Study on the Equivalent Conformation of Retinoids

具有诱导细胞分化作用及癌和皮肤病化学治疗作用的维甲类化合物，不仅要求分子一端有疏水性、另一端为极性羧基和整个分子的共轭性，而且分子的构象也起重要作用。本文合成的Ｎ（４羧基苯基）３，５双叔丁基４羟基苯甲酰胺（２）具有与全反式维甲酸（ＡＴＲＡ，１）相似性质的基团配置和构象，表现有维甲酸的生物活性。然而Ｎ甲基化合物３，由于构象的完全不同，丧失了活性。用Ｘ线晶体学、紫外和核磁共振等方法研究了化合物２、３和ＡＴＲＡ的结构异同。     

 Simulation Study on the Entrance of

d fund industries.The research indicates that the entrance of commercial banks into the property insurance and fund industries can increase their revenue and return per unit of risk,and significantly reduce their probability of bankruptcy.The results also indicate that appropriate proportion of nonbanking assets is indispensable for achieving the optimal effect of diversification.In addition,a comparative study shows that the simultaneous diversification into the property insurance and fund industries generates higher divers2;P<0.01)C与胰岛素水平、C反应蛋白、类风湿因子(RF)、肿胀指数、压痛指数、晨僵时间、病程、年龄、性别等无关;瘦素及瘦素受体在RA患者滑膜中的表达明显高于正常对照组。结论:瘦素可能通过在靶器官的高表达而起到调节炎症的作用;可能在炎性反应中参与急性时相蛋白的合成与调节而影响疾病的发展过程。     

Study of the Interaction Between β-Cyclodextrin and Chlorhexidine

Pharmaceutical Research -     

Study on the metastable state of dilution of spectinomycin

The metastable state of dilution of spectinomycin has been studied by both induction period method and direct method.The polynuclear mechanism of lsing metastability has been disclosed,The metatable zone for dilution of spectinomycin was presented .The influence ofacetone concentraion and temperature on the metastability has been investigated.The induction period elongated as acetone concentraion increased and temperature decreasd The metastable zone-with was broadened with the decreasement of solubility,High superastruation level for nucleation indicated that spectinomycfin belongs to class I system.On the basis of classical nucleation theory the fundamental nucleation parameters for dilution have also been estimated,All the results were important for the control of industrial dilution of spectinomycin.     

Experimental Study on the Acceleration of the Hemato Immunological Reconstitution of the Lethally Irradiated Mice Following B

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Study of the Complexation Behaviour of Fexofenadine with β-Cyclodextrin

Fexofenadine is a selective histamine H(1) receptor antagonist, used for relief of the symptoms of allergy. However its aqueous solubility is very poor. Solid inclusion complexes of fexofenadine and β-cyclodextrin were prepared at the molar ratios of 1:1 and 1:2 by kneading, and coprecipitation methods to improve its solubility. Characterization of the complexes was performed using infrared spectroscopy, X-ray diffractometry, and in vitro dissolution studies. Fexofenadine was found to exhibit interaction with β-cyclodextrin both in solid and liquid state. Phase solubility studies indicated that fexofenadine forms a stable complex with β-cyclodextrin. Both IR spectroscopy and X-ray diffractometry studies indicated interaction of fexofenadine with β-cyclodextrin. Kneading method at 1:1 and co-precipitation method at 1:1 and 1:2 molar ratios showed significant interaction. In vitro dissolution studies confirmed the same results.     

β-adrenoceptor blockers and pulmonary function in the general population: the Rotterdam Study

Aim

β-adrenoceptor blockers have been used with caution in patients with obstructive lung diseases such as asthma or chronic obstructive pulmonary disease (COPD), due to the potentially increased airway reactivity and risk of bronchial obstruction. Cardioselective β-adrenoceptor blockers have a more beneficial profile than non-cardioselective β-adrenoceptor blockers and can be safely prescribed to patients with both cardiovascular disease and COPD. We hypothesized that cardioselective β-adrenoceptor blockers also affect pulmonary function.

Methods

This study was performed within the Rotterdam Study, a prospective population-based cohort study. Effects of cardioselective and non-cardioselective β-adrenoceptor blockers on pulmonary function were analysed using regression techniques with multivariable adjustment for potential confounders.

