Acquired and specific immunological mechanisms co-responsible for efficacy of polymer-bound drugs.

We present data providing new evidence that poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA)-bound drugs, unlike free drugs, have both cytostatic and immunomobilizing activity (CIA). Immediately after injection, due to the high level of the drug, the main activity of the polymeric conjugate is cytotoxic and cytostatic. Later on, long-term circulating PHPMA-bound drug, at concentrations lower than its minimal inhibitory levels, mobilizes the defense mechanisms of the host. Cytotoxic and cytostatic effects of drug-PHPMA were repeatedly confirmed. The following data support the concept of the immunomobilizing activity of the N-(2-hydroxypropyl)methacrylamide (HPMA) conjugates: (a) pre-treatment with free drugs (doxorubicin, cyclosporin A) accelerates the appearance of EL4 mouse T-cell lymphoma while a similar pre-treatment with doxorubicin-PHPMA induces limited but definitive mobilization of the host's defense mechanisms; (b) mice cured of EL4 mouse T-cell lymphoma, BCL1 mouse B-cell leukemia and 38C13 mouse B-cell lymphoma by injection of doxorubicin-PHPMA conjugate targeted with monoclonal antibodies (anti-Thy 1.2 for EL4, anti-B1 for BCL1 and anti-CD71 for 38C13) and re-transplanted with a lethal dose of the same cancer cells survive without any treatment considerably longer than control mice; (c) increased NK activity and anti-cancer antibody was detected only in animals treated with doxorubicin-PHPMA conjugate; and (d) considerably increased NK and LAK activity was seen in a human patient treated for generalized breast carcinoma with doxorubicin-PHPMA-IgG.     

Laparolithic cholecystectomy: laboratory data and first clinical case

A method of laparoscopic cholecystectomy is described. After control of the cystic duct and artery, gallstones are emulsified with a laparoscopic lithotriptor and the debris aspirated from the gallbladder. The free wall of the gallbladder is excised and the remaining gallbladder mucosa ablated with holmium:yttrium-aluminum-garnet (Ho:YAG) laser. This technique eliminates the need for dissection of the gallbladder from the liver, thereby reducing the possibility of hemorrhage from the gallbladder fossa. At the same time stones and bile are aspirated so that the excised portion of gallbladder can be easily removed through an access port without spillage of contaminated bilious debris into the abdominal cavity or puncture wound that could cause infection. Acute and chronic animal studies confirm the feasibility of this technique. A clinical case is described.     

Interactions between herbs and conventional drugs: overview of the clinical data

This article provides an overview of the clinical evidence of interactions between herbal and conventional medicines. Herbs involved in drug interactions--or that have been evaluated in pharmacokinetic trials--are discussed in this review. While many of the interactions reported are of limited clinical significance and many herbal products (e.g. black cohosh, saw palmetto, echinacea, hawthorn and valerian) seem to expose patients to minor risk under conventional pharmacotherapy, a few herbs, notably St. John's wort, may provoke adverse events sufficiently serious to endanger the patients' health. Healthcare professionals should remain vigilant for potential interactions between herbal medicines and prescribed drugs, especially when drugs with a narrow therapeutic index are used.     

Transmyocardial laser revascularization: overview of clinical and experimental data]

Transmyocardial laser revascularization (TMLR) using carbon dioxide and Holmium YAG laser has been approved by FDA and is now under clinical evaluation in patients with refractory angina who are not candidate of CABG or PTCA. Original concept of TMLR was direct perfusion from left ventricle through channel created by laser. However, pathological analysis showed closed channel in almost all cases, and most possible mechanism of TMLR are now thought to be angiogenesis following to inflammatory response of laser injury. Most prospective randomized trial comparing TMLR and conservative medical treatment demonstrated significantly less angina in TMLR patients and better exercise tolerance and angina-free survival rate during follow-up period. On the other hand, no significant differences were demonstrated in overall mortality rate, myocardial perfusion or cardiac function.     

Ultraharmonic myocardial contrast imaging: in vivo experimental and clinical data from a novel technique.

Myocardial contrast echocardiography (MCE) with high-mechanical-index (MI), triggered harmonic imaging is the best-established technique to date for the assessment of myocardial perfusion. A high signal-to-noise ratio, which is significantly influenced by precontrast tissue signals, is an important prerequisite. Our goal was to evaluate the efficacy of ultraharmonic MCE, a technique that rejects tissue signals by receiving signals beyond the second but below the third harmonic. Imaging was performed in 6 closed-chest dogs and in 15 healthy volunteers (11 of whom also had dipyridamole stress). Analyses of videointensity (VI) confirmed uniformly low precontrast tissue VI, a significant increase of postcontrast VI (before and after dipyridamole), and a significant decrease in VI after microbubble destruction. We conclude that ultraharmonic MCE produces low precontrast tissue signals, thus optimizing postcontrast myocardial opacification, and exhibits efficient microbubble destruction with use of multiple-frame triggering. Thus this new technique opens up a new possibility of further optimizing coronary microcirculation imaging with microbubbles.     

