Conventional and hypobaric activation of an ultrasound contrast agent

Hypobaric activation is a new injection technique for use with the contrast agent EchoGen and, in this study, the agent's ability to produce parenchymal enhancement in vivo, with and without prior hypobaric activation, was investigated. Injections, ranging in dose from 0.05 to 0.5 mL/kg, were administrated through a peripheral vein to eight woodchucks with multiple hepatomas. At the 0.10 mL/kg dose level, seven of eight injections following hypobaric activation (88%) resulted in definite parenchymal enhancement. Conversely, dosages of 0.10 mL/kg without prior hypobaric activation produced no grey-scale changes. Only at the 0.4 and 0.5 mL/kg dosage level did the conventional administration technique obtain similar results (4 of 5 injections increased the echogenicity for a 0.4 mL/kg dose). These differences were statistically significant (p = 0.031). In vitro experiments were conducted to establish the physical mechanisms behind hypobaric activation. Relative measurements of contrast microbubble sizes were performed with a phase Doppler particle analyzer after hypobaric and after conventional (bolus) activation. Hypobaric activation produced approximately 20 times more microbubbles per unit volume than the conventional method. In conclusion, this investigation has demonstrated the benefits of prior hypobaric activation when performing in vivo contrast studies with EchoGen and determined the physical mechanisms behind this new injection technique. Hypobaric activation of EchoGen increases contrast enhancement and reduces dose size.     

MnPcS4: a new MRI contrast enhancing agent for tumor localisation in mice

Manganese-tetrasulfonated phthalocyanine (MnPcS4) has been evaluated as a potential contrast agent in Magnetic resonance imaging (MRI) for tumor localisation in mice. MnPcS4 showed favourable molar relaxivity, much better than Gd-DTPA and comparable to tetrasulfonated manganese complex of porphyrin (TPPS4). Tumors showed selective retention of the metal complex (dye) with the peak value reached at 24 hours following intravenous administration. Dye concentration in tumors remained consistently higher than either kidney or muscle tissue both at 1 and 24 hours and a 10-fold increase in tumor-to-muscle ratio over the control was seen at 24 hr. Normal liver tissue, however, showed higher concentration than tumor at all times during the study. A linear correlation was found between longitudinal relaxation rate (1/T1) and the corresponding concentration of MnPcS4 in various tissues. MR imaging done in animals using 1.5 T superconducting clinical imager showed a mean percent increase in signal intensity of 131.8% (SD +/- 32.86) in the tumor and a 70% increase in tumor-to-muscle ratio over the pretreatment value, at 24 hr. The results suggest that MnPcS4 is a potential tumor-selective contrast agent in MRI.     

Acoustic backscatter properties of the particle/bubble ultrasound contrast agent

Bubble-based suspensions with diameters in the 1-5 microns range have been developed for use as ultrasound contrast agents. Bubbles of these dimensions have resonance frequencies in the diagnostic ultrasonic range, thus improving their backscatter enhancement capabilities. The durability of these bubbles in the blood stream has been found to be limited, providing impetus for a number of approaches to further stabilize them. One of the approaches has been the development of micrometer-size porous particles or 'nano-sponges' with properties suitable for the entrapment and stabilization of gas bubbles. However, the complex morphology and surface chemistry involved in the production of this type of agent makes it unfeasible to directly measure the volume of the entrained gas. A model based on acoustic scattering principles is proposed which indicates that only a small volume fraction of gas should be necessary to significantly enhance the echogenicity of this type of particle-based contrast agent. In the model, the effective scattering cross-section is evaluated as a function of the volume fraction of gas contained in the overall scatterer and the overall scatterer diameter. Initially, the volume fraction of gas is considered as a discrete entity of single bubble. Using common mixture rules, it is then shown that the gas can be considered to be distributed throughout the particle and still arrive at a result that is similar to that for a single, discrete volume of gas. The main contribution to the increased scattering cross-section is due to the compressibility difference between gas and water. The backscatter coefficient is computed as the product of the resulting differential scattering cross-section and the scatterer number density. This approach facilitates comparison with known backscatter coefficients of biological targets such as liver and blood. Simple experimental results are presented for comparison with the model, and the implications relevant to clinical use are suggested.     

