RESUMO
Ebastine, a histamine H1 antagonist, nonsedating, belonging to BCS class II is used in the treatment of allergic rhinitis and chronic idiopathic urticaria. The current study was intended in augmenting the aqueous solubility and dissolution rate of ebastine, by formulating a microemulsion system using oleic acid, Transcutol® HP, and Tween®80 as oily phase, cosurfactant, and surfactant, respectively, by the phase titration method. A custom mixture design with optimality D was used to design the formulation by using the Design Expert® Software (Version 11; Stat-Ease, Inc., Minneapolis, MN, USA). Optimization of formulation was performed using the numerical optimization technique, where optimization is based upon the desirability. The optimized formulation was evaluated for transmittance, viscosity, globule size, polydispersity index, zeta potential, drug content, morphological studies, and in vitro studies. The optimized formulation displayed percent cumulative drug release, ranging from 82.9% to 90.6% obtained after dissolution studies and the percent cumulative drug release after diffusion studies ranged from 83.3% to 100%. The in vitro release data were subjected to kinetic treatment. The zero-order and first-order plots were linear and showed the highest values for R2, which indicated mixed-order release. The Higuchi plot was linear, indicating diffusion as the mechanism of release. From Peppas plot, it was further confirmed that the release for dissolution studies was anomalous and for diffusion studies it was zero order. Thus, the studies concluded that the microemulsion technique is a very good approach for enhancing the solubility and dissolution rate of the BCS class II drug ebastine.
Assuntos
Ácido Oleico , Polissorbatos , Butirofenonas , Emulsões , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Piperidinas , Solubilidade , TensoativosRESUMO
Drugs used to treat psychotic disorders ('antipsychotics') have been widely used in psychiatry since the introduction of chlorpromazine in the mid-1950s. The categorization of these drugs evolved in a piecemeal way, relying initially on grouping by chemical structure (e.g. phenothiazines, butyrophenones), then by epoch of introduction (e.g. first generation ('conventional') vs second generation ('atypical')). As psychopharmacological expertise has advanced, it has become possible to quantify affinities for each drug in this class for relevant receptors including dopamine D2, 5HT2A, 5HT2C, histamine H1 and others. However, until the recent emergence of a new generation of agents known collectively as dopamine D2 receptor partial agonists (e.g. aripiprazole, brexpiprazole and cariprazine), there had been little reference in drug classification to specific pharmacological properties. An overview of data on receptor affinities across multiple drugs and receptor types would permit categorization according to binding affinities and putative pharmacological mechanisms. In this paper, we have attempted to construct a 'subway map' of 32 drugs used for treatment of psychotic disorders. This design allows a visualization of both the historical classifications by structure and epoch of introduction, and of the binding affinities for key receptors based on appraisal of scientific literature. The map represents a step towards categorization by mechanism, allowing prescribers and patients to understand which drugs share common biological features and the extent to which drugs may have similarities and differences in their mechanisms. In addition, this approach may encourage more logical groupings of drugs to be used in systematic reviews and meta-analyses.
