RESUMO
BACKGROUND: Smoking mixtures containing synthetic cannabinoids (SCs) have become very popular over the last years but pose a serious risk for public health. Limited knowledge is, however, available regarding the acute effects of SCs on cognition and psychomotor performance. Earlier we demonstrated signs of impairment in healthy volunteers after administering one of the first SCs, JWH-018, even though subjective intoxication was low. In the current study, we aimed to investigate the acute effects of JWH-018 on several cognitive and psychomotor tasks in participants who are demonstrating representative levels of acute intoxication. METHODS: 24 healthy cannabis-experienced participants took part in this placebo-controlled, cross-over study. Participants inhaled the vapor of 75 µg JWH-018/kg body weight and were given a booster dose if needed to induce a minimum level of subjective high. They were subsequently monitored for 4 h, during which psychomotor and cognitive performance, vital signs, and subjective experience were measured, and serum concentrations were determined. RESULTS: Maximum subjective high (average 64%) was reached 30 min after administration of JWH-018, while the maximum blood concentration was shown after 5 min (8 ng/mL). JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), it lowered speed-accuracy efficiency (MFFT) and slowed down response speed (DAT). CONCLUSION: In accordance with our previous studies, we demonstrated acute psychomotor and cognitive effects of a relatively low dose of JWH-018.
Assuntos
Canabinoides/toxicidade , Cannabis/química , Disfunção Cognitiva/induzido quimicamente , Drogas Ilícitas/toxicidade , Indóis/toxicidade , Naftalenos/toxicidade , Extratos Vegetais/toxicidade , Transtornos Psicomotores/induzido quimicamente , Uso Recreativo de Drogas/psicologia , Medicamentos Sintéticos/toxicidade , Administração por Inalação , Adulto , Atenção/efeitos dos fármacos , Canabinoides/administração & dosagem , Canabinoides/sangue , Cognição/efeitos dos fármacos , Disfunção Cognitiva/sangue , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Drogas Ilícitas/sangue , Indóis/administração & dosagem , Indóis/sangue , Masculino , Naftalenos/administração & dosagem , Naftalenos/sangue , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Transtornos Psicomotores/sangue , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Medicamentos Sintéticos/administração & dosagem , Adulto JovemRESUMO
In vitro incubation of rat liver microsomes with 30 µL of 100⯵mol·L-1 dapoxetine and 30 µL of 10, 100, 250, 500, 1000, 2500, or 5000⯵g·mL-1 Wuziyanzong pill was performed at 37⯰C for 60 min. Dapoxetine concentration was analyzed by high performance liquid chromatography (HPLC). The half maximal inhibitory concentration (IC50) of Wuziyanzong pill on metabolism of dapoxetine was 296.10 µg mL-1in vitro. Twelve SD rats were randomly divided into 2 groups: Control group and Wuziyanzong pill group. The two groups were administrated with 10 mL·kg-1 saline (Control group) or 10 mL·kg-1 Wuziyanzong pill solution (Experimental group, solution contained 200 mg mL-1 Wuziyanzong pill) for 15 consecutive days. Following administration of saline or Wuziyanzong pill on the 15th day, 20 mg kg-1 dapoxetine was administered to all rats. Blood was collected from the tail vein (0.3 mL) at multiple time points, and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was used to determine the concentration of dapoxetine and its main metabolites, dapoxetine-N-oxide and desmethyldapoxetine in rats. Pharmacokinetic analysis of dapoxetine showed that area under the concentration-time curve (AUC) and mean maximum plasma concentration (Cmax) of the Wuziyanzong pill group were decreased, while plasma clearance (CLz) was increased compared with control group (Pâ¯<â¯0.01). The HPLC method for determination of dapoxetine in vitro was accurate and specific. The UHPLC-MS/MS method established for determination of dapoxetine and its major metabolites in rat plasma was rapid and specific, which met the requirements of pharmacokinetic guidelines. Wuziyanzong pill had a weak inhibitory effect on metabolism of dapoxetine in vitro, but had a very strong induction effect in vivo, suggesting the dosage of dapoxetine should be increased when administered in combination with Wuziyanzong pill.
