必特螺旋霉素的工业结晶过程

以未知杂质为考察的着重点,探索了25℃下必特螺旋霉素最佳结晶时的pH以及同一pH下温度对工业结晶的影响。利用高效液相色谱对结晶产品进行检测,并用外标法对必特螺旋霉素中各部分杂质进行了详细的分析,通过对比结晶过程有效组分和总未知杂质对螺旋霉素的选择性系数,在兼顾有效组分含量合格和杂质质量分数最低的前提下,确定最优结晶终点pH为7.5~8.0,最优结晶温度为25~35℃。该方法首次以未知杂质的含量变化来探索必特螺旋霉素结晶的规律,工业上便于实施,有利于指导工业生产。     

In vitro cytotoxicity of pyrazine-2-diazohydroxide: specificity for hypoxic cells and effects of microsomal coincubation

Summary The antitumor drug pyrazine-2-diazohydroxide exhibits cytotoxicity to A204 tumor cells in vitro under acid conditions. The IC₅₀ with a 1 hr drug exposure at pH of 7.4 was 61 g/ml and at pH of 6.0 it was 31 g/ml. It is suggested that the increased cytotoxicity is due to the acid catalyzed formation of a reactive pyrizinyldiazonium ion from pyrazine-2-diazohydroxide. Pyrazine-2-diazohydroxide is also more cytotoxic to A204 cells under hypoxic conditions in the presence of glucose with an IC₅₀ at pH 7.4 of 22 g/ml. The increased cytotoxicity of pyrazine-2-diazohydroxide under acid and hypoxic conditions may favor selective toxicity to solid tumors in vivo. Coincubation with rat hepatic microsomes increased the cytotoxicity of pyrazine-2-diazohydroxide to A204 cells. The effect did not require NADPH and was not due to formation of metabolites. There was an increased rate of degradation of pyrazine-2-diazohydroxide in the presence of microsomes, presumably with formation of the pyrizinyldiazonium ion. The final degradation product 2-hydroxypyrazine was not cytotoxic to A204 cells. The effect of microsomes on pyrazine-2-diazohydroxide cytotoxicity is probably of little in vivo significance.     

Potential Improvement in the Shelf Life of Parenterals Using the Prodrug Approach: Bacampicillin and Talampicillin Hydrolysis Kinetics and Utilization Time

The utilization time for a parenteral prodrug solution with a bioavailable fraction of unity was defined as the time during which the total of the prodrug concentration and the drug concentration equals or exceeds 90% of the initial prodrug concentration. This utilization time was calculated as a function of pH, buffer, and temperature using the experimentally determined rate expressions for bacampicillin and talampicillin. The results were compared to the shelf life of ampicillin solutions under identical storage conditions. First-order rate constants were determined for conversion of the prodrugs to ampicillin (k _c), for -lactam degradation of the prodrugs (k _nc), for the overall loss of prodrugs (k _sum), and for -lactam degradation of ampicillin (k _h) in aqueous solutions at 25.0 to 60.0°C, µ = 0.5, in the pH range 0.90 to 8.4. Loss of bacampicillin proceeded primarily by degradation at pH levels below 4 but was due predominantly to conversion at pH levels above 5. Loss of talampicillin was due primarily to conversion throughout the entire pH range. While the prodrug utilization times were approximately twice the shelf life of ampicillin in acidic solutions, ampicillin was significantly better in neutral solutions. The results illustrate the potential for increased prodrug storage periods when utilization time is defined on the basis of the bioactivity rather than on the prodrug concentration alone.     

Bay K 8644 induced necrosis in murine skeletal muscle in vitro: myofibre breakdown precedes significant alterations of intracellular [Ca] or pH