Results

Current use of non-cardioselective β-adrenoceptor blockers was significantly associated with a lower forced expiratory volume in 1 s (FEV₁) of −198 ml (95% CI −301, −96), with a lower forced vital capacity (FVC) of −223 ml (95% CI −367, −79) and with a decreased FEV₁ : FVC of −1.38% (95% CI −2.74, −0.13%). Current use of cardioselective β-adrenoceptor blockers was significantly associated with a lower FEV₁ of −118 ml (95% CI −157, −78) and with a lower FVC of −167 ml (95% CI −222, −111), but did not affect FEV₁ : FVC. After exclusion of patients with COPD, asthma and heart failure the effects of cardioselective β-adrenoceptor blockers remained significant for FEV₁ (−142 ml [95% CI −189, −96]) and for FVC (−176 ml [95% CI −236, −117]).

Conclusion

In our study both non-cardioselective and cardioselective β-adrenoceptor blockers had a clinically relevant effect on both FEV₁ and FVC. In contrast to cardioselective β-adrenoceptor blockers, use of non-cardioselective β-adrenoceptor blockers was associated with a significantly lower FEV₁ : FVC.     

Study of the dissolution characteristics of oxazepam via complexation with β-cyclodextrin

Complex formation of oxazepam and β-cyclodextrin in solution was studied by phase solubility and spectral shift methods. The value of the apparent stability constant, K_c, calculated using these techniques, was 205 and 498 M⁻¹, respectively. Solid complexes of oxazepam and β-CD were prepared using the kneading and spray-drying methods. These complexes led to an improvement in the dissolution rate over free oxazepam, spray-drying being the most efficient technique. These complexes were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray diffraction.     

Eudragit? Microparticles for the Release of Budesonide: A Comparative Study

This study compares the behaviour of budesonide-containing microparticles made of Eudragit^®RS or Eudragit^®RS/Eudragit^®RL 70:30 (w/w) prepared either by solvent evaporation or spray-drying technique. The loading efficiency of budesonide within microparticles was about 72% for microparticles prepared by solvent evaporation and around 78% for spray-dried microparticles. Thermal analyses were assessed to collect information about the structural stability of budesonide within the polymeric microspheres. The in vitro release was performed using simulating gastric (fasted state simulated gastric fluid) and intestinal (fasted state simulated intestinal fluid) fluids as the receiving solutions. After 3 h the drug release from Eudragit^®RS/Eudragit^®RL microparticles was about 6-fold higher than that obtained in the case of monopolymer microparticles. Using fasted state simulated intestinal fluid the drug was released between 4 and 30% in both types of preparations. Eudragit^®RS microparticles showed a better protection of the drug from gastric acidity than those of Eudragit^®RS/Eudragit^®RL allowing us to propose Eudragit^®RS microparticles as a hypothetical system of colon specific controlled delivery.     

Use of the InteliSite® Capsule to Study Ranitidine Absorption from Various Sites Within the Human Intestinal Tract

Purpose. The purpose of this study was to evaluate the extent of ranitidine absorption from an externally activated drug-delivery system in two distinct regions of the intestine (jejunum and ileum) in healthy human volunteers. This investigation also was designed to evaluate the utility of the InteliSite ^® capsule for studying regional intestinal drug absorption in humans. Methods. The intestinal absorption of ranitidine from the jejunum and ileum was compared in eight, healthy volunteers in this open-label, two-way crossover study. In two of the eight volunteers, absorption from the colon also was studied. Subjects swallowed the capsule containing ranitidine solution (121 mg) and 100 Ci of ^99mTc-DTPA. The endcap of the capsule contained 20 Ci of ¹¹¹In-DTPA. At the desired intestinal site, the capsule was activated by the application of an external RF magnetic signal (6.78 MHz operating frequency) and the ranitidine solution was released. Blood samples were collected from a forearm vein for 12 hours after capsule activation. Results. The capsule released the ranitidine solution when activated in the jejunum, ileum and colon (visualized by the gamma camera). There was no difference in the extent of ranitidine absorption or ranitidine pharmacokinetics when the capsule was activated in the jejunum or ileum. Conclusions. This study demonstrates the utility of a novel, externally activated drug-delivery system to assess site-specific intestinal drug absorption in humans. Results indicate that use of the InteliSite ^® capsule method to evaluate site-specific intestinal ranitidine absorption in humans yields data similar to that obtained previously by means of oral intubation studies.     