Assuntos
Benzilaminas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Naftalenos/farmacocinética , Animais , Benzilaminas/sangue , Cromatografia Líquida de Alta Pressão , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/metabolismo , Naftalenos/sangue , Ratos , Espectrometria de Massas em TandemRESUMO
The hypothalamus determinates metabolic processes in liver through endocrine and autonomic control. Hypothalamic neuropeptides, such as thyrotropin releasing hormone or vasopressin, have been involved in liver metabolism. The thyroid status influences metabolic processes including liver metabolism in modulating those hypothalamic peptides whose functional status is regulated in part by aminopeptidase activities. In order to obtain data for a possible coordinated interaction between hypothalamus, plasma and liver, of some aminopeptidase activities that may partially reflect the hydrolysis of those peptides, pyroglutamyl- (pGluAP) and cystinyl- (CysAP) beta-naphthylamide hydrolyzing activities were determined fluorimetrically, both in their soluble and membrane-bound forms, in eu- hypo- and hyperthyroid adult male rats. Hyperthyroidism and hypothyroidism were induced with daily subcutaneous injections of tetraiodothyronine (300 µg/kg/day) or with 0.03% methimazole in drinking water for 6 weeks. Results demonstrated significant changes depending on the type of enzyme and the thyroid status. The most striking changes were observed for CysAP in liver where it was reduced in hypothyroidism and increased in hyperthyroidism. Significant intra- and inter-tissue correlations were observed. While there were positive inter-tissue correlations between liver, plasma and hypothalamus in eu-and hypothyroid rats, a negative correlation between hypothalamus and liver was observed in hyperthyroidism. These results suggest the influence of thyroid hormones and an interactive role for these activities in the control of liver metabolism. The present data also suggest a role for CysAP and pGluAP activities in liver function linked to their activities in hypothalamus.
Assuntos
Hipertireoidismo/metabolismo , Hipotálamo/metabolismo , Hipotireoidismo/metabolismo , Fígado/metabolismo , Naftalenos/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Hidrólise , Hipertireoidismo/sangue , Hipotireoidismo/sangue , Masculino , Naftalenos/sangue , Ácido Pirrolidonocarboxílico/sangue , Ácido Pirrolidonocarboxílico/metabolismo , Ratos Sprague-DawleyRESUMO
The aim of study is to develop a high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method to investigate the pharmacokinetic interaction of Epimedium extract on the dapoxetine in rats. Experimental rats were divided into the following four parallel groups: (1) dapoxetine alone (10mg/kg, i.v.); (2) oral administration of Epimedium extract (2g/kg) for 3 consecutive days and on the fourth day dapoxetine was administered (10mg/kg, i.v.); (3) dapoxetine alone (10mg/kg, p.o.); (4) oral administration of Epimedium extract (2g/kg) for 3 consecutive days and on the fourth day dapoxetine was administered (10mg/kg, p.o.). The calibration curves of dapoxetine were acquired over a concentration ranges from 1 to 500ng/mL with the R(2)=0.999. The mean matrix effects and extraction recoveries of dapoxetine at three different concentrations (1, 10, 500ng/mL) ranged from 107.3 to 110.9% and from 25.5 to 28.2% respectively. The interday and intraday relative standard deviation were both <6% while the bias were both <14%. The pharmacokinetic results demonstrated that pretreated with/without Epimedium extract for three consecutive days did not significant alter the pharmacokinetics of dapoxetine in rats. The oral bioavailability of dapoxetine was about 75% in rats.