Summary The effect of the Ca²⁺-channel agonist Bay K 8644 (1 mol/l) on the ultrastructure, Ca²⁺-homeostasis, pH and membrane potential of murine diaphragm muscle, in vitro, has been investigated. Treatment with Bay K 8644 in a standard physiological saline, for 1–2 h, induced swelling of the muscle mitochondria and minor damage to the myofibrils. Ultrastructural Ca-localisation by antimonate precipitation revealed no differences between treated and control preparations. Accompanying the structural changes there was a small, non-significant increase in muscle Ca content. In EGTA-buffered (Ca-free) standard saline the induction of damage was not inhibited. When [K⁺]_o was raised to 20 mmol/l, a procedure that approximately halved the resting potential, Bay K 8644 induced severe ultrastructural damage within 1 h, and complete cellular necrosis within 2 h. Induction of myopathy was unaffected by synaptic blockade (150 mol/ld-tubocurarine). Necrosis was accompanied by depolarisation of membrane potential (Em) and increased antimonate precipitation in the sarcoplasm, and was abolished by buffering of [Ca²⁺]_o with EGTA. However, muscles did not develop tension and measurements of both total Ca and [Ca²⁺]_i suggest that cellular Ca²⁺ buffering was not seriously impaired until 2 h after Bay K 8644 application. Measurement of sarcoplasmic pH revealed no significant change during fibre necrosis. It is proposed that in partially depolarised preparations Bay K 8644 acts on a Ca²⁺-channels in the cell membrane, probably the T-tubules, to induce muscle necrosis through enhanced influx of Ca²⁺. However, muscle necrosis occurs before significant elevation of [Ca²⁺]_i and does not require sarcoplasmic acidification.     

Use of the computer program EQUIL to estimate pH in model solutions and human urine

Summary The computer program EQUIL was designed to calculate relative supersaturations of solute components of common urinary stones. In an extended software version, quantitative consideration of charge balance for a priori or a posteriori pH estimation was added. The reliability of this computation was tested with hydrogen ion titration of buffer solutions containing HEPES [N-(2-hydroxyethyl)piperaizine-N-ethanesulfonic acid] as well as samples of normal human urine. In the model solutions with HEPES, the difference between calculated pH values and the measured pH was smaller than 1.2% for any titration step within the buffer zone (pH 8.5-6.8). The pH values calculated for whole urine differed from the measured pH by 7% to 53%, and the calculated charge inbalance ranged from 2.6 to 9.6 mM. This net cation inbalance indicates that there is a need to account for other anionic components, including hippurate, amino acids, and isocitrate. In experimental solutions, charge balance calculations with EQUIL can be of great utility because they permit a priori estimation of pH or computation of the composition at a desired pH.Deceased July 22, 1988     

Gastric acid secretion and gastrin release in the baboon

Significant species differences have been demonstrated in gastric physiology, a factor that limits extrapolation of animal data to man. Primate physiology is thought to be similar to that of man; however, gastric function has not been adequately documented in the primate. In the present study six baboons (body weight 25.5±1.8 kg) were trained to sit in a chair and gastric acid secretion and gastrin release was studied in conscious animals. Mean basal acid secretion was 1.3±0.1 mmol (H⁺)/hr. Maximum output after pentagastrin (12 g/kg/hr) was 9.5±0.9 mmol (H⁺)/hr and 11.0±0.4 mmol (H⁺)/hr after histamine (40 g/kg/hr). A statistically significant (by cosinor analysis) circadian rhythm was demonstrated for intragastric pH over 24 hr in fasted baboons (P<0.001). Mean basal serum gastrin level was 37.7±8.3 pg/ml. The integrated gastrin response after administration of a protein rich meal was 2.52±0.07 ng×min/ml and this increased to 5.17±0.18 ng×min/ml (P<0.05) following simultaneous administration of a meal with atropine (0.2 mg/kg) (P<0.05). Our results suggest that there is significant basal and stimulated acid secretion in the baboon; the amount of acid secreted is similar to that reported in man. Gastric pH demonstrated a circadian rhythm. Postprandial gastrin release was significantly enhanced by cotreatment with atropine. As the present findings are similar to those previously reported in man, the baboon may be a useful model for further studies in gastric physiology and experimental peptic ulceration.     

Calcium, magnesium and phosphate during and after hypothermic cardiopulmonary bypass without temperature correction of acid base status

The plasma concentration variations of calcium, magnesium and phosphate were studied in ten patients during and after hypothermic cardiopulmonary bypass (CPB) without temperature correction of acid base status. During the study, pH remained stable, but all the other studied components varied significantly (P less than 0.001). At the start of CPB, the mean ionized calcium concentration increased 25%, and magnesium and phosphate decreased 29% and 40%, respectively, from their control values. At the end of blood cooling, ionized calcium was still 11% above its initial value, magnesium 50% above, and phosphate 39% below. Before weaning from CPB, ionized calcium remained 10% above its initial level, magnesium 41% above, and phosphate 26% below. After CPB, the different divalent ions returned to their initial levels within 1 h for ionized calcium, 6 h for phosphate and 9 h for magnesium. One day post-CPB, ionized calcium was at its start level, magnesium 13% lower, and phosphate 36% higher. During cardiac surgery, the acid base regulation without temperature correction (so-called "alpha stat mode") avoided the appearance of carbon dioxide acidosis. There were widespread disturbances of the divalent ions concentrations, due principally to the different fluids used during CPB, pump priming fluids and cardioplegic solution.     