Concurrent validity of the CAGE questionnaire. The Nord-Trøndelag Health Study

The aim of this study was to examine the psychometric properties of the CAGE questionnaire, and the questionnaire's concurrent validity with current and previous alcohol consumption. This study employed data from the Nord-Trøndelag Health Survey wave 1 (HUNT-1 in 1984–86: N = 24,900) and wave 2 (HUNT-2 in 1995–97: N = 36,350). The concurrent validity of the CAGE questionnaire was examined both as a dichotomous variable with the recommended cut-off (≥2 affirmative answers) for alcohol problems, and as a categorical scale. The categorical scale was constructed by counting responses from 0 to 4, and a separate category for current abstainers in HUNT-2. Current self-reported consumption above the gender specific 80th percentile was defined as “current excessive consumption”. “Previous excessive consumers” were defined by meeting at least one of the two following criteria at the time of HUNT-1: reporting drinking too much alcohol in any period of their life, or reporting a high level of alcohol consumption. The internal reliability of CAGE was adequate, and in relation to alcohol consumption, there was a linear relationship between the CAGE score and both the current and previous excessive consumption. In conclusion, this study indicates good concurrent validity and adequate psychometric properties of the CAGE questionnaire. The dose–response pattern seen between the CAGE score and alcohol consumption, suggests that it can be used as an ordinal measure, rather than with a cut-off of two or more. The concurrent validity of the CAGE is better in women than in men.     

Study on the inclusion complex of OGP-49 with hydroxypropyl -β-cyclodextrin

目的 制备OGP - 49羟丙基-β-环糊精包合物,为OGP - 49的注射给药提供基础.方法 采用超声法制备.经差示扫描量热法、红外光谱法验证包合物的形成.结果 羟丙基-β-环糊精和OGP - 49以20∶1的比例形成包合物,40％的羟丙基-β-环糊精可使OGP - 49的水中溶解度提高330倍.结论 OGP - 49羟丙基-β-环糊精包合物能显著提高OGP -49的水中溶解度.     

Drug-induced immune thrombocytopaenia: results from the Berlin Case–Control Surveillance Study

Purpose

Drug-induced immune thrombocytopaenia is a rare, serious condition that can be triggered by numerous medications. To characterize the spectrum of drugs associated with immune thrombocytopaenia (ITP) in the Berlin Case–Control Surveillance Study (FAKOS).

Methods

Adult hospitalized patients with new onset idiopathic, secondary or drug-induced acute ITP and hospital control patients were ascertained by active surveillance in 50 Berlin hospitals (>180 clinical departments) between 2000 and 2009. Drug exposures were obtained in a personal interview. Chronic cases were excluded in a follow-up after 6 or more months. A standardized causality assessment was conducted for each ITP patient to assess possible drug aetiology. Drug risks were quantified in a case–control design with unconditional logistic regression analysis.

Results

Ninety out of 169 validated cases of acute ITP were assessed as being at least possibly drug-related (n?=?85 different drugs overall, n?=?30 drugs with certain or probable causality). Drugs involved in ≥2 cases with a probable or certain relationship were tirofiban (n?=?10 cases), abciximab (n?=?4), trimethoprim/sulphamethoxazole (n?=?4), influenza vaccine (n?=?3), and citalopram (n?=?2). Pneumococcal and poliomyelitis vaccine were assessed as probably causing ITP in one case each. In the case–control analyses, significantly increased risks were observed for tirofiban, abciximab, trimethoprim/sulphamethoxazole, gentamicin, triamterene/hydrochlorothiazide, drospirenone/ethinylestradiol, and influenza vaccination.

Conclusions

Our study confirms known ITP risks for glycoprotein IIb/IIIa receptor antagonists and sulphonamides and generates signals for several other drugs and vaccines. New onset of ITP should not only direct attention to drugs as possible aetiological agents, but also to vaccines that are known to cause autoimmune phenomena.     

Study on effects of cinobufagin on the immunologic function of mice in vitro

华蟾毒精对小鼠免疫功能影响的体外研究@宋宇$College of Animal Science and Veterinary Medicine,Jilin University!Changchun 130062,Jilin,China;National Standard Laboratory of Pharmacology for Traditional Chinese Medicine, Jilin Natural Pharmatech Co.Ltd, Chang     

Comparative Study of the Pharmacokinetics and Bioequivalence of Meldonium and Mildronate® Preparations

Pharmaceutical Chemistry Journal - Acomparative study of the pharmacokinetics, bioequivalence, and safety of two marketed meldonium dosage forms Meldonium Organika (meldonium, 500 mg capsules,...     

