 1-THC during two days and then abstain from all marijuana use for 4 weeks. The pharmacokinetic behavior was consistent with a multicompartment model with a mean plasma elimination half-life of delta 1-THC of 4.3 days when concentrations were followed for 10-15 days after smoking. In the two subjects with detectable plasma levels during 4 weeks, half-lives of 9.6 and 12.6 days was obtained.
Assuntos
Dronabinol/farmacocinética , Fumar Maconha/sangue , Dronabinol/sangue , Dronabinol/urina , Meia-Vida , Humanos , Técnicas Imunoenzimáticas , MasculinoRESUMO
The aim of this study was to characterize the elimination half-life of delta 1-tetrahydrocannabinol in blood plasma in chronic marijuana users. The subjects smoked four cigarettes during a two day period, each cigarette containing 15 mg deuterium-labelled delta 1-tetrahydrocannabinol. The plasma concentrations of deuterium-labelled tetrahydrocannabinol were measured for 13 days using gas chromatography-mass spectrometry equipped with selected ion monitoring. The elimination half-life for delta 1-tetrahydrocannabinol in blood plasma was calculated to be 4.1 +/- 1.1 days (range 2.9-5.0 days) from the two week plasma level curves. Albeit the present results are based upon a small sample, an elimination half-life of delta 1-tetrahydrocannabinol in blood plasma of about 4 days is more in line with apparent half-life excretion of delta 1-tetrahydrocannabinol metabolites in the urine of chronic marijuana smokers.
Assuntos
Dronabinol/farmacocinética , Abuso de Maconha/sangue , Dronabinol/sangue , Meia-Vida , Humanos , MasculinoRESUMO
The single dose pharmacokinetics of deuterium-labelled cannabinol (2H2-CBN) were evaluated in six male cannabis users with different degree of abuse after smoking an average dose of 19 mg and after intravenous administration of 20 mg CBN. Plasma levels were measured for up to 72 h with selected ion monitoring by GC/MS using 2H7-CBN as internal standard. The systemic availability of smoked CBN was found to be 39 +/- 26% (min-max 6-65%). The mean plasma clearance was 19.1 +/- 2.6 ml min-1 kg-1 and the volume of distribution was determined to 50 +/- 23 l kg-1. The apparent terminal half lives for CBN were 32 +/- 17 h and 43 +/- 29 h after intravenous administration and smoking, respectively.
Assuntos
Canabinoides/farmacocinética , Canabinol/farmacocinética , Fumar Maconha , Adulto , Canabinol/administração & dosagem , Humanos , Injeções Intravenosas , MasculinoRESUMO
The disposition of deuterium-labelled cannabidiol, 2H2-CBD, was studied in five young men who were marihuana smokers. The pattern of use ranged from infrequent to frequent use of the drug. Plasma concentrations, determined by mass fragmentography, were followed for 72 h after both intravenous administration of 20 mg 2H2-CBD and smoking of an estimated amount of 18.8-19.4 mg 2H2-CBD. Systemic availability after smoking was determined by comparing the areas under the plasma concentration versus time curves for the two treatments and was found to be 31 +/- 13%. A four-fold difference in the availability of the compound was noted for the five subjects. Based on the area under the curve and the dose after intravenous administration, a plasma clearance of 960-1560 ml min-1 was calculated. A terminal elimination phase was not reached at 72 h, but the kinetic parameters were estimated from the 72 h beta-elimination. A half-life of 31 +/- 4 h after smoking and 24 +/- 6 h after injection was estimated as well as a distribution volume of 2520 +/- 470 l (32.7 +/- 8.61 kg-1).