Assuntos
Antipsicóticos , Transtornos Psicóticos , Ferrovias , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Butirofenonas/uso terapêutico , Clorpromazina , Dopamina/metabolismo , Agonistas de Dopamina/uso terapêutico , Histamina , Humanos , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Receptores de Dopamina D2/metabolismo , Revisões Sistemáticas como AssuntoRESUMO
BACKGROUND: The increase in drug-resistant opportunistic pathogenic bacteria, especially of antibiotic-resistant Staphylococcus epidermidis (S. epidermidis), has led to difficulties in the treatment of skin and soft tissue infections (SSTI). The major reason for bacterial resistance is the formation of bacterial biofilm. Here, we report a promising combination therapy of flavaspidic acid BB (BB) and mupirocin, which can effectively eradicate the biofilm of S. epidermidis and eliminate its drug resistance. RESULT: The susceptibility test showed that the combination of BB and mupirocin has good antibacterial and antibiofilm activities, and the fractional inhibitory concentration index (FICI) of BB combined with mupirocin was 0.51 ± 0.00 ~ 0.75 ± 0.05, showing synergistic effect. Moreover, the time-kill curve assay results indicated that the combination of drugs can effectively inhibit the planktonic S. epidermidis. After drugs treatment, the drug-combination showed significantly inhibitory effects on the metabolic activity and total biomass in each stage of biofilm formation. The synergistic effect is likely related to the adhesion between bacteria, which is confirmed by field emission scanning electron microscope. And the expression level of aap, sarA and agrA genes were detected by real-time quantitative PCR (qRT-PCR). CONCLUSION: Our study provides the experimental data for the use of BB for the clinical treatment of skin infections and further demonstrate the potential of BB as a novel biofilm inhibitor.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Staphylococcus epidermidis , Antibacterianos/farmacologia , Biofilmes , Butirofenonas , Testes de Sensibilidade Microbiana , Mupirocina/farmacologiaRESUMO
Ebastine is a long-acting, nonsedating, second-generation antihistaminic drug that prevents histamine action, mainly in immediate hypersensitivity. This project was aimed to formulate and characterize orodispersible tablets of ebastine, utilizing different proportions of three disintegrants, namely crospovidone, sodium starch glycolate, and coprocessed superdisintegrant. Initially, fifteen trial batches of ebastine orodispersible tablets were outlined using the central composite design of Minitab software. The tablets were formulated by the direct compression method. The compressed tablets were then evaluated for precompression and postcompression physicochemical parameters, such as angle of repose, Carr's index, Hausner's ratio, hardness, thickness, weight variation, drug content, friability, wetting time, disintegration time, dispersion time, and water absorption ratio. The in vitro dissolution test was conducted according to Indian Pharmacopeia 2018, with the help of the rotating paddle method using 0.5% w/v sodium lauryl sulfate buffer in 0.1 N HCl. For the optimized batch (8th batch), all the physicochemical parameters like angle of repose (33.77°), Carr's index (19.34%), Hausner's ratio (1.24), weight variation (202.5 mg), hardness (4.3 kg/cm2), friability (0.44%), thickness (3.16 mm), dissolution (95.78%), and drug content (101.67%) were within the acceptable limit as per Indian Pharmacopeia 2018. The wetting time, disintegration time, dispersion time, and water absorption ratio were reported to be 25.1 seconds, 16.0 seconds, 38.6 seconds, and 91.92%, respectively. Hence, the results suggested that orodispersible tablets of ebastine can be formulated. Furthermore, the mixing of crospovidone, sodium starch glycolate, and coprocessed super disintegrants can result in excellent desirable properties in the orodispersible tablet.
Assuntos
Química Farmacêutica , Povidona , Butirofenonas , Química Farmacêutica/métodos , Piperidinas , Controle de Qualidade , Solubilidade , Comprimidos/química , ÁguaRESUMO
Cytochrome P450s (P450s) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans, but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized, along with pig CYP2J34 previously identified. The cDNAs of these CYP2Js contain open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and share high sequence identity (77%-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven CYP2J genes contain nine coding exons and are located in corresponding genomic regions, with the pig CYP2J genes forming a gene cluster. These CYP2J2 mRNAs were predominantly expressed in the small intestine with additional expression in the kidney and brain for dog CYP2J2 and pig CYP2J91 mRNAs, respectively. All seven CYP2Js metabolized human CYP2J2 substrates terfenadine, ebastine, and astemizole, indicating that they are functional enzymes. Dog CYP2J2 and pig CYP2J34 and CYP2J35 efficiently catalyzed ebastine primary hydroxylation and secondary carebastine formation at low substrate concentrations, just as human CYP2J2 does. Velocity-versus-substate plots exhibited sigmoidal relationships for dog CYP2J2, cat CYP2J2, and pig CYP2J33, indicating allosteric interactions. These results suggest that dog, cat, and pig CYP2Js have similar functional characteristics to human CYP2J2, with slight differences in ebastine and astemizole oxidations. SIGNIFICANCE STATEMENT: Dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, homologous to human CYP2J2, were identified and characterized by sequence, phylogenetic, and genomic structure analyses. Intestinal expression patterns of CYP2J mRNAs were characteristic in dogs, cats, and pigs. Dog, cat, and pig CYP2Js likely play roles as drug-metabolizing enzymes in the small intestine, similar to human CYP2J2.
