Benzodiazepines(BDZs)are used in clinics for anxiolysis,anticonvulsants,sedative hypnosis,and muscle relaxation.They have high consumptions worldwide because of their easy availability and potential addiction.They are...Benzodiazepines(BDZs)are used in clinics for anxiolysis,anticonvulsants,sedative hypnosis,and muscle relaxation.They have high consumptions worldwide because of their easy availability and potential addiction.They are often used for suicide or criminal practices such as abduction and drug-facilitated sexual assault.The pharmacological effects of using small doses of BDZs and their detections from complex biological matrices are challenging.Efficient pretreatment methods followed by accurate and sensitive detections are necessary.Herein,pretreatment methods for the extraction,enrichment,and preconcentration of BDZs as well as the strategies for their screening,identification,and quantitation developed in the past five years have been reviewed.Moreover,recent advances in various methods are summarized.Characteristics and advantages of each method are encompassed.Future directions of the pretreatment and detection methods for BDZs are also reviewed.展开更多
Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite t...Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.展开更多
Jiu Ai Tu(The Moxa Treatment)from the Song dynasty is the earliest surviving painting that focuses on the subject of acupuncture and moxibustion.This paper takes the medical activities depicted in the artwork as its r...Jiu Ai Tu(The Moxa Treatment)from the Song dynasty is the earliest surviving painting that focuses on the subject of acupuncture and moxibustion.This paper takes the medical activities depicted in the artwork as its research object and systematically analyzes the external treatment methods for abscesses during the Song dynasty reflected in Jiu Ai Tu.By examining the understanding of abscesses during that period,the paper explores the level of development in external medicine techniques.By analyzing the medical awareness and behaviors of patients when facing such severe illnesses,it aims to explore the societal cognition and experiences regarding health and disease.The paper attempts to present the folk medical ecology of the Song dynasty represented by Jiu Ai Tu.展开更多
A simple and high-throughput method to simultaneously determine selected benzodiazepines (i.e., diazepam, lorazepam, clonazepam, and bromazepam) in urine was developed and validated. The entire methodology consisted o...A simple and high-throughput method to simultaneously determine selected benzodiazepines (i.e., diazepam, lorazepam, clonazepam, and bromazepam) in urine was developed and validated. The entire methodology consisted of the application of an innovative extraction/cleanup procedure, namely liquid-liquid extraction with low-temperature partitioning (LLE-LTP), and analysis by liquid chromatography combined with high-resolution mass spectrometry (LC-HRMS). The LLE-LTP procedure was optimized via factorial design and by evaluating crucial variables, specifically the freezing mode (either slow or fast), the urine/acetonitrile volume ratio, and the sample ionic strength. The benzodiazepines were quantified using matrix-matched calibration curves where the following parameters were assessed by validation protocol: in general, linearity range of 17 - 200 μg?L–1 (r > 0.9957);limits of detection lower than 5 μg?L–1;relative standard deviations (RSD) lower than 12.5%;and accuracy ranging from 72.3 to 117%. To test this procedure’s performance, the method was applied to determine the content of diazepam in actual urine samples. The validation results obtained for the method demonstrated that the present methodology could be potentially applied in proficient laboratories as a routine approach for determining benzodiazepines compounds content in urine.展开更多
Objective:To determine the active components of Eupolyphaga sinensis Walker(Tu Bie Chong)and explore the mechanisms underlying its fracture-healing ability.Methods: A modified Einhorn method was used to develop a rat ...Objective:To determine the active components of Eupolyphaga sinensis Walker(Tu Bie Chong)and explore the mechanisms underlying its fracture-healing ability.Methods: A modified Einhorn method was used to develop a rat tibial fracture model.Progression of bone healing was assessed using radiological methods.Safranin O/fast green and CD31 immunohistochemical staining were performed to evaluate the growth of bone cells and angiogenesis at the fracture site.Methylthiazoletetrazolium blue and wound healing assays were used to analyze cell viability and migration.The Transwell assay was used to explore the invasion capacity of the cells.Tubule formation assays were used to assess the angiogenesis capacity of human vascular endothelial cells(HUVECs).qRT-PCR was used to evaluate the changes in gene transcription levels.Results: Tu Bie Chong fraction 3(TF3)significantly shortened the fracture healing time in model rats.X-ray results showed that on day 14,fracture healing in the TF3 treatment group was significantly better than that in the control group(P=.0086).Tissue staining showed that cartilage growth and the number of