Assuntos
Canabidiol/metabolismo , Canabinoides/metabolismo , Adulto , Canabidiol/administração & dosagem , Canabidiol/sangue , Deutério , Meia-Vida , Humanos , Injeções Intravenosas , Cinética , Masculino , Abuso de Maconha , Saliva/análiseRESUMO
The co-operation between industry and academia in Sweden has been subject to changing views in the society. The experiences of Astra Läkemedel AB are described and placed in a more general perspective. The co-operation in drug development includes the testing of biological hypotheses, drug formulation, preclinical and clinical studies, etc. An interesting way of collaboration is the position of 'adjunct professor'. Some problems and concerns relating to these kinds of co-operation are discussed. It is concluded that co-operation is very useful, provided that one is aware of possible pitfalls.
Assuntos
Indústria Farmacêutica , Sistemas Multi-Institucionais , Universidades/tendências , Antivirais/farmacologia , Composição de Medicamentos , Farmacologia , Projetos de Pesquisa , SuéciaRESUMO
The preclinical development of zimeldine according to the 5-HT (serotonin) hypothesis is briefly reviewed. Zimeldine is a selective 5-HT reuptake inhibitor based on the "chemical lead" of brompheniramine--an antihistamine with some 5-HT reuptake inhibitory properties. By chemical manipulation of the position of the pyridine ring in brompheniramine and the stereochemistry of the side chain, a selective 5-HT reuptake inhibitor has been developed.
Assuntos
Serotonina/metabolismo , Zimeldina/farmacologia , Animais , Química Farmacêutica , Avaliação Pré-Clínica de Medicamentos , Humanos , Transtornos do Humor/fisiopatologia , Norepinefrina/metabolismo , Sinapses/fisiologiaRESUMO
Deuterium labelled delta 1-tetrahydrocannabinol was administered intravenously (5.0 mg) and by smoking (10.0 mg) to five heavy and four light marihuana users. All subjects smoked an estimated amount of 8.6-9.9 mg delta 1-tetrahydrocannabinol. The plasma levels of delta 1-tetrahydrocannabinol were followed for 48 hours and in two subjects fof 72 hours after administration. The systemic availability after inhalation calculated from the area under curve values was in the range of 27 +/- 10% for the heavy users and 14 +/- 1% for the light users. There was little difference between the groups with regard to the amount of smoked delta 1-tetrahydrocannabinol or plasma levels and area under curve values obtained after i.v. administration. Thus, it seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users. It is also indicated that heavy users prefer slightly higher delta 1-tetrahydrocannabinol plasma levels than light users. Based on the area under curve values after i.v. administration, a plasma clearance of 760-1190 ml min-1 was calculated. The elimination half-life of delta 1-tetrahydrocannabinol is more than 20 hours. The present results do not suggest that tolerance or sensitivity to delta 1-tetrahydrocannabinol in heavy users is readily achieved.
Assuntos
Cannabis , Dronabinol/sangue , Adolescente , Adulto , Canabinoides/urina , Deutério , Dronabinol/administração & dosagem , Dronabinol/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Meia-Vida , Humanos , Injeções Intravenosas , Cinética , Masculino , Fumar , Fatores de TempoRESUMO
The metabolism of delta 1-tetrahydrocannabinol (delta 1-THC) was studied in man after oral administration. Twelve acidic metabolites were isolated from human urine and identified by gas chromatography-mass spectrometry. One additional metabolite was tentatively identified. Hitherto, only one of the metabolites (delta 1-THC-7-oic acid, ) has been identified in man. Three of the metabolites have not been identified in any species before. delta 1-THC-7-oic acid (1) corresponding to 27% of the urinary metabolites was the most abundant metabolite. 4"-Hydroxy-delta 1-THC-7-oic acid (6) was the second most abundant monocarboxylic acid. The remaining eleven monocarboxylic acids predominantly oxidized at C-7 and at C-2" and C-3" of the side-chain, unsubstituted as well as monohydroxylated, were present in small amounts.