Assuntos
Gatos , Sistema Enzimático do Citocromo P-450 , Cães , Suínos , Animais , Astemizol , Butirofenonas , Gatos/genética , Citocromo P-450 CYP2J2 , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Cães/genética , Humanos , Filogenia , Piperidinas , Suínos/genética , TerfenadinaRESUMO
The second-generation antihistamines at licensed doses are first-line treatment in urticaria and up-dosing is recommended as second-line treatment. To assess the efficacy and safety of escalated doses of ebastine in patients with chronic urticaria (CU), we designed this study. Recruited patients with CU were treated with increasing doses of ebstine. Treatment started at the daily dose of 10 mg. The symptom is assessed weekly, and if there is no significant improvement, the dose is increased from 10 mg to 20 mg, and if still no significant improvement, up to 40 mg. Pruritus, number, diameter, duration and frequency of wheals, and adverse reactions were assessed. One hundred and forty (76.50%) patients achieved marked effect with ebastine 10 mg/day, 27 (14.75%) patients with ebastine 20 mg/day and 13 (7.10%) patients with ebastine 40 mg/day, while 3(1.64%) patients did not get marked effect. There was no significant difference of effect between factitious urticaria, CSU, cholinergic urticaria and CSU with factitious urticaria in different dose (all p > 0.05). Common adverse reactions of ebstine treatment, included dry mouth, somnolence, tiredness and headache, were mild or moderate. There was no significant difference between the degree score of dry mouth with different doses of ebastine, and the same to somnolence, tiredness and headache (all p > 0.05). Doses escalation of ebastine should be effective in treatment of factitious urticaria, CSU and cholinergic urticaria with poorly treated by standard of double doses. Increasing ebastine dose did not increase the incidence of adverse reactions.
Assuntos
Urticária Crônica , Urticária , Xerostomia , Butirofenonas , Colinérgicos/uso terapêutico , Doença Crônica , Cobre , Cefaleia/induzido quimicamente , Cefaleia/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H1 , Humanos , Piperidinas , Estudos Prospectivos , Sonolência , Urticária/induzido quimicamente , Urticária/diagnóstico , Urticária/tratamento farmacológico , Xerostomia/induzido quimicamente , Xerostomia/tratamento farmacológicoRESUMO
Urticaria affects all age groups of a population. It is triggered by allergens in foods, insect bites, medications, and environmental conditions. Urticaria is characterized by itching, a burning sensation, wheals and flares, erythema, and localized edema. The aim of this study was to develop a polymeric dosage form of ebastine using Carbopol 940 and mixture of span and tween. The emulsion was prepared, the gelling agent was added and the desired emulgel loaded with active drug was formulated. The formulations were subjected to physical stability, pH, viscosity, spreadability, drug content analysis, thermal analysis, in vitro drug release, and in vivo anti-allergic activity in animal model. The formulated emulgel exhibited good physical stability. The pH of the formulation was in the range of 5.2 ± 0.17 to 5.5 ± 0.20 which is suitable for topical application. Insignificant changes (p > .05) were observed in viscosity and spreadability of stored emulgels. The drug content was in the official limit of Pharmacopeia (i.e. 100 ± 10%). DSC measurements predicted that there is no interaction between the active moiety and excipients in emulgel formulation. The optimized formulation (ES3) released 74.25 ± 1.8% of ebastine after 12 h. The ebastine emulgel showed significant (p < .05; ANOVA) in vivo anti-allergic activity as compared to commercial product Benadryl® in histamine-induced allergy in rabbits. This study concluded that a topical drug delivery of ebastine-loaded emulgel could be well tolerated and safe for the treatment of urticaria/hives.