HRM、24 h pH-MII 在内镜阴性烧心 诊断中的应用研究

目的 利用高分辨率食管测压（HRM）和24 h 食管多通道腔内阻抗pH 监测（24 h pH-MII） 探讨内镜阴性烧心患者的食管动力及反流特点。方法 选取在四川省医学科学院·四川省人民医院消化内科 门诊就诊的以反流症状为主的问卷调查量表（GerdQ）评分>8 分和胃镜阴性患者303 例,分为非糜烂性反流 病（NERD）组、高敏感性食管（HE）组及功能性烧心（FH）组。搜集指标：食管远端收缩积分（DCI）、 下食管括约肌静息压（LESP）、有效蠕动百分比及食管- 胃连接部（EGJ）分型;阻抗基线值、不同性质及 性状反流次数及近端反流次数。结果 ①食管基线阻抗值：NERD 组、HE 组低于FH 组（P <0.05）;②酸 反流：NERD 组DeMeester 评分、最长反流时间（AET）、立/ 卧位AET 高于HE 组、FH 组（P <0.05）;③ 化学及物理反流：NERD 组以酸、液体及混合反流为主,HE 组以弱酸、液体及混合反流为主,FH 组以非酸 及气体反流为主;④动力指标：NERD 组食管LESP 低于HE 组、FH 组（P <0.05）,NERD 组和HE 组DCI 低于FH 组（P <0.05）,FH 组有效蠕动比高于其他两组（P <0.05）,NERD 组EGJ Ⅱ型比例（29%）多于HE 组（9%）、FH 组（1%）（P <0.05）。结论 ① NERD 在食管动力及反流事件方面更符合GERD 的发病机制; ② HE 患者较FH 在食道动力的减弱及反流事件中增多更明显,FH 患者在食道动力及反流方面无明显异常; ③食管HRM 联合24 h pH-MII 在诊断内镜阴性烧心上更有优势,给临床治疗提供依据和指导。     

中药口腔护理液在危重患者中的应用效果

【摘要】 目的 观察医院自制中药口腔护理液用于危重患者的临床效果。方法 观察组采用医院自制的中药口腔护理液,对照组使用生理盐水,观察护理前后两组患者口腔pH值、口臭改善程度、口腔粘膜感染率以及患者的满意度。结果 观察组总满意率为785%,对照组438%;观察组口臭改善率为90%,对照组为70%,差异均有统计学意义（P＜005）;两组患者在干预前口腔pH值无统计学意义,干预后观察组pH值改变,差异有统计学意义（P＜005）;观察组口腔粘膜感染率为10%低于对照组的333%,差异有统计学意义。结论 在口腔护理中,运用中药口腔护理液能够改善危重患者口腔pH值及口臭症状,降低危重病口腔粘膜感染率和增加患者的满意度,可在临床推广应用。     

A pH and thermosensitive choline phosphate-based delivery platform targeted to the acidic tumor microenvironment

Solid tumors generally exhibit an acidic microenvironment which has been recognized as a potential route to distinguishing tumor from normal tissue for purposes of drug delivery or imaging. To this end we describe a pH and temperature sensitive polymeric adhesive that can be derivatized to carry drugs or other agents and can be tuned synthetically to bind to tumor cells at pH 6.8 but not at pH 7.4 at 37 °C. The adhesive is based on the universal reaction between membrane phosphatidyl choline (PC) molecules and polymers derivatized with multiple copies of the inverse motif, choline phosphate (CP). The polymer family we use is a linear copolymer of a CP terminated tetraethoxymethacrylate and dimethylaminoethyl (DMAE) methacrylate, the latter providing pH sensitivity. The copolymer exhibits a lower critical solution temperature (LCST) just below 37 °C when the DMAE is uncharged at pH 7.4 but the LCST does not occur when the group is charged at pH 6.8 due to the ionization hydrophilicity. At 37 °C the polymer binds strongly to mammalian cells at pH 6.8 but does not bind at pH 7.4, potentially targeting tumor cells existing in an acidic microenvironment. We show the binding is strong, reversible if the pH is raised and is followed rapidly by cellular uptake of the fluorescently labeled material. Drug delivery utilizing this dually responsive family of polymers should provide a basis for targeting tumor cells with minimal side reactions against untransformed counterparts.