Antibacterial activities of the antiparasitic drugs nifurtimox and benznidazole.

Both nifurtimox and benznidazole, which are used for the treatment of Chagas' disease, also display marked antibacterial activities. Characteristically for nitroheterocyclic compounds, they are much more active against anaerobic and microaerophilic bacteria than against aerobic bacteria. Nitroreductase-deficient aerobes are completely resistant, whereas SOS-repair-deficient strains are moderately susceptible. Those strains are rapidly killed.     

Dissociation between opiate-like and antidiarrheal activities of antidiarrheal drugs.

Three synthetic antidiarrheals, diphenoxylate, loperamide and SC 27166, and two narcotics, morphine and codeine, were evaluated in rats by the intravenous and oral route for specificity and duration of their antidiarrheal, opiate-like and acute toxic effects. The activity in the castor oil test, the tail withdrawal test and the acute toxicity test was used to determine the relative antidiarrheal specificity and relative safety margins. An analysis of animal and clinical data indicate these tests to be excellent indicators of clinical usefulness and specificity. Intravenously, all five agents induced opiate-like central effects, loperamide and SC 27166 at near toxic doses only. When administered orally loperamide and SC 27166 were devoid of opiate-like central nervous system activity. Analysis of the plasma levels after oral loperamide indicated that this drug does not attain a concentration high enough to induce opiate-like central effects. All agents were effective antidiarrheals by the oral route with loperamide being the most potent (ED50 = 0.15 mg/kg), longest acting (ED50 8 hr = 1.81 mg/kg) and most specific (relative antidiarrheal specificity, 8 hr greater than or equal to 88) and having the greatest relative safety margin (8 hr = 102).     

Counterflow centrifugal elutriation: experimental and clinical applications.

Counterflow centrifugal elutriation (CCE) separates mixed cell populations into distinct subpopulations, on the basis of different sedimentation characteristics, without impairment of cell function or yield. The advantages of this technique are the high recovery and viability of fractionated cells, as well as the rapidity and the reproducibility of results. CCE alone, or in combination with other separation methods, can provide homogeneous populations of cells for further investigations. Recently, CCE was employed in clinical studies aimed at preventing graft-versus-host disease in bone marrow transplant recipients, by depleting lymphocytes prior to bone marrow infusion. This article reviews the principles of elutriation and describes the possible experimental and clinical applications of this technique, which seems suitable for both peripheral blood (PB) and bone marrow (BM) separation.     

Venous air embolism: clinical and experimental considerations.

OBJECTIVE: To examine the existing literature concerning venous air embolism. Causes, pathophysiology, and management are emphasized. DATA SOURCES: The literature that was reviewed was retrieved from the MEDLINE System under the headings "venous air embolism," "air embolism," "therapy of air embolism," "etiology of venous air embolism," and "pathophysiology of venous air embolism" for the years 1970 to 1991. A manual search, derived from the references of these papers, was performed to obtain relevant citations for the years preceding 1970. STUDY SELECTION: Experimental (animal) data, case reports, case series, and clinical investigations are included. CONCLUSIONS: Venous air embolism is an infrequent complication of invasive diagnostic and therapeutic maneuvers. The cardiovascular, pulmonary, and central nervous systems may all be affected, with severity ranging from no symptoms to immediate cardiovascular collapse. Therapeutic interventions include mechanical measures, such as positioning, withdrawal of air from the right atrium, and measures aimed at reducing bubble size. Hyperbaric oxygen therapy holds some promise in accomplishing the latter, but randomized, controlled trials demonstrating efficacy have yet to be performed.     

Photodynamic therapy of esophageal varices: experimental studies in animal veins, and first clinical cases