Assuntos
Resinas Acrílicas/química , Butirofenonas/farmacologia , Géis/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Piperidinas/farmacologia , Urticária/patologia , Administração Cutânea , Animais , Butirofenonas/administração & dosagem , Química Farmacêutica , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões/química , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Concentração de Íons de Hidrogênio , Masculino , Piperidinas/administração & dosagem , Coelhos , Reologia , ViscosidadeRESUMO
In anaesthetic practice the risk of hypoxia and arterial blood gas disturbances is evident, as most anaesthetic regimens depress the respiratory function. Hypoxia may be extended during recovery, and for this reason we wished to investigate if oxygen supply during a one hour post-operative period reduced the development of hypoxia and respiratory acidosis in rats anaesthetized with fentanyl/fluanisone and midazolam. Twelve Sprague Dawley rats underwent surgery and were divided in two groups, breathing either 100% oxygen or atmospheric air during a post-operative period. The peripheral blood oxygen saturation and arterial acid-base status were analyzed for differences between the two groups. We found that oxygen supply after surgery prevented hypoxia but did not result in a significant difference in the blood acid-base status. All rats developed respiratory acidosis, which could not be reversed by supplemental oxygen supply. We concluded that oxygen supply improved oxygen saturation and avoided hypoxia but did not have an influence on the acid-base status.
Assuntos
Midazolam , Animais , Butirofenonas , Fentanila , Masculino , RatosRESUMO
OBJECTIVES: Since melperone abuse with lethal intoxication is common, expert opinions based on therapeutical and lethal concentration ranges can be considered as important. Because there is a lack of information about fatalities caused by melperone mono-intoxications and data on tissue samples with concentration distribution, the aim of this work is the examination of lethal concentration ranges of melperone and drug quantification in different matrices. METHODS: An LC-MS/MS method was applied for analyses performed in blood and tissue samples. Quantification based on standard addition and sample preparation on liquid-liquid extraction with 1-chlorobutane. An appropriate tissue homogenization was performed ahead of extraction with an IKA Ultra-Turrax-Tube-Drive®. A Luna 5 µm C18 (2) 100 Å, 150 × 2 mm analytical column was used for chromatographic separation and the elution was performed with two mobile phases consisted of A (H2O/methanol = 95/5, v/v) and B (H2O/methanol = 3/97, v/v) both with 10 mM ammonium acetate and 0.1% acetic acid. RESULTS: A multi-drug LC-MS/MS analytical method developed was applied successfully for melperone quantification in different post-mortem matrices. No analytical problems could be identified during method development and analyses of real samples. The melperone lethal concentration calculated in femoral blood of the drug mono-intoxication investigated was 10 mg/L. Melperone concentration distribution was presented for the first time. CONCLUSIONS: The lethal reference concentration of melperone in femoral blood of 17.1 mg/L pointed out in different reference lists should be used with caution. Instead, a lower lethal melperone concentration should be considered. The post-mortem concentration distribution of the drug presented could be helpful in the interpretation of cases where no blood samples are available.
Assuntos
Butirofenonas , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Humanos , Extração Líquido-Líquido , Espectrometria de Massas em Tandem/métodosRESUMO
We present a case of fatal poisoning by 4-F-methcathinone (4-FMC; also called flephedrone), 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-α-PVP), 4-fluoro-α-pyrrolidinopentiophenone (4-F-α-PVP), and α-pyrrolidinohepatanophenone (PV8). In this study, we compared the mass spectra of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, PV8, and α-pyrrolidinohexanophenone between LC-ESI-LIT-MS and GC-EI-MS analyses. Subsequently, we applied LC-ESI-LIT-MS for detection and quantification analyses of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in human authentic whole blood samples. More specific mass spectra for the target compounds were obtained with the LC-ESI-LIT-MS qualitative analyses than with the GC-EI-MS analyses, indicating that LC-ESI-LIT-MS was more suitable for the qualitative analysis of cathinones. The LC-ESI-LIT-MS validation data showed moderately good linearity and reproducibility for the compounds in the quantitative analyses at the range of 1-500 ng/mL. The detection limits of four cathinones ranged from 0.1 to 1 ng/mL. The concentrations of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in heart whole blood samples were 365, 449, 145, and 218 ng/mL, respectively. Those of the 4 cathinones in femoral vein whole blood samples were 397, 383, 127, and 167 ng/mL, respectively. We can then assume that the cause of death was acute poisoning by a combination of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8. In this article, we present a detailed LC-ESI-LIT-MS procedure for detection and quantification analyses of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in authentic human whole blood samples.