Assuntos
Dronabinol/urina , Biotransformação , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , MetilaçãoAssuntos
Canabidiol/administração & dosagem , Canabinoides/administração & dosagem , Canabinol/administração & dosagem , Dronabinol/administração & dosagem , Administração Oral , Adolescente , Adulto , Canabidiol/sangue , Canabinol/sangue , Dronabinol/sangue , Interações Medicamentosas , Cromatografia Gasosa-Espectrometria de Massas , Humanos , MasculinoRESUMO
Plasma concentrations of THC were measured by gas-liquid chromatography and mass spectrometry following three routes of administration and correlated with clinical effects. Plasma concentrations peaked at 3 minutes after intravenous injection and then sharply declined. The peak "high" occurred at 30 minutes while plasma concentrations were declining. This lag between plasma concentration and "high" continued during most of the span of the drug's effects. The situation was quite similar following smoking, except that peak plasma concentrations were lower. After oral administration of THC, absorption was slow, with peak concentration occurring at 1 to 2 hours. Plasma concentrations were much lower. Correlations between plasma concentrations of drug and "high" were significant but not impressive. The degree of "high" was quite variable in relation to the prevailing plasma concentration. Conjunctival injection was found so long as plasma concentration of THC could be measured. Pulse rate increases occurred at lower concentration after oral administration than after the other two routes. It is unlikely that a range of plasma concentrations can be reliably equated with impaired performance. The mode of administration will become important should THC or some homolog become a therapeutic agent.
Assuntos
Dronabinol/sangue , Administração Oral , Adolescente , Adulto , Túnica Conjuntiva/efeitos dos fármacos , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Emoções/efeitos dos fármacos , Humanos , Injeções Intravenosas , Masculino , Pulso Arterial/efeitos dos fármacos , Fatores de TempoAssuntos
Dronabinol/análogos & derivados , Fumar , Administração Oral , Adolescente , Adulto , Túnica Conjuntiva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/sangue , Dronabinol/metabolismo , Glucuronatos/sangue , Glucuronatos/metabolismo , Humanos , Injeções Intravenosas , Cinética , MasculinoRESUMO
The involvement of biogenic amines--primarily noradrenaline (NA) and serotonin (5-HT)--in depressive disorders was suggested by the finding more than twenty years ago that imipramine possessed antidepressant properties and concomitantly altered the availability of NA in the brain. Since then, numerous antidepressants closely related chemically and pharmacologically to imipramine have been introduced. It has generally been assumed that these "tricyclics" alleviate depression by influencing the neurotransmitters (NA, 5-HT) at crucial receptor sites in the brain. Thus, the "biogenic amine hypothesis of depression" postulates that depression is due to a reduced functional activity of one or more brain amines. The tricyclics appear to be antidepressants due to their inhibition of the neuronal reuptake of NA in the brain. A decade ago, Carlsson, Coppen, Lapin, van Praag and other suggested that compounds selectively affecting the 5-HT uptake mechanism might be more effective antidepressants. This symposium will describe the clinical and preclinical results with zimelidine--the first 5-HT-selective uptake inhibitor.
Assuntos
Aminas Biogênicas/fisiologia , Transtorno Depressivo/fisiopatologia , Antidepressivos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Humanos , Serotonina/metabolismoRESUMO
delta 9-Tetrahydrocannabinol (delta 9-THC) was administered in a crossover design by smoking and IV injection to groups of heavy and light users of marihuana. Plasma concentrations of delta 9-THC were similar for the groups after IV injection of 5.0 mg delta 9-THC, but the AUC0-240 min showed a trend towards lower values for the heavy user group. To achieve a maximum desired "high", both groups smoked similar amounts (about 13 mg) of delta 9-THC. Heavy users tended to have higher plasma levels than light users. The systemic availability of smoked delta 9-THC was significantly higher for the heavy users (heavy users 23 +/- 16% vs 10 +/- 7% for light users). These results also indicate that heavy cannabis users smoke more efficiently than casual smokers. Both light and heavy users showed more clinical effect following IV administration than after smoking. The response of the heavy users, both with respect to effect on heart and "high", was quite comparable to that of light users. The present study does not suggest that tolerance readily develops in heavy users.
