头孢氨苄缓释片的研制

目的:制备头孢氨苄缓释片,通过溶出度试验研究其生物利用度和药代动力学。方法:EudragitⅡ和HPMC作为缓释材料制备头孢氨苄缓释片,并与日本进口头孢氨苄缓释片(Syncl SR tablets)进行了体外释放度比较。结果:本制备品与进口片溶出结果相似,经人体生物利用度研究表明,头孢氨苄缓释片比普通胶囊口服后能明显推迟达峰时间,并降低峰浓度(P<0.01),缓释片与普通胶囊的AUC_(0→24)之间没有显著性差异(P>0.05)。缓释片相对于普通胶囊生物利用度为(104.90±8.35)％。结论:体内和体外实验结果表明本品达到预期效果。     

利用生物粘附技术提高萘哌地尔的生物利用度

目的为提高萘哌地尔生物利用度,制备生物粘附性萘哌地尔胶囊。方法制备萘哌地尔胶囊、生物粘附胶囊I和II;比较两种生物粘附性胶囊与大鼠离体胃肠组织的粘附力;用自身对照方式单剂量分别给予家犬3种胶囊200mg,比较3种胶囊在家犬体内的药物动力学与生物利用度。结果与普通胶囊相比,生物粘附性萘哌地尔胶囊I和II在家犬体内的血药峰浓度(C_max)下降,达峰时间(T_max)延迟,药时曲线下面积(AUC_0→∞)明显增加,两者为生物不等效制剂,与普通胶囊相比,萘哌地尔粘附胶囊I与II的生物利用度分别为150%±14%和154%±23%,两种生物粘附胶囊的药动学参数间无明显差异。结论利用生物粘附技术能明显提高萘哌地尔的生物利用度。     

多剂量口服5-单硝酸异山梨酯缓释片及普通片的药代动力学和生物利用度研究

对10名健康男性受试者连续6d多剂量交叉poIS-5-MN缓释片和普通片的药代动力学性质和相对生物利用度进行了研究。结果表明:IS-5-MN缓释片和普通片的T_max分别为5.0h和1.4h(P<0.05),前者的缓释效果十分明显;AUC经对数转换后的多种统计分析表明,IS-5-MN缓释片(40mg)与IS-5-MN普通片(20mg×2)生物等效;IS-5-MN缓释片的相对生物利用度为108.95%;IS-5-MN缓释片和普通片的C_min分别为74.20ng·ml^-1和134.42ng·ml^-1(P<0.05),而两种制剂的其他药代动力学参数如C_max,AUC²⁴₀,AUC^∞₀,Ke,T_1/2以及波动系数(FI)等均无显著性差异(P<0.05)。多次给药后两种制剂都无明显的蓄积。     

酮洛芬缓释片与常释片在健康受试者的药代动力学及生物利用度

目的:酮洛芬缓释片与常释片单次给药的生物利用度和多次给药的峰谷浓度波动大小。方法:采用以萘普生(naproxen)为内标的HPLC测定方法,测定健康男性受试者按交叉试验单剂量和多剂量服用酮洛芬缓释片和常释片后的血中酮洛芬浓度。结果:单剂量服用酮洛芬缓释片和常释片后,常释片的Cmax显著高于缓释片(P<0.01),缓释片给药后的Tmax延迟,t_1/2ke显著延长,相对生物利用度为97.13%。缓释片在稳态时的C_min为0.401μg·mL^-1,而常释片为0.190μg·mL^-1(P<0.01)。在稳态时缓释片的峰谷浓度波动度(DF)、峰谷比(PTR)都显著小于常释片,说明缓释片的峰谷浓度波动程度优于常释片。结论:经统计学检验表明这两种制剂具有生物等效性,该缓释片具有峰谷浓度差异小,波动幅度小的特点,显示出缓释特征。     

贝诺酯片剂的研制及生物利用度研究

通过减小药物粒径,提高贝诺酯片剂的生物利用度。在市售片以A(500mg)基础上研制了新处方片剂B(400mg)。建立贝诺酯片剂体外溶出度试验方法,即以表面活性剂溶液作溶出介质,以浆法进行溶出度测定。用HPLC法测定贝诺酯在体内的水解产物水杨酸和扑热息痛的血药浓度。结果表明药物研磨粉碎前后体外溶出速度常数分别为0.0152min-1及0.0337min^-1(P<0.001)。A及B体外平均溶出时间分别为42.25min及15.77min(P<0.001)。体内研究表明A及B水杨酸的C_max,T_p,AUC之间均无显著性差异(P>0.1)(A,B的服用量分别为4.5g及3.6g),B的相对生物利用度为125.59%。     