Gas-body-based contrast agent enhances vascular bioeffects of 1.09 MHz ultrasound on mouse intestine

Anesthetized hairless mice were exposed to continuous or pulsed 1.09-MHz ultrasound with or without prior injection of a gas-body-based ultrasound contrast agent. Albunex at a dose of 10 mL/kg increased the production of intestinal hyperemia, petechia and hemorrhages by continuous ultrasound. For pulsed ultrasound, with 10 micros pulses and 0.01 duty cycle, petechiae were produced for exposures as low as 1 MPa spatial peak pressure amplitude with added gas bodies. The enhancement of petechiae production was robust for pulsed exposure; for example, at 2.8 MPa, an average of 227 petechiae was obtained with added gas bodies, which was 30 times more than without the agent. The production of petechia was roughly proportional to the dosage of Albunex for pulsed exposure. Results did not appear to be strongly dependent on pulsing parameters, but long bursts (0.1 s) were somewhat more effective than pulses (10 micros). The observed vascular bioeffects appeared to involve both thermal and nonthermal mechanisms for continuous exposure, but to result primarily from gas-body activation for pulsed exposure.     

Myocardial contrast echocardiography: reliable, safe, and efficacious myocardial perfusion assessment after intravenous injections of a new echocardiographic contrast agent

Reliable and reproducible myocardial opacification after intravenous administration of echocardiographic contrast agents has remained elusive. This study was performed to determine whether a new agent, FS069, a suspension of perfluoropropane-filled albumin microspheres (3.6 microns average microbubble size, concentration 8 x 8(8)/ml), could achieve safe and successful myocardial opacification in open-chest dogs. Seventeen dogs (group 1, n = 7, group 2, n = 10) underwent two-dimensional echocardiography before, during, and after the administration of intravenous FS069. Safety was evaluated by measuring arterial and pulmonary artery pressures, heart rate, blood gases, systolic function, myocardial blood flow, and postmortem analysis of myocardial viability by triphenyl-tetrazolium chloride staining. Efficacy to detect changes in regional myocardial perfusion was assessed by injecting FS069 at baseline, after sequential coronary occlusions and reperfusion, and during intravenous vasodilators with and without coronary occlusions. Results were compared with radiolabeled microspheres. FS069 was found to be safe and effective. In the absence of coronary occlusions, uniform myocardial opacification was observed in all dogs. A perfusion defect was observed in all dogs during coronary occlusions. Background-subtracted peak contrast intensity in the myocardium correctly identified regional myocardial blood flow changes and showed a significant correlation with radiolabeled microspheres (r = 0.65, p = 0.0001).     

Cellulose as a gastrointestinal US contrast agent

Ultrasound (US) imaging of the abdomen often is compromised by artifacts due to adjacent bowel gas. In an attempt to decrease gas artifacts and improve US image quality, the authors evaluated the use of cellulose preparations as gastrointestinal US contrast agents. Optimal homogeneity and reflectivity were evaluated in phantom solutions, and two suitable agents were selected for clinical trial. Ten volunteers underwent abdominal US imaging before and after contrast agent administration on three separate occasions. The volunteers drank 800 mL of freshly degassed water and two different gastrointestinal US contrast agents. US images obtained before and after administration of contrast material were evaluated by five radiologists and scored for bowel marking, visualization of abdominal anatomy, and image degradation by bowel gas. Compared with water, the orally administered US contrast agents improved visualization of bowel and abdominal anatomy, with diminished gas artifact.     