BACKGROUND AND STUDY AIMS: Endoscopic injection sclerotherapy and endoscopic variceal ligation have been found to have shortcomings in the treatment of esophageal varices. In this study the effectiveness of photodynamic therapy (PDT) in the obliteration of veins was investigated to evaluate its potential in the treatment of esophageal varices. METHODS: Auricular margin veins of rabbits were irradiated by copper vapor laser after intravenous injection of 10 mg/kg of hematoporphyrin monomethyl ether (which is a hematoporphyrin derivative) into the rabbits. Control groups included rabbits that received irradiation only, that received injection of photosensitizer only, and that received injection sclerotherapy (using sodium morrhuate). The treated areas were observed macroscopically and also identified using with ultrasonic miniprobe. Biopsies were performed and the specimens were examined microscopically after hematoxylin-eosin staining and Victoria blue staining. In addition, two patients with newly visible veins within the esophageal wall after endoscopic injection sclerotherapy underwent PDT. Intravenous injection of 5 mg/kg of hematoporphyrin monomethyl ether was given, and the newly visible veins were endoscopically irradiated by copper vapor laser. Endoscopic re-examination was performed 1 month later to evaluate the therapeutic effect. RESULTS: Thrombi of the auricular margin vein were formed and blood flow was obstructed after PDT. Thrombus formation and diffused necrosis of adjacent tissue was found after injection of sodium morrhuate. On ultrasonic examination, the lumina of the veins showed a slightly higher echo after PDT compared with a lower echo before treatment, which was another sign of thrombus formation. The rabbit ears showed a diffused low echo after injection of sodium morrhuate, indicating diffuse necrosis. On microscopic observation, destruction of the endothelium and formation of thrombus was seen after PDT. Further observation of specimens stained with Victoria blue showed that the layer of elastic fiber was intact. After injection of sodium morrhuate, extensive necrosis of tissue was seen microscopically. No macroscopic, ultrasonic, or microscopic change was found in the rabbits that received irradiation only or injection of photosensitizer only. The rate of thrombus formation in rabbits that received PDT was significantly higher than that in the rabbits that received irradiation only or injection of photosensitizor only ( P = 0.015, P = 0.015), and comparable to that in the rabbits that received sclerotherapy ( P = 0.467). In the clinical study, at endoscopy 1 month after PDT both the number and the "red sign" of newly visible veins were found to have decreased. No adverse effect was found. CONCLUSION: PDT can destroy the endothelium of the vein, result in thrombus formation, and eventually obliterate the vein. It is potentially a new method for the treatment of esophageal varices.     

抗精神病药物所致迟发性运动障碍临床资料分析

目的 了解抗精神病药物所致迟发性运动障碍的临床特征.方法 对110例迟发性运动障碍患者应用Simpson迟发性运动障碍专用量表和异常不自主运动量表评定不自主运动的发生状况及严重程度.结果 本组患者上肢、下肢和舌部的异常不自主运动发生率较高,均≥80.9％.不同性别、年龄段、应用抗精神病药物类型患者异常不自主运动量表总分及各项分值和比较差异无显著性(P＞0.05).结论 抗精神病药物所致迟发性运动障碍主要表现为四肢末端和舌部的异常不自主运动,严重程度不存在性别、年龄段、应用药物差别.     

Skeletal tissue engineering using mesenchymal or embryonic stem cells: clinical and experimental data

Introduction: Mesenchymal stem cells (MSCs) can be obtained from a wide variety of tissues for bone tissue engineering such as bone marrow, adipose, birth-associated, peripheral blood, periosteum, dental and muscle. MSCs from human fetal bone marrow and embryonic stem cells (ESCs) are also promising cell sources.

Areas covered: In vitro, in vivo and clinical evidence was collected using MEDLINE® (1950 to January 2014), EMBASE (1980 to January 2014) and Google Scholar (1980 to January 2014) databases.

Expert opinion: Enhanced results have been found when combining bone marrow–derived mesenchymal stem cells (BMMSCs) with recently developed scaffolds such as glass ceramics and starch-based polymeric scaffolds. Preclinical studies investigating adipose tissue–derived stem cells and umbilical cord tissue–derived stem cells suggest that they are likely to become promising alternatives. Stem cells derived from periosteum and dental tissues such as the periodontal ligament have an osteogenic potential similar to BMMSCs. Stem cells from human fetal bone marrow have demonstrated superior proliferation and osteogenic differentiation than perinatal and postnatal tissues. Despite ethical concerns and potential for teratoma formation, developments have also been made for the use of ESCs in terms of culture and ideal scaffold.     

A new endotoxin adsorber: first clinical application.

In an open, uncontrolled pilot study, 5 men and 1 woman with suspected gram-negative sepsis were treated with a new whole-blood endotoxin adsorption system. Lipopolysaccharide (LPS) adsorption was carried out by hemoperfusion over high-affinity polymethacrylate-bound albumin (Fresenius Endotoxin Adsorber EN 500). All patients suffered from endotoxemia (>20 pg/ml LAL) and met at least two systemic inflammatory response syndrome (SIRS) criteria. Four patients suffered from pneumonia due to mechanical ventilation, one from peritonitis, and one from pneumonia and peritonitis. Endotoxin adsorption was very well tolerated, and efficient LPS removal was shown in all patients. Apache II score immediately before immunoadsorption was 23.5 and was 22.3 after the last treatment. All 6 critically ill patients improved substantially and were discharged from the intensive care unit. LPS whole blood immunoadsorption is a promising new method. No side effects have been observed thus far. A large controlled study to prove clinical efficacy in patients with severe sepsis is under way.