Assuntos
Cannabis , Dronabinol/sangue , Adulto , Disponibilidade Biológica , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Feminino , Humanos , Injeções Intravenosas , Cinética , Masculino , Pulso Arterial/efeitos dos fármacos , Fatores de TempoAssuntos
Canabinoides/farmacologia , Cannabis , Dronabinol/metabolismo , Animais , Biotransformação , Fenômenos Químicos , Química , Cromatografia Gasosa , Humanos , Espectrometria de Massas , Camundongos , Coelhos , RatosRESUMO
Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.
Assuntos
Dronabinol/sangue , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Cannabis , Túnica Conjuntiva/efeitos dos fármacos , Dronabinol/administração & dosagem , Humanos , Infusões Parenterais , Cinética , Masculino , Pulso Arterial/efeitos dos fármacosRESUMO
Potential metabolites of (-)-3,4-trans-tetrahydrocannabinol (THC) with a carboxylic acid function in the side chain were synthesized as their methyl esters in the delta1(6)-series. The chromatographic and mass-spectrometric properties of the five side-chain homologues were examined and utilized to facilitate the isolation and the identification of the corresponding monocarboxylic acid metabolites of delta1(6)-THC in the mouse, guinea pig, and rabbit formed after ip administration. The metabolites were identified by gas chromatography and mass fragmentography. In mouse liver delta1(6)-THC-7-oic acid and 3'',4'',5''-trisnor delta1(6)-THC-2''-oic acid were identified as metabolites. In guinea pig liver these acids occurred together with 4'',5''-bisnor-delta1(6)-THC-3''-oic acid and 5''-nor-delta1(6)-THC-4''-oic acid. Rabbit liver contained delta1(6)-THC-7-oic acid, 2'',3'',4'',5''-tetranor-delta1(6)-THC-1''-oic acid and 4'',5''-bisnor-delta1(6)-THC-3''-oic acid. Further, the structure of three dicarboxylic acid metabolites of delta1(6)-THC in rabbit kidney were determined by mass spectrometry and proton magnetic resonance spectroscopy.
Assuntos
Dronabinol/síntese química , Animais , Cromatografia Gasosa , Dronabinol/análogos & derivados , Dronabinol/isolamento & purificação , Dronabinol/metabolismo , Feminino , Cobaias , Masculino , Espectrometria de Massas , Camundongos , Coelhos , Especificidade da Espécie , Distribuição TecidualRESUMO
1,2-Epoxyhexahydrocannabinol is a metabolite of delta 1-tetrahydrocannabinol. Because many epoxides are mutagens, we investigated 1,2-epoxyhexahydrocannabinol as well as delta 1-tetrahydrocannabinol for mutagenicity with Salmonella typhimurium TA1535, TA1537, TA98 and TA100 in the presence and in the absence of S9 mix from liver homogenate of rats treated with Aroclor 1254. Additionally, an epoxide hydratase inhibitor was used in some experiments. Whereas several other epoxides and further positive controls, not requiring activation or activated under the same conditions, respectively, showed strong mutagenicity, no indications of a mutagenic hazard by 1,2-epoxyhexahydrocannabinol or by delta 1-tetrahydrocannabinol were found.
Assuntos
Dronabinol/análogos & derivados , Dronabinol/farmacologia , Mutagênicos , Avaliação Pré-Clínica de Medicamentos , Técnicas Genéticas , Salmonella typhimurium/genéticaRESUMO
The in vivo metabolism of delta1-tetrahydrocannabinol (delta1-THC) was investigated in the rabbit after i.v. administration. Thirteen acidic metabolites were isolated from rabbit urine and identified by gas chromatography-mass spectrometry and by proton magnetic resonance spectroscopy. One additional metabolite was tentatively identified. All but three were new metabolites and all but one were oxidized in the pentyl side chain. The metabolites included dicarboxylic acids, monocarboxylic acids and mono- or dihydroxylated derivatives thereof. However, the dicarboxylic acid metabolites were the most prominent.