Assuntos
Benzilaminas/sangue , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Epimedium/química , Interações Ervas-Drogas , Naftalenos/sangue , Inibidores Seletivos de Recaptação de Serotonina/sangue , Animais , Benzilaminas/administração & dosagem , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Limite de Detecção , Masculino , Naftalenos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Espectrometria de Massas em Tandem/métodosRESUMO
This study firstly describes the development of an accurate and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of Taiwanin E methyl ether (TEME) in rat plasma. The assay involved a simple liquid-liquid extraction step with ethyl acetate and a gradient elution using a mobile phase consisting of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. Chromatographic separation was successfully achieved on an Agilent Zorbax-C(18) column (2.1 × 50 mm, 3.5 µm) with a flow rate of 0.40 mL/min. The multiple reaction monitoring was based on the transitions of m/z = 379.1 â 320.1 for TEME and 386.1 â 122.0 for buspirone (internal standard). The assay was validated to demonstrate the specificity, linearity, recovery, accuracy, precision and stability. The lower limit of quantification was 0.50 ng/mL in 50 µL of rat plasma. The developed and validated method was successfully applied to the quantification and pharmacokinetic study of TEME in rats after intravenous and oral administration of 1.45 mg/kg TEME. The oral absolute bioavailability of TEME was estimated to be 5.85 ± 1.41% with an elimination half-life value of 2.61 ± 0.55 h, suggesting its poor absorption and/or strong metabolism in vivo.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Lignanas/sangue , Lignanas/farmacocinética , Naftalenos/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Acanthaceae , Administração Intravenosa , Administração Oral , Animais , Buspirona , Estabilidade de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Lignanas/química , Extração Líquido-Líquido , Masculino , Naftalenos/sangue , Naftalenos/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The disposition in mice of the cannabimimetics JWH-018 and JWH-073 in blood and brain following inhalation of the smoke from the herbal incense product (HIP) "Magic Gold" containing 3.6% JWH-018, 5.7% JWH-073 and less than 0.1% JWH-398 (w/w) is presented. Specimens were analyzed by HPLC/MS/MS. The validation of the method is also presented. Five C57BL6 mice were sacrificed 20 min after exposure to the smoke of 200 mg of "Magic Gold" and a second set of five exposed mice were sacrificed after 20 h. Twenty minutes after exposure to "Magic Gold" smoke, blood concentrations of JWH-018 ranged from 42 to 160 ng/mL (mean: 88 ng/mL ± 42) and those of JWH-073 ranged from 67 to 244 ng/mL (mean: 134 ng/mL ± 62). Brain concentrations 20 min after exposure to "Magic Gold" smoke for JWH-018 ranged from 225 to 453 ng/g (mean: 317 ng/g ± 81) and those of JWH-073 ranged from 412 to 873 ng/g (mean: 584 ng/g ± 163). Twenty hours after exposure to "Magic Gold" smoke, JWH-018 was detected and quantified in only two of the five blood samples. Blood concentrations of JWH-018 were 3.4 ng/mL and 9.4 ng/mL. JWH-073 was detected in only one blood specimen 20 h after exposure at 4.3 ng/mL. Brain concentrations 20 h post exposure for JWH-018 ranged from 7 to 32 ng/g (mean: 19 ng/g ± 9). JWH-073 was not detected in 20 h post exposure brain specimens. JWH-398 was not detected in any of the blood or brain samples. The disposition data presented with the limited data available from human experience provide reasonable expectations for forensic toxicologists in JWH-018 or JWH-073 cases. As with THC after smoking marijuana, blood and brain concentrations of JWH-018 and JWH-073 after HIP smoking can be expected to rise initially to readily detected values, and then drop dramatically over the next few hours to several ng/mL or ng/g, and finally to be at extremely low or undetectable concentrations by 24h apparently due to extensive biotransformation, and redistribution to body fat.