Assuntos
Alcaloides/sangue , Butirofenonas/sangue , Pentanonas/sangue , Propiofenonas/sangue , Psicotrópicos/sangue , Pirrolidinas/sangue , Adulto , Cromatografia Líquida , Toxicologia Forense , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Chronic exposure to cathinone derivatives increases the risk of severe health hazards, whereas little is known about the detailed pathogenic mechanisms triggered by the derivatives. We have recently shown that treatment with α-pyrrolidinononanophenone (α-PNP, a highly lipophilic cathinone derivative possessing a long hydrocarbon main chain) provokes neuronal cell apoptosis and its 4'-fluorinated analog (F-α-PNP) potently augments the apoptotic effect. In this study, we found that neuronal SK-N-SH cell damage elicited by F-α-PNP treatment is augmented most potently by pre-incubation with an AKR1B1 inhibitor tolrestat, among specific inhibitors of four aldo-keto reductase (AKR) family members (1B1, 1C1, 1C2, and 1C3) expressed in the neuronal cells. In addition, forced overexpression of AKR1B1 remarkably lowered the cell sensitivity to F-α-PNP toxicity, clearly indicating that AKR1B1 protects from neurotoxicity of the derivative. Treatment of SK-N-SH cells with F-α-PNP resulted in a dose-dependent up-regulation of AKR1B1 expression and activation of its transcription factor NF-E2-related factor 2. Metabolic analyses using liquid chromatography/mass spectrometry/mass spectrometry revealed that AKR1B1 is hardly involved in the F-α-PNP metabolism. The F-α-PNP treatment resulted in production of reactive oxygen species and lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE) in the cells. The enhanced HNE level was reduced by overexpression of AKR1B1, which also lessened the cell damage elicited by HNE. These results suggest that the AKR1B1-mediated neuronal cell protection is due to detoxification of HNE formed by F-α-PNP treatment, but not to metabolism of the derivative.
Assuntos
Aldeído Redutase/biossíntese , Butirofenonas/toxicidade , Drogas Desenhadas/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neuroproteção/fisiologia , Pirrolidinas/toxicidade , Aldeído Redutase/antagonistas & inibidores , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Naftalenos/farmacologia , Neurônios/patologiaRESUMO
BACKGROUND: Local ischemic preconditioning (IPC) and remote ischemic conditioning (RIC) induced by brief periods of ischemia and reperfusion protect against ischemia-reperfusion injury. METHODS: We studied the sensitivity to IR-injury and the influence of strain, age, supplier, and anesthesia upon the efficacy of IPC and RIC in 7- and 16-weeks-old Sprague-Dawley and Wistar rats from three different suppliers. The influence of sedation with a hypnorm and midazolam mixture (rodent mixture) and pentobarbiturate was compared. RESULTS: IPC attenuated infarct size in both 7-weeks-old Sprague-Dawley (48.4 ± 17.7% vs. 20.3 ± 6.9, p < 0.001) and 7-weeks-old Wistar (55.6 ± 10.9% vs. 26.8 ± 5.0%, p < 0.001) rats. Infarct size was larger in 16-weeks-old Sprague-Dawley rats, however, IPC still lowered infarct size (78.8 ± 9.2% vs. 58.3 ± 12.3%, p < 0.01). RIC reduced infarct sizes in 7-weeks-old Sprague-Dawley (75.3 ± 11.8% vs. 58.6 ± 8.9%, p < 0.05), but not in 7-weeks-old Wistar rats (31.7 ± 17.6% and 24.0 ± 12.6%, p = 0.2). In 16-weeks-old Sprague-Dawley rats, RIC did not induce protection (76.4 ± 5.5% and 73.2 ± 14.7%, p = 0.6). However, RIC induced protection in 16-weeks-old Wistar rats (45.2 ± 8.5% vs. 14.7 ± 10.8%, p < 0.001). RIC did not reduce infarct size in 7-weeks-old Sprague-Dawley rats from Charles River (62.0 ± 13.5% and 69.4 ± 10.4% p = 0.3) or 16-weeks-old Wistar rats from Janvier (50.7 ± 11.3 and 49.2 ± 16.2, p = 0.8). There was no difference between sedation with rodent mixture or pentobarbiturate. CONCLUSION: The cardioprotective effect of IPC is consistent across rat strains independent of age, strain, and supplier. RIC seems to be less reproducible, but still yields protection across different rat strains. However, age, animal supplier, and anesthetics may modulate the sensitivity of IR-injury and the response to RIC.