H-shaped blood vessels at the fracture site of the TF3 treatment group were better than those of the control group.In vitro,TF3 significantly promoted the proliferation and wound healing of MC3T3-E1s and HUVECs(all P<.01).Transwell assays showed that TF3 promoted the migration of HUVECs,but inhibited the migration of MC3T3-E1 cells.Tubule formation experiments confirmed that TF3 markedly promoted the ability of vascular endothelial cells to form microtubules.Gene expression analysis revealed that TF3 significantly promoted the expression of VEGFA,SPOCD1,NGF,and NGFR in HUVECs.In MC3T3-E1 cells,the transcript levels of RUNX2 and COL2A1 were significantly elevated following TF3 treatment.Conclusion: TF3 promotes fracture healing by promoting bone regeneration associated with the RUNX2 pathway and angiogenesis associated with the VEGFA pathway.展开更多
Carissa edulis Vahl is well known in Sudanese herbal medicine,commonly used for treatment of epilepsy,headache,chest pains,rheumatism,skin lesions,mania and other psychoactive diseases.The investigations of the safety...Carissa edulis Vahl is well known in Sudanese herbal medicine,commonly used for treatment of epilepsy,headache,chest pains,rheumatism,skin lesions,mania and other psychoactive diseases.The investigations of the safety use for psychoactive purposes in Sudanese healing traditions and identifying secondary metabolites of the plant extracts are the key steps towards determination of appropriate medicinal doses.Therefore,one of the chemical constituents was isolated and structurally identified by 1H-NMR and LC-MS.With the aim of evaluating Carissa edulis folk random uses,the isolated compound was compared with reference artificial drugs Lormetazepam,a potentially toxic compound.Structure investigations confirm that the isolated product was benzodiazepines analogous 7-chloro 1,4-benzodiazepine-2-ones.It is important to know the potential toxicity of certain plant in order to assess the therapeutic effect of it,as these are slight distinctions between the medicinal and toxic doses.In general the results obtained justify the use of the roots of Carissa edulis in traditional medicine for the treatment of some psychiatric diseases.展开更多
o-Nitrophenylazide was reduced by SmI2 in anhydrous THF at room temperature to produce active intermediate 2 (samarium amide), "living" double-anion in situ which reacted smoothly with α，β-unsaturated ket...o-Nitrophenylazide was reduced by SmI2 in anhydrous THF at room temperature to produce active intermediate 2 (samarium amide), "living" double-anion in situ which reacted smoothly with α，β-unsaturated ketones to afford 2,3-dihydro-1H-1,5-benzodiazepines in good yields under mild and neutral conditions.展开更多
On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated ...On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines”. With this announcement, the FDA proclaimed that much more needs to be known about the initiation, continuation, and discontinuation of these widely-used drugs. Unfortunately, relevant information is lacking, since for many years, there has been a notable sparsity in the funding and conduct of basic and clinical research on these drugs. In order to begin to fill the void, it is valuable to (re)examine animal models. We here describe a model of conditioned place-preference (CPP) for rats and for the first time, to our knowledge, show that the representative benzodiazepine alprazolam induces positive place-preference in male rats.展开更多
MgBr2 performs as a novel catalyst for the synthesis of various 1,5-benzodiazepine derivatives from wide range of substituted o- phenylenediamines and various ketones in good to excellent isolated yields （93-98%） us...MgBr2 performs as a novel catalyst for the synthesis of various 1,5-benzodiazepine derivatives from wide range of substituted o- phenylenediamines and various ketones in good to excellent isolated yields （93-98%） using water as solvent at ambient temperature. Several solvents were examined for this reaction; however, in terms of reaction yield and time, water was found to be the optimum solvent. The remarkable advantages offered by this method are easily and inexpensive available catalyst, simple procedure, mild conditions, much faster （40-60 man） reactions and good to excellent yields of products.展开更多
The crystal structure of the title compound, 1,1 dichloro 3 dichloro 3 dichloromethyl 1a,3 diphenyl 1a,2,3,4 tetrahydro 1H azirino 1,2 a 1,5 benzodiazepine (C 23 H 18 Cl 4N 2, M r =4...The crystal structure of the title compound, 1,1 dichloro 3 dichloro 3 dichloromethyl 1a,3 diphenyl 1a,2,3,4 tetrahydro 1H azirino 1,2 a 1,5 benzodiazepine (C 23 H 18 Cl 4N 2, M r =464.22) was crystallized in triclinic, space group P 1, with cell dimensions a=9.621(7), b=9.694(9), c=12.669(6) , α=107.99(5)°, β=101.42(5)°, γ=69.94(6)°, V=1050.2(4) 3, Z=2, D c =1.468 g/cm 3 , Cu Kα(λ=1.5418 ). F(000)=1816, μ =2.44 mm -1 . The structure was solved by direct methods and refined by full matrix least squares method, and the final crystallographic discrepancy factor is 0.063 for 2555 observed reflections. The molecular backbone is a tricyclic system with the central seven membered 1,5 diazepine ring in twisted boat like conformation and cis fused to both aziridine ring and benzene ring.展开更多