Assuntos
Indóis/farmacocinética , Exposição por Inalação , Naftalenos/farmacocinética , Preparações de Plantas/química , Animais , Química Encefálica , Cromatografia Líquida de Alta Pressão , Toxicologia Forense , Humanos , Indóis/sangue , Modelos Lineares , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Naftalenos/sangue , Fatores de TempoRESUMO
Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund's complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Canabinoides/uso terapêutico , Inflamação/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptor CB1 de Canabinoide/metabolismo , Animais , Benzimidazóis/uso terapêutico , Benzoxazinas/sangue , Benzoxazinas/uso terapêutico , Bloqueadores dos Canais de Cálcio/sangue , Bloqueadores dos Canais de Cálcio/uso terapêutico , Carragenina/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Adjuvante de Freund/efeitos adversos , Humanos , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfolinas/sangue , Morfolinas/uso terapêutico , Naftalenos/sangue , Naftalenos/uso terapêutico , Neuralgia/induzido quimicamente , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/deficiência , Receptor CB2 de Canabinoide/deficiência , Sulfonamidas/uso terapêutico , Fatores de TempoRESUMO
The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO-4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO-4641, a sphingosine 1-phosphate receptor modulator. Using a two-compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO-4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO-4641 was described by an indirect-response model. The indirect-response model had an I(max) value of 0.828 and an IC(50) value of 1.29 ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO-4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies.
Assuntos
Azetidinas/farmacologia , Azetidinas/farmacocinética , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/farmacocinética , Naftalenos/farmacologia , Naftalenos/farmacocinética , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Animais , Azetidinas/efeitos adversos , Azetidinas/sangue , Simulação por Computador , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Lisofosfolipídeos/efeitos adversos , Lisofosfolipídeos/sangue , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Naftalenos/efeitos adversos , Naftalenos/sangue , Ligação Proteica , Esfingosina/efeitos adversos , Esfingosina/sangue , Esfingosina/farmacocinética , Esfingosina/farmacologiaRESUMO
The synthetic retinoic acid analog, 9-cis-UAB30 [(2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid], is a specific ligand for the retinoid X receptor. Murine oncogenicity and pharmacokinetics studies were performed as part of the preclinical development of 9-cis-UAB30 for breast cancer chemoprevention. In the oncogenicity study, TSG-p53((+/-)) (p53 knockout) mice (25 per sex per group) received daily gavage exposure to 9-cis-UAB30 doses of 0 (control), 30, 100, or 300 mg/kg/d for 6 months. Positive controls received p-cresidine (400 mg/kg/d) for 6 months. 9-cis-UAB30 had no biologically significant effects on survival, body weight, body weight gain, clinical signs, hematology, or clinical chemistry but induced dose-related hepatomegaly in both sexes and decreased thymus weights in high-dose females. Gross and microscopic pathology provided no evidence of 9-cis-UAB30 toxicity or oncogenicity; by contrast, p-cresidine induced urinary bladder neoplasms in more than 60% of male and female mice. It was concluded that 9-cis-UAB30 is not oncogenic in p53((+/-)) mice. In the pharmacokinetics study, C57BL/6 mice received daily gavage exposure to 9-cis-UAB30 (100 or 300 mg/kg/d) for 1 or 7 days. Pharmacokinetic parameters were similar after 1 and 7 days of dosing. Dose-related peak plasma levels of 9-cis-UAB30 were seen between 0.25 and 3 hours; volume of distribution was comparable at both dose levels. Increases in area under the curve were less than proportional to dose and were associated with an increased rate of apparent clearance and decreased elimination half-life. These results suggest decreased absorption and/or possible induction of clearance mechanisms. Enzyme induction may underlie the hepatomegaly seen in mice treated with 9-cis-UAB30 for 6 months in the oncogenicity study.