麝香保心pH依赖型梯度释药微丸的研究

目的制备麝香保心pH依赖型梯度释药微丸并进行体内外考察。方法分别以HPMC,Eudragit L-30D-55和Eudragit L100-Eudragit S100(1∶5)为包衣材料制备pH依赖型梯度释药微丸,并进行体外释放度、胃肠道转运和体内药代动力学研究。结果冰片和人参总皂苷体外释放度的f₂值为79.6,3种包衣微丸分别在胃、十二指肠和空回肠部崩解,由3种微丸组成的缓释胶囊中冰片的T_max与原丸剂相近,而C_max明显降低,相对生物利用度为96%。结论 缓释胶囊中的冰片和人参总皂苷在体外可同步缓释,在体内具有pH依赖性崩解溶散的特征,冰片作为指标性成分具有梯度缓释的药代动力学特点。     

消炎痛缓释胶囊的生物利用度研究

消炎痛普通制剂口服吸收迅速,可出现不必要的高血药浓度,导致不良反应。为此我们对三种消炎痛缓释胶囊(A,B,C)和一种常用片剂(D)作了体外溶出试验和体内生物利用度比较。胶囊制剂由丙烯酸类树脂材料E₃₀D包衣的药物小丸制成,其体外溶出行为显示缓慢释放图象。在8名成年男性交叉实验中,不同胶囊制剂和普通片剂之间的Tmax,Cmax和AUC_0～12h经方差分析无统计学差异,但是在给药后4至12小时的血清浓度—时间曲线,均比普通片剂高而平滑。在第12小时,三种胶囊产生的血清浓度显著高于普通片剂(P<0.1)。根据体外溶出行为和体内生物利用度发现T₅₀或Tmax和包衣厚度呈良好线性关系。     

美沙拉嗪肠溶缓释片的制备与体外释放度考察

目的 制备美沙拉嗪肠溶缓释片,考察其体外释放。方法 以体外释放相似因子（f₂）为主要评价指标,通过单因素处方筛选和正交试验设计得到最优处方,重现三批,比较自制美沙拉嗪肠溶缓释片与参比制剂的体外释放行为。 结果 片芯中羧甲基纤维素钠（CMC 7HXF PH）用量为45 mg,羧甲淀粉钠（CMSNa）用量为35 mg;肠溶包衣层中Eudragit L100和Eudragit S100以2:3的比例联用,包衣增重为6%。自制肠溶缓释片与参比制剂的相似因子f₂值均大于50。 结论 自制美沙拉嗪肠溶缓释片与参比制剂体外释放相似,处方工艺稳定可重现,可用于美沙拉嗪肠溶缓释片的制备。     

家犬单剂量和多剂量口服阿昔莫司缓释制剂的药代动力学和生物等效性研究

目的研究阿昔莫司缓释片在家犬体内单剂量和多剂量的药代动力学和生物等效性。方法测定6只家犬单剂量和多剂量口服缓释片和普通胶囊后的血药浓度。结果阿昔莫司的药-时曲线符合非隔室模型。单剂量给药后，缓释片和普通胶囊的AUC分别为(158±30)和(147±37) μg·h·mL^-1；T_max分别为(4.3±0.8)和(2.6±1.3) h；C_max分别为(29±6)和(42±10) μg·mL^-1；T_1/2分别为(2.3±0.7)和(1.60±0.10) h；MRT分别为(6.0±0.8)和(3.9±0.7) h；F_r为(108±16)%。多剂量给药后，缓释片和普通胶囊的AUC分别为(209±23)和(195±26) μg·h·mL^-1；T_max分别为(6.3±0.8)和(3.4±1.5) h；C_max分别为(27±4)和(36±5) μg·mL^-1；Cmin分别为(2.2±1.0)和(0.20±0.20) μg·mL^-1；C_av分别为(8.7±1.0)和(8.1±1.1) μg·mL^-1；FI分别为(293±73)%和(448±91)%；F_r为(114±19)%。结论单剂量实验的双单侧检验结果表明：缓释片和普通胶囊生物等效；缓释片具有良好的缓释效果。多剂量实验结果表明：缓释片和普通胶囊生物等效；缓释片的波动系数优于普通胶囊。     

复方丹参pH依赖型延迟释药微丸在家犬体内的药效动力学

目的制备复方丹参pH依赖型延迟释药微丸填充胶囊并进行家犬体内药效动力学研究。方法分别用HPMC，Eudragit L-30D-55，Eudragit L100/S100 (1∶6)包衣制备pH依赖型延迟释药微丸，测定体外释放曲线，并用血清药理学方法进行家犬体内的药效动力学研究。结果制备了复方丹参pH依赖型延迟释药微丸，体外溶出曲线呈pH依赖特征。单剂量给药后自制速释片R的药效动力学参数T_max为0.58 h，E_max为34.63%，延迟释药胶囊T1和T2的T_max分别延长至2.42和3.17 h，E_max分别降低至13.57%和14.52%，相对生物利用度分别为99.3%和133.6%。多剂量给药后自制速释片R波动度DF 7.32，延迟释药胶囊T1和T2的波动度DF 3.40和3.03。结论复方丹参pH依赖型延迟释药胶囊体外释放具有pH依赖特征，体内具有明显的延迟释药作用，多剂量达到稳态时，药效动力学波动系数低于普通片。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.