A series of 3-methoxycarbonylpropoxy-7-(imidazol-4-ylpropinamide)-1, 3-dihydrogen- 1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-ones, as farnesyltransferase(Ftase) inhibitors, were synthesized. The preparation of the ke...A series of 3-methoxycarbonylpropoxy-7-(imidazol-4-ylpropinamide)-1, 3-dihydrogen- 1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-ones, as farnesyltransferase(Ftase) inhibitors, were synthesized. The preparation of the key intermediate, 7-amino-3-methoxycabonylpropoxy-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, was improved.展开更多
A novel N-methyl, N-phenyl-[6-chloro-2-（4-chlorophenyl）-8-iodoimidazo[1, 2-a]- pyridine-3-yl]acetamide （compound Ⅴ） was synthesized, radiolabelled with 131I and evaluated in vitro. In vitro cell uptake studies sh...A novel N-methyl, N-phenyl-[6-chloro-2-（4-chlorophenyl）-8-iodoimidazo[1, 2-a]- pyridine-3-yl]acetamide （compound Ⅴ） was synthesized, radiolabelled with 131I and evaluated in vitro. In vitro cell uptake studies showed that MDA-MB-231 cells yield four-fold higher specific uptake of [^131I]-compound Ⅵ than MCF-7 cells, corresponding to the increased expression of PBR in MDA-MB-231 cells. Blocking studies significantly reduced the MDA-MB-231 cells uptake of [^131I]-compound Ⅵ. It indicated that [^131I]-compound Ⅵ might be a potential SPECT radioligand for imaging of PBR.展开更多
Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, d...Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 μl spray (d ≈ 1.00 g/ml). The nasal absorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal administration using this formulation was 33.45% ± 12.36% and the tmax was 18.33 ± 23.09 min, which was twice longer than the tmax obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (tmax), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (Cmax) and the absolute bioavailability (FA) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 μg/ml vs. 15.44 ± 4.00 μg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, respectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.展开更多
Benzodiazepines are psychotropic medications for effective management of anxiety. However, after over 50 years of unrestrained prescription use, prescribers realize the severity of side effects in select patients. The...Benzodiazepines are psychotropic medications for effective management of anxiety. However, after over 50 years of unrestrained prescription use, prescribers realize the severity of side effects in select patients. The most challenging of these side effects is the emergence of a physiological dependence that explains virtual impossibility of successful withdrawal that can ensure sustained abstinence. We propose a method for successful withdrawal using substitution and innovative downward tapering of diazepam oral solution for all benzodiazepines to attain sustained remission. Our protocol reported here allowed not only successful withdrawal for all of 20 patients included in this pilot study but also helped in totally weaning them off of benzodiazepines demonstrating absence of relapse even 2 years after the total discontinuance.展开更多
基金supported by the Scientific Research Project of the Department of Education of Liaoning Province,China(Grant No.:ZF2019036).
文摘Benzodiazepines(BDZs)are used in clinics for anxiolysis,anticonvulsants,sedative hypnosis,and muscle relaxation.They have high consumptions worldwide because of their easy availability and potential addiction.They are often used for suicide or criminal practices such as abduction and drug-facilitated sexual assault.The pharmacological effects of using small doses of BDZs and their detections from complex biological matrices are challenging.Efficient pretreatment methods followed by accurate and sensitive detections are necessary.Herein,pretreatment methods for the extraction,enrichment,and preconcentration of BDZs as well as the strategies for their screening,identification,and quantitation developed in the past five years have been reviewed.Moreover,recent advances in various methods are summarized.Characteristics and advantages of each method are encompassed.Future directions of the pretreatment and detection methods for BDZs are also reviewed.
文摘Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.
基金financed from the grant of the National Social Science Foundation General Project(No.23BZS010)。
文摘Jiu Ai Tu(The Moxa Treatment)from the Song dynasty is the earliest surviving painting that focuses on the subject of acupuncture and moxibustion.This paper takes the medical activities depicted in the artwork as its research object and systematically analyzes the external treatment methods for abscesses during the Song dynasty reflected in Jiu Ai Tu.By examining the understanding of abscesses during that period,the paper explores the level of development in external medicine techniques.By analyzing the medical awareness and behaviors of patients when facing such severe illnesses,it aims to explore the societal cognition and experiences regarding health and disease.The paper attempts to present the folk medical ecology of the Song dynasty represented by Jiu Ai Tu.