Assuntos
Neoplasias da Mama/prevenção & controle , Ácidos Graxos Insaturados/toxicidade , Naftalenos/toxicidade , Animais , Área Sob a Curva , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Ácidos Graxos Insaturados/sangue , Ácidos Graxos Insaturados/farmacocinética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naftalenos/sangue , Naftalenos/farmacocinética , Receptores X de Retinoides/agonistas , Proteína Supressora de Tumor p53/genéticaRESUMO
The pre-clinical pharmacokinetics of AZD3582 (4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate) and its primary metabolites (naproxen and nitrate) were evaluated. AZD3582 had intermediate and passive intestinal permeability (40 times lower than for naproxen), high systemic plasma clearance (CL), substantial gastrointestinal hydrolysis, intermediate volume of distribution (Vss; >or=3.4 L kg-1) and half-life (t1/2; 7 h), negligible plasma protein binding (approximately 0.1%), low/intermediate oral uptake (>or=13% as intact substance) and low and varying oral bioavailability (mean 1.4% in minipigs and 3.9% in dogs). Following administration of therapeutically relevant oral doses, plasma concentrations of AZD3582 were very low (
Assuntos
Inibidores de Ciclo-Oxigenase/farmacocinética , Naftalenos/farmacocinética , Doadores de Óxido Nítrico/farmacocinética , Animais , Bile/química , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Inibidores de Ciclo-Oxigenase/sangue , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Humanos , Técnicas In Vitro , Absorção Intestinal , Masculino , Leite/química , Naftalenos/sangue , Naproxeno/análogos & derivados , Doadores de Óxido Nítrico/sangue , Ligação Proteica , Coelhos , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos , Porco Miniatura , Distribuição TecidualRESUMO
A case of disseminated infection with Fusarium oxysporum following chemotherapy of acute myelogenous leukemia is reported. Antifungal treatment was successful with a 13-day course of oral terbinafine 250 mg t.i.d. in combination with amphotericin B deoxycholate 1.0-1.5 mg/kg qd and subsequently intravenous liposomal amphotericin B 5 mg/kg qd. Preceding monotherapy with amphotericin B deoxycholate 1.0-1.5 mg/kg qd had not stopped the progression of infection. The combination therapy described here represents a novel approach to the treatment of Fusarium spp. in the immunocompromised host in whom Fusarium spp. are known to cause disseminated infection with high mortality.
Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Dermatomicoses/tratamento farmacológico , Fusarium , Naftalenos/administração & dosagem , Dermatomicoses/sangue , Dermatomicoses/imunologia , Dermatomicoses/patologia , Quimioterapia Combinada , Humanos , Hospedeiro Imunocomprometido , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Naftalenos/sangue , Neutropenia/tratamento farmacológico , Neutropenia/patologia , Terbinafina , Resultado do TratamentoRESUMO
A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of terbinafine (TBF) and fluconazole (FCZ). Hydrocortisone acetate-treated New Zealand White male rabbits were infected intracisternally with either 2.2 x 10(4) or 6.4 x 10(4) Coccidioides immitis arthroconidia. Oral treatment with polyethylene glycol 200 (PEG) twice daily (n = 8), TBF twice daily (n = 9; 200 mg/kg of body weight/day), or FCZ once daily (n = 8; 80 mg/kg/day) began on day 5 and continued for 21 days. Mean survival times were 20, 24, and 32 days for rabbits treated with PEG, TBF, and FCZ, respectively. All of the FCZ-treated animals (100%; P = 0.003), 56% of the TBF-treated animals (P = 0.4), and 25% of the PEG-treated animals survived the length of the study. Both FCZ and TBF were effective at reducing the incidence of paresis. Only FCZ was effective at reducing most neurological and systemic signs. FCZ treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of CSF fungal cultures compared with those for PEG-treated controls, but TBF treatments had no significant effect on these parameters. Neither drug affected CSF glucose levels. Mean serum TBF levels by bioassay were within the range of 3.5 to 6.2 microgram/ml at 1, 2, and 4 h postdosing and 0.35 to 7.0 microgram/ml at 14 h postdosing. No TBF was detected in CSF. Mean FCZ levels (24 to 25.5 h postdosing) by bioassay were 16.4 to 19.2 and 13.5 to 19.2 microgram/ml in serum and CSF, respectively. The reduction in the numbers of CFU in the spinal cord and brain was over 100-fold (P = 0.0005) in FCZ-treated animals and 2-fold (P = 0.2) in TBF-treated animals compared with those in PEG-treated animals. Histopathologic severity (semiquantitative scoring system) was significantly attenuated by FCZ treatment (P = 0. 05) and was slightly attenuated by TBF treatment compared with that for the controls. In conclusion, TBF appeared to have a slight effect on survival, histology, and reduction of the numbers of CFU in tissue; however, these effects were not significant. FCZ was effective at controlling coccidioidal meningitis.