The Study of the Influence of Formulation and Process Variables on the Functional Attributes of Simvastatin–Phospholipid Complex

Purpose

The aim of the present study was to examine the influence of the formulation and process variables on the entrapment efficiency of simvastatin–phospholipid complex (SPC), prepared with a goal of improving the solubility and permeability of simvastatin.

Methods

The SPC was prepared using a solvent evaporation method. The influence of formulation and process variables on simvastatin entrapment was assessed using a central composite design. An additional SPC was prepared using the optimized variables from the developed quadratic model. This formulation was characterized for its physical–chemical properties. The functional attributes of the optimized SPC formulation were analyzed by apparent aqueous solubility analysis, in vitro dissolution studies, dissolution efficiency analysis, and ex vivo permeability studies.

Results

The factors studied were found to significantly influence the entrapment efficiency. The developed model was validated using the optimized levels of formulation and process variables. The physical–chemical characterization confirmed a formation of the complex. The optimized SPC demonstrated over 25-fold higher aqueous solubility of simvastatin, compared to that of pure simvastatin. The optimized SPC exhibited a significantly higher rate and extent of simvastatin dissolution (>98 %), compared to that of pure simvastatin (～16 %). The calculated dissolution efficiency was also found to be significantly higher for the SPC (～54 %), compared to that of pure simvastatin (～8 %). Finally, the optimized SPC exhibited a significantly higher simvastatin permeability (>78 %), compared to that of pure simvastatin (～11 %).

Conclusion

The present study shows that SPC can be a promising strategy for improving the delivery of simvastatin and similar drugs with low aqueous solubility.

     

To which chemical mixtures is the French population exposed? Mixture identification from the second French Total Diet Study

Through their diet, humans are exposed to a wide range of substances with possible adverse effects. Total diet studies (TDS) assess exposure and risk for many single substances or mixtures from the same chemical family.This research aims to identify from 440 substances in the second French TDS, the major mixtures to which the French population is exposed and their associated diet. Firstly, substances with a contamination value over the detection limit were selected. Secondly, consumption systems comprising major consumed foods were identified using non-negative matrix factorisation and combined with concentration levels to form the main mixture. Thirdly, individuals were clustered to identify “diet clusters” with similar consumption patterns and co-exposure profiles.Six main consumption systems and their associated mixtures were identified. For example, a mixture of ten pesticides, six trace elements and bisphenol A was identified. Exposure to this mixture is related to fruit and vegetables consumed by a diet cluster comprising 62% of women with a mean age of 51 years. Six other clusters are described with their associated diets and mixtures. Cluster co-exposures were compared to the whole population.This work helps prioritise mixtures for which it is crucial to investigate possible toxicological effects.     

Advances in the study of drug metabolism – symposium report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX)

Abstract

The 12th International Society for the Study of Xenobiotics (ISSX) meeting, held in Portland, OR, USA from July 28 to 31, 2019, was attended by diverse members of the pharmaceutical sciences community. The ISSX New Investigators Group provides learning and professional growth opportunities for student and early career members of ISSX. To share meeting content with those who were unable to attend, the ISSX New Investigators herein elected to highlight the “Advances in the Study of Drug Metabolism” symposium, as it engaged attendees with diverse backgrounds. This session covered a wide range of current topics in drug metabolism research including predicting sites and routes of metabolism, metabolite identification, ligand docking, and medicinal and natural products chemistry, and highlighted approaches complemented by computational modeling. In silico tools have been increasingly applied in both academic and industrial settings, alongside traditional and evolving in vitro techniques, to strengthen and streamline pharmaceutical research. Approaches such as quantum mechanics simulations facilitate understanding of reaction energetics toward prediction of routes and sites of drug metabolism. Furthermore, in tandem with crystallographic and orthogonal wet lab techniques for structural validation of drug metabolizing enzymes, in silico models can aid understanding of substrate recognition by particular enzymes, identify metabolic soft spots and predict toxic metabolites for improved molecular design. Of note, integration of chemical synthesis and biosynthesis using natural products remains an important approach for identifying new chemical scaffolds in drug discovery. These subjects, compiled by the symposium organizers, presenters, and the ISSX New Investigators Group, are discussed in this review.