基金Conselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais(FAPEMIG)for financial support and research fellowships.
文摘A simple and high-throughput method to simultaneously determine selected benzodiazepines (i.e., diazepam, lorazepam, clonazepam, and bromazepam) in urine was developed and validated. The entire methodology consisted of the application of an innovative extraction/cleanup procedure, namely liquid-liquid extraction with low-temperature partitioning (LLE-LTP), and analysis by liquid chromatography combined with high-resolution mass spectrometry (LC-HRMS). The LLE-LTP procedure was optimized via factorial design and by evaluating crucial variables, specifically the freezing mode (either slow or fast), the urine/acetonitrile volume ratio, and the sample ionic strength. The benzodiazepines were quantified using matrix-matched calibration curves where the following parameters were assessed by validation protocol: in general, linearity range of 17 - 200 μg?L–1 (r > 0.9957);limits of detection lower than 5 μg?L–1;relative standard deviations (RSD) lower than 12.5%;and accuracy ranging from 72.3 to 117%. To test this procedure’s performance, the method was applied to determine the content of diazepam in actual urine samples. The validation results obtained for the method demonstrated that the present methodology could be potentially applied in proficient laboratories as a routine approach for determining benzodiazepines compounds content in urine.
基金supported by“the Fundamental Research Funds for the Central Universities”(2020-JYB-ZDGG-054)“Beijing university of Chinese medicine XINAO Award Fund”(2019)Beijing University of Chinese Medicine Scientific Research and Development Fund(2170072220002).
文摘Objective:To determine the active components of Eupolyphaga sinensis Walker(Tu Bie Chong)and explore the mechanisms underlying its fracture-healing ability.Methods: A modified Einhorn method was used to develop a rat tibial fracture model.Progression of bone healing was assessed using radiological methods.Safranin O/fast green and CD31 immunohistochemical staining were performed to evaluate the growth of bone cells and angiogenesis at the fracture site.Methylthiazoletetrazolium blue and wound healing assays were used to analyze cell viability and migration.The Transwell assay was used to explore the invasion capacity of the cells.Tubule formation assays were used to assess the angiogenesis capacity of human vascular endothelial cells(HUVECs).qRT-PCR was used to evaluate the changes in gene transcription levels.Results: Tu Bie Chong fraction 3(TF3)significantly shortened the fracture healing time in model rats.X-ray results showed that on day 14,fracture healing in the TF3 treatment group was significantly better than that in the control group(P=.0086).Tissue staining showed that cartilage growth and the number of H-shaped blood vessels at the fracture site of the TF3 treatment group were better than those of the control group.In vitro,TF3 significantly promoted the proliferation and wound healing of MC3T3-E1s and HUVECs(all P<.01).Transwell assays showed that TF3 promoted the migration of HUVECs,but inhibited the migration of MC3T3-E1 cells.Tubule formation experiments confirmed that TF3 markedly promoted the ability of vascular endothelial cells to form microtubules.Gene expression analysis revealed that TF3 significantly promoted the expression of VEGFA,SPOCD1,NGF,and NGFR in HUVECs.In MC3T3-E1 cells,the transcript levels of RUNX2 and COL2A1 were significantly elevated following TF3 treatment.Conclusion: TF3 promotes fracture healing by promoting bone regeneration associated with the RUNX2 pathway and angiogenesis associated with the VEGFA pathway.
文摘Carissa edulis Vahl is well known in Sudanese herbal medicine,commonly used for treatment of epilepsy,headache,chest pains,rheumatism,skin lesions,mania and other psychoactive diseases.The investigations of the safety use for psychoactive purposes in Sudanese healing traditions and identifying secondary metabolites of the plant extracts are the key steps towards determination of appropriate medicinal doses.Therefore,one of the chemical constituents was isolated and structurally identified by 1H-NMR and LC-MS.With the aim of evaluating Carissa edulis folk random uses,the isolated compound was compared with reference artificial drugs Lormetazepam,a potentially toxic compound.Structure investigations confirm that the isolated product was benzodiazepines analogous 7-chloro 1,4-benzodiazepine-2-ones.It is important to know the potential toxicity of certain plant in order to assess the therapeutic effect of it,as these are slight distinctions between the medicinal and toxic doses.In general the results obtained justify the use of the roots of Carissa edulis in traditional medicine for the treatment of some psychiatric diseases.