Assuntos
Analgesia/métodos , Precondicionamento Isquêmico/métodos , Traumatismo por Reperfusão Miocárdica/terapia , Pesquisa Translacional Biomédica/normas , Analgesia/efeitos adversos , Animais , Barbitúricos/administração & dosagem , Butirofenonas/administração & dosagem , Combinação de Medicamentos , Fentanila/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Preparação de Coração Isolado/normas , Masculino , Midazolam/administração & dosagem , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
Synthetic cathinones are among the most popular new psychoactive substances, being abused for their stimulant properties, which are similar to those of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Considering that the liver is a likely target for cathinones-induced toxicity, and for their metabolic activation/detoxification, we aimed to determine the hepatotoxicity of three commonly abused synthetic cathinones: butylone, α-methylamino-butyrophenone (buphedrone) and 3,4-dimethylmethcathinone (3,4-DMMC). We characterized their cytotoxic profile in primary rat hepatocytes (PRH) and in the HepaRG and HepG2 cell lines. PRH was the most sensitive cell model, showing the lowest EC50 values for all three substances (0.158 mM for 3,4-DMMC; 1.21 mM for butylone; 1.57 mM for buphedrone). Co-exposure of PRH to the synthetic cathinones and CYP450 inhibitors (selective and non-selective) proved that hepatic metabolism reduced the toxicity of buphedrone but increased that of butylone and 3,4-DMMC. All compounds were able to increase oxidative stress, disrupting mitochondrial homeostasis and inducing apoptotic and necrotic features, while also increasing the occurrence of acidic vesicular organelles in PRH, compatible with autophagic activation. In conclusion, butylone, buphedrone and 3,4-DMMC have hepatotoxic potential, and their toxicity lies in the interference with a number of homeostatic processes, while being influenced by their metabolic fate.
Assuntos
3,4-Metilenodioxianfetamina/análogos & derivados , Butirofenonas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Metilaminas/toxicidade , Propiofenonas/toxicidade , 3,4-Metilenodioxianfetamina/administração & dosagem , 3,4-Metilenodioxianfetamina/toxicidade , Animais , Autofagia/efeitos dos fármacos , Butirofenonas/administração & dosagem , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/patologia , Drogas Desenhadas/administração & dosagem , Drogas Desenhadas/toxicidade , Relação Dose-Resposta a Droga , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Masculino , Metilaminas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Propiofenonas/administração & dosagem , Ratos , Ratos WistarRESUMO
Photoinitiators (PIs) are widely used for photopolymerization in industrial area and recently paid close attention to in biomedical field. However, there are few reports on their toxicity to human health. Here we explored cytotoxicity and cytocompatibilty of seven commercial and industrial-used PIs for developing their potential clinical application. Phenylbis(acyl) phosphine oxides (BAPO), 2-Benzyl-2-(dimethylamino)-4'-morpholinobutyrophenone (369), 4,4'-Bis(diethylamino) benzophenone (EMK), Diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (TPO), and 2-Isopropylthioxanthone (ITX) caused different extent cytotoxicities to four tissue types of cells at the concentrations of 1 to 50 µM under a non-irradiation condition, of which the BAPO cytotoxicity was the highest, whereas Ethyl (2,4,6-trimethylbenzoyl) phenylphosphinate (TPOL) and Methyl benzoylformate (MBF) displayed the lowest cellular toxicity. The cell lines and primary cells appeared highly sensitive to BAPO toxicity, the primary lymphocytes relatively to photoinitiator 369 (369) and EMK toxicities, LO2 cells to EMK and TPO toxicities, the primary lymphocytes and HUVEC-12 cells to MBF toxicity, but only HEK293T cells not to 369 toxicity. Furthermore, these PIs led to increasing cytotoxicity to different extents after exposure to 455 nm blue light, which is consistent with non-irradiation tendency. All the cells presented low sensitivity to TPOL and MBF, of which TPOL-triggered polymer is dramatically superior in its cytocompatibility to MBF, and in its transparency to clinically exclusively-used camphorquinone (CQ). The novel findings indicate that BAPO is the most toxic among the seven PIs, but TPOL and MBF are the least toxic, directing their development and application. Combined their triggered polymer cytocompatibility and color with reported deep curing efficiency, TPOL is more promising to be applied especially to clinical practice.