Assuntos
Antifúngicos/uso terapêutico , Coccidioidomicose/tratamento farmacológico , Fluconazol/uso terapêutico , Meningite Fúngica/tratamento farmacológico , Naftalenos/uso terapêutico , Animais , Antifúngicos/sangue , Antifúngicos/líquido cefalorraquidiano , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/microbiologia , Coccidioides/efeitos dos fármacos , Coccidioidomicose/patologia , Ensaio de Unidades Formadoras de Colônias , Modelos Animais de Doenças , Fluconazol/sangue , Fluconazol/líquido cefalorraquidiano , Glucose/líquido cefalorraquidiano , Leucócitos , Masculino , Meningite Fúngica/patologia , Testes de Sensibilidade Microbiana , Naftalenos/sangue , Naftalenos/líquido cefalorraquidiano , Coelhos , Terbinafina , Resultado do TratamentoRESUMO
Micellar electrokinetic chromatography (MEKC) was applied to the separation of the anti-HIV agents, michellamines A and B, and two other structurally related monomers found in the extract of the Ancistrocladus plants. Using buffers containing either 10 mM sodium phosphate (pH 7.0), 50 mM sodium deoxycholate and 10-20% acetonitrile or 5 mM sodium phosphate (pH 7.0), 20 mM sodium dodecyl sulfate and 25% acetonitrile allowed baseline separations of the four components in the mixture in less than 10 min. The MEKC methods gave sharper peaks and better resolution compared to high-performance liquid chromatography. For MEKC separation of the plant extracts, UV absorption detection provided adequate sensitivity; however, higher sensitivity could be achieved with UV laser-induced fluorescence detection (LIF). Using the sodium dodecyl sulfate-containing buffer and LIF, the limit of detection for michellamine B was approximately 2 ng/mL. The sensitivity was degraded approximately 100-fold when using the deoxycholate buffer because of high background fluorescence. Preliminary results show that MEKC with LIF is feasible for the sensitive detection of michellamine B in serum.
Assuntos
Antivirais/isolamento & purificação , Cromatografia/métodos , Eletroforese/métodos , Isoquinolinas/isolamento & purificação , Naftalenos/isolamento & purificação , Antivirais/sangue , Antivirais/química , Cromatografia Líquida de Alta Pressão , Eletroquímica , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Isoquinolinas/sangue , Isoquinolinas/química , Micelas , Estrutura Molecular , Naftalenos/sangue , Naftalenos/química , Extratos Vegetais/química , Espectrometria de FluorescênciaRESUMO
The authors investigated the pharmacokinetics of the pressor substance 5,8-dimetoxy-trans-2-/2-hydroxyethyl/-amino-3-hydroxy-1,2,3,4-tetrahydronaphthaline hydrochloride (1b), which possessed strong pressor action. Blood concentrations after venous administration in a dose of 1 mg/kg of body weight were determined by means of exctration spectrofluorometric method. The data complied with the biexponential equation, meeting the requirements of an open two-compartment model. There was a quick elimination of the substance from the central compartment, which correlated also with the data for quick disappearances of the effect on the arterial pressure.