基金We thank the National Natural Science Foundation of China (Project No.29872010) NSF of Zhejiang province for financial support.
文摘o-Nitrophenylazide was reduced by SmI2 in anhydrous THF at room temperature to produce active intermediate 2 (samarium amide), "living" double-anion in situ which reacted smoothly with α，β-unsaturated ketones to afford 2,3-dihydro-1H-1,5-benzodiazepines in good yields under mild and neutral conditions.
文摘On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines”. With this announcement, the FDA proclaimed that much more needs to be known about the initiation, continuation, and discontinuation of these widely-used drugs. Unfortunately, relevant information is lacking, since for many years, there has been a notable sparsity in the funding and conduct of basic and clinical research on these drugs. In order to begin to fill the void, it is valuable to (re)examine animal models. We here describe a model of conditioned place-preference (CPP) for rats and for the first time, to our knowledge, show that the representative benzodiazepine alprazolam induces positive place-preference in male rats.
文摘MgBr2 performs as a novel catalyst for the synthesis of various 1,5-benzodiazepine derivatives from wide range of substituted o- phenylenediamines and various ketones in good to excellent isolated yields （93-98%） using water as solvent at ambient temperature. Several solvents were examined for this reaction; however, in terms of reaction yield and time, water was found to be the optimum solvent. The remarkable advantages offered by this method are easily and inexpensive available catalyst, simple procedure, mild conditions, much faster （40-60 man） reactions and good to excellent yields of products.
文摘The crystal structure of the title compound, 1,1 dichloro 3 dichloro 3 dichloromethyl 1a,3 diphenyl 1a,2,3,4 tetrahydro 1H azirino 1,2 a 1,5 benzodiazepine (C 23 H 18 Cl 4N 2, M r =464.22) was crystallized in triclinic, space group P 1, with cell dimensions a=9.621(7), b=9.694(9), c=12.669(6) , α=107.99(5)°, β=101.42(5)°, γ=69.94(6)°, V=1050.2(4) 3, Z=2, D c =1.468 g/cm 3 , Cu Kα(λ=1.5418 ). F(000)=1816, μ =2.44 mm -1 . The structure was solved by direct methods and refined by full matrix least squares method, and the final crystallographic discrepancy factor is 0.063 for 2555 observed reflections. The molecular backbone is a tricyclic system with the central seven membered 1,5 diazepine ring in twisted boat like conformation and cis fused to both aziridine ring and benzene ring.
文摘A series of 3-methoxycarbonylpropoxy-7-(imidazol-4-ylpropinamide)-1, 3-dihydrogen- 1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-ones, as farnesyltransferase(Ftase) inhibitors, were synthesized. The preparation of the key intermediate, 7-amino-3-methoxycabonylpropoxy-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, was improved.
文摘A novel N-methyl, N-phenyl-[6-chloro-2-（4-chlorophenyl）-8-iodoimidazo[1, 2-a]- pyridine-3-yl]acetamide （compound Ⅴ） was synthesized, radiolabelled with 131I and evaluated in vitro. In vitro cell uptake studies showed that MDA-MB-231 cells yield four-fold higher specific uptake of [^131I]-compound Ⅵ than MCF-7 cells, corresponding to the increased expression of PBR in MDA-MB-231 cells. Blocking studies significantly reduced the MDA-MB-231 cells uptake of [^131I]-compound Ⅵ. It indicated that [^131I]-compound Ⅵ might be a potential SPECT radioligand for imaging of PBR.
文摘Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 μl spray (d ≈ 1.00 g/ml). The nasal absorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal administration using this formulation was 33.45% ± 12.36% and the tmax was 18.33 ± 23.09 min, which was twice longer than the tmax obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (tmax), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (Cmax) and the absolute bioavailability (FA) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 μg/ml vs. 15.44 ± 4.00 μg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, respectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.
文摘Benzodiazepines are psychotropic medications for effective management of anxiety. However, after over 50 years of unrestrained prescription use, prescribers realize the severity of side effects in select patients. The most challenging of these side effects is the emergence of a physiological dependence that explains virtual impossibility of successful withdrawal that can ensure sustained abstinence. We propose a method for successful withdrawal using substitution and innovative downward tapering of diazepam oral solution for all benzodiazepines to attain sustained remission. Our protocol reported here allowed not only successful withdrawal for all of 20 patients included in this pilot study but also helped in totally weaning them off of benzodiazepines demonstrating absence of relapse even 2 years after the total discontinuance.