Assuntos
Benzofenonas/toxicidade , Butirofenonas/toxicidade , Óxidos N-Cíclicos/toxicidade , Luz , Fosfinas/toxicidade , Fotoiniciadores Dentários/toxicidade , Polímeros/toxicidade , Tioxantenos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Masculino , Camundongos Endogâmicos C57BL , PolimerizaçãoRESUMO
Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.
Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Condicionamento Psicológico/efeitos dos fármacos , Drogas Desenhadas/administração & dosagem , Locomoção/efeitos dos fármacos , Metilaminas/administração & dosagem , Propiofenonas/administração & dosagem , Síndrome de Abstinência a Substâncias/psicologia , Animais , Butirofenonas/administração & dosagem , Condicionamento Psicológico/fisiologia , Dopamina/metabolismo , Esquema de Medicação , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pirrolidinas/administração & dosagem , Síndrome de Abstinência a Substâncias/metabolismo , Fatores de TempoRESUMO
The recent development of high throughput compound screening has allowed drug repurposing to emerge as an effective avenue for discovering novel treatments for cancer. FDA-approved antipsychotic drugs fluspirilene, penfluridol, and pimozide are clinically used for the treatment of psychotic disorders, primarily schizophrenia. These compounds, belong to diphenylbutylpiperidine class of antipsychotic drugs, are the potent inhibitors of dopamine D2 receptor and calcium channel. A correlation has been found that patients treated for schizophrenia have lower incidences of certain types of cancer, such as respiratory, prostate, and bladder cancers. These compounds have also been shown to inhibit cancer proliferation in a variety of cancer cells, including melanoma, lung carcinoma, breast cancer, pancreatic cancer, glioma, and prostate cancer, among others. Antipsychotic drugs induce apoptosis and suppress metastasis in in vitro and in vivo models through mechanisms involving p53, STAT3, STAT5, protein phosphatase 2A, cholesterol homeostasis, integrins, autophagy, USP1, wnt/ß-catenin signaling, and DNA repair. Additionally, pre-clinical evidence suggests that penfluridol and pimozide act synergistically with existing chemotherapeutic agents, such as dasatinib, temozolomide, and cisplatin. Some studies have also reported that the cytotoxic activity of the antipsychotics is selective for dividing cells. Based on this growing body of evidence and the availability and previous FDA-approval of the drugs, the compounds appear to be promising anti-cancer agents.
Assuntos
Antineoplásicos/uso terapêutico , Antipsicóticos/uso terapêutico , Butirofenonas/química , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Piperidinas/química , Animais , HumanosRESUMO
Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. (±)-MRJF22, a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(-)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(-)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(-)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.