Sonographic detection of tumor blood flow using a new contrast agent in woodchuck hepatomas

The aim of this study was to assess the ability of perfluoropropane-filled albumin microspheres to visualize tumor blood flow in woodchuck hepatomas. Ten tumors in five woodchucks with hepatomas were imaged before and after intravenous injection (dosages of 0.01 ml/kg to 2.0 ml/kg) of an agent using color Doppler sonography and gray scale ultrasonography. Both enhanced imaging modalities demonstrated blood flow around and within all tumors. Enhanced gray scale ultrasonography demonstrated sonographic "tumor blush" in seven tumors (70%). In conclusion, tumor blood flow in woodchucks was visualized more clearly using the agent on both color Doppler and gray scale ultrasonography.     

Tumor imaging with a macromolecular paramagnetic contrast agent: gadopentetate dimeglumine-polylysine

RATIONALE AND OBJECTIVES: We evaluated magnetic resonance (MR) contrast enhancement of tumor tissue following injection of the macromolecular conjugate, gadopentetate dimeglumine-polylysine. METHODS: T1-weighted MR imaging scans were performed on female Fisher-344 rats with subcutaneously implanted mammary adenocarcinoma tumors. Following the baseline scan, gadopentetate dimeglumine-polylysine or gadopentetate dimeglumine was injected at a dose of 0.1 mmol gadolinium per kilogram. RESULTS: Gadopentetate dimeglumine-polylysine injection resulted in a maximum enhancement of tumor contrast of 310 +/- 60% (n = 7). Tumor tissue remained enhanced and well defined for several days after gadopentetate dimeglumine-polylysine injection. Gadopentetate dimeglumine injection at the same dose resulted in a 70 +/- 25% (n = 4) maximal tumor enhancement and a corresponding 25 +/- 4% muscle enhancement. CONCLUSION: Gadopentetate dimeglumine-polylysine provides higher, more sustained tumor contrast than does gadopentetate dimeglumine for the same dosage of gadolinium.     

Human biodistribution of an ultrasound contrast agent (Quantison) by radiolabelling and gamma scintigraphy

The biodistribution and kinetics of an air filled human serum albumin microcapsule formulation (Quantison) intended for use as an intravenous ultrasound contrast agent have been examined. 12 healthy subjects were administered with approximately 50 million microcapsules per kilogram body weight, radiolabelled with 50 MBq 123I. Imaging was performed over a period of 58 h using a large field-of-view gamma camera and the amount of labelled material present in the blood, urine and faeces measured. Imaging demonstrated that the liver was the organ with the highest uptake, with a mean uptake of 41.8% (SD 10.4%) of the administered dose 1 h following administration. The maximum uptake of the agent in the lungs was low, mean 4.0% (SD 3.4%). A small amount of uptake was visible in the bone marrow; however, this was not quantifiable. There was also evidence of minimal myocardial activity within 5 min of administration. No adverse events were observed and there were no changes in any of the individual post-study indices. The present study demonstrates the safety of Quantison. Gamma scintigraphy played a useful role in confirming the biodistribution of the agent with little lung uptake, high liver uptake and evidence of myocardial uptake.     

Regulating angiogenesis: a new therapeutic strategy

Angiogenesis is the proliferation of endothelial and smooth muscle cells to form new blood vessels. Largely muted after adolescence, angiogenesis may be reignited by cancerous cells. Neoangiogenesis plays a primary role in tumor growth and metastases. Antiangiogenic therapy to limit and even reverse the growth of tumors are under investigation and showing promise. A derivative of fumagillin, TNP 470, is the first angiogenesis inhibitor to be given to humans. Surprisingly, several potent inhibitors are derived from tumors themselves. Researchers nowc recognize that stimulation of angiogenesis may have a place in the treatment of cardiovascular disease. Reestablishing blood flow to ischemic tissue through angiogenesis may provide a biologic "bypass" for patients with ischemic heart disease. The same applies to the treatment of peripheral vascular disease.     