Assuntos
Inibidores da Angiogênese/farmacologia , Butirofenonas/farmacologia , Melanoma/tratamento farmacológico , Ácidos Pentanoicos/farmacologia , Piperidinas/farmacologia , Pró-Fármacos/farmacologia , Neoplasias Uveais/tratamento farmacológico , Valeratos/farmacologia , Inibidores da Angiogênese/síntese química , Butirofenonas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ácidos Pentanoicos/síntese química , Piperidinas/líquido cefalorraquidiano , Pró-Fármacos/síntese química , Estereoisomerismo , Valeratos/líquido cefalorraquidianoRESUMO
N-Ethylhexedrone (NEH) and buphedrone (Buph) are emerging synthetic cathinones (SC) with limited information about their detrimental effects within central nervous system. Objectives: To distinguish mice behavioural changes by NEH and Buph and validate their differential harmful impact on human neurons and microglia. In vivo safety data showed the typical induced behaviour of excitation and stereotypies with 4-64 mg/kg, described for other SC. Buph additionally produced jumping and aggressiveness signs, while NEH caused retropulsion and circling. Transient reduction in body-weight gain was obtained with NEH at 16 mg/kg and induced anxiolytic-like behaviour mainly with Buph. Both drugs generated place preference shift in mice at 4 and 16 mg/kg, suggestive of abuse potential. In addition, mice withdrawn NEH displayed behaviour suggestive of depression, not seen with Buph. When tested at 50-400 µM in human nerve cell lines, NEH and Buph caused neuronal viability loss at 100 µM, but only NEH produced similar results in microglia, indicating different cell susceptibilities. NEH mainly induced microglial late apoptosis/necrosis, while Buph caused early apoptosis. NEH was unique in triggering microglia shorter/thicker branches indicative of cell activation, and more effective in increasing microglial lysosomal biogenesis (100 µM vs. 400 µM Buph), though both produced the same effect on neurons at 400 µM. These findings indicate that NEH and Buph exert neuro-microglia toxicities by distinct mechanisms and highlight NEH as a specific inducer of microglia activation. Buph and NEH showed in vivo/in vitro neurotoxicities but enhanced specific NEH-induced behavioural and neuro-microglia dysfunctionalities pose safety concerns over that of Buph.
Assuntos
Alcaloides/toxicidade , Comportamento Animal/efeitos dos fármacos , Butirofenonas/toxicidade , Metilaminas/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Microglia/efeitos dos fármacosRESUMO
Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.
Assuntos
Astemizol/química , Butirofenonas/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Piperidinas/química , Ácido Araquidônico/genética , Ácido Araquidônico/metabolismo , Astemizol/farmacologia , Butirofenonas/farmacologia , Domínio Catalítico/efeitos dos fármacos , Citocromo P-450 CYP2J2 , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Simulação de Acoplamento Molecular , Oxirredução/efeitos dos fármacos , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Especificidade por SubstratoRESUMO
N-ethylhexedrone (NEH) and buphedrone (BUPH) are synthetic drugs structurally related to natural cathinone. These synthetic cathinones (SC) are members of the heterogenous family of new psychoactive substances (NPS), which have caused major concern in scientific and forensic communities over the past years, due to their widespread consume. Thus, there is a constant need for monitoring the use of these new substances and gather knowledge on their metabolism and excretion profiles, in order to try to identify markers of NPS consumption. This study aimed at the identification and quantification of NEH, BUPH and selected phase I metabolites using HPLC-MS/MS. NEH, BUPH and some related metabolites were synthesized in-house and quantified in 24 h mice urine, following single dose administration of each drug (64 mg kg-1, i.p.). NEH and BUPH were quantified in mice urine at 58.3 ± 14.4 and 146.2 ± 14.9 µg mL-1, respectively. Similar metabolic pathways were observed for both drugs. Among the metabolites studied, the most excreted ones derived from N-dealkylation of either NEH or BUPH (at around 80 µg mL-1 of urine). Other metabolites resulting from ketone reduction and ketone reduction combined with N-dealkylation or 4-aryl hydroxylation (detected for the first time in non-ring substituted SC) were also identified and quantified. Urine samples were screened using liquid chromatography-high resolution mass spectrometry and various phase II metabolites, including N-acetylated, glucuronides and dicarboxylic acid conjugates were tentatively identified, some of them for the first time. This work is a contribution to the identification of metabolites from SC that can become potential markers to estimate drug consumption.