Oral administration of a low-cost negative contrast agent: a three-year experience in routine practice

A low cost, well tolerated, and effective gastrointestinal contrast agent is needed for abdominal MRI. The authors tested, in vitro and in routine practice, a mixture of 192 g of barium sulfate (Micropaque HD oral, Guerbet, France) diluted in 500 ml of gastric antacid (Maalox, Rohrer, Fort Washington, PA). Its T1 and T2 relaxation times were 324 and 14 msec, respectively (.2 T). This contrast agent was used in routine practice in 789 patients (.5 T). It had a low signal intensity in 86% and 82% of the cases on T1- and T2-weighted sequences, respectively. No side effect due to magnetic susceptibility was seen, even with gradient-echo sequences. The dilution of barium sulfate in gastric antacid, instead of water, causes a low signal intensity on all sequences for a low barium sulfate concentration (38% w/v). This product is an effective and low cost contrast agent in routine practice.     

On the effect of lung filtering and cardiac pressure on the standard properties of ultrasound contrast agent

The goal standard of contrast echocardiography is the absolute measure of myocardial perfusion using a contrast agent. Actually, several contrast agents are developed. All these agents show left ventricular opacification after intravenous injection. However, none of these agents shows an acceptable enhancement of the myocardium yet using conventional imaging techniques. The explanation of this phenomenon should be easy by measuring the acoustic characteristics of the contrast agent and then making a comparison of these characteristics with those of the myocardium. In this study we present definitions of standard acoustic parameters of ultrasound contrast agent, the backscatter coefficient Bs and the scattering-to-attenuation ratio STAR. Afterwards, considering an intravenous injection of the contrast agent, and taking into account the effects of lung filtering and cardiac pressure, the standard properties of contrast agents are determined in different sites: right ventricle (before lung passage), left ventricle (after lung passage and taking into account the pressure effect) and in the coronary system. Calculations showed that the acoustic properties are considerably influenced by these two effects: lung filtering and cardiac pressure. Comparison of these properties with the tissue properties (myocardium) is then performed. This determines the contribution of the contrast agent to the enhancement of the tissue visualization. The simulations are performed on Albunex microspheres. The results reveal that the difference between scattering of the myocardium and scattering of intravenously injected Albunex is too slight to be visible on an echographic image.     

Example of active therapeutic follow-up: itraconazole

The systematic fungal infections are very serious diseases, the crude mortality in invasive aspergillosis reaches 75 to 100 per cent. Systemic mycosis tends to develop in immunocompromised patients with subsequent physiopathological state, causing a risk of impairment in their digestive absorption potential; in addition these patients are polymedicated and the emergence of multiple drug interactions is frequent. Itraconazole is a very potent antifungal drug with large safety margin and the drug monitoring to maintain a satisfactory plasma level. Immunocompromised patients with suspected malabsorption and treated with oral capsule itraconazole were monitored during two years. In such difficult patients (approximately equal to 500 cases), the result has shown good trough steady-state plasma levels in 72 per cent and insufficient in 28 per cent of the observed patients. However concomitant treatments with antacids produce, in a lot of cases (approximately equal to 48 per cent), a noticeable decrease of the itraconazole availability for these patients. A training program was established to perform the analytical determination of itraconazole and hydroxyitraconazole in biological samples by HPLC method. Analytical validation procedures were associated to this training program which included 115 scientific, technical staff (pharmacists, biochemists ...) from 56 hospitals and institutes.     

Patient compliance: the effect of the doctor as a therapeutic agent

This paper is a review of the available literature on patient complicance with medical regimens. An effort is made to focus on those features or characteristics associated with compliance or noncompliance that are clinically relevant for the practicing physician. These include the intelligence of the patient, the patient's knowledge of his disease, the complexity of the medical regimen, the influence of the family, the health belief model, and the doctor-patient relationship. From this review of research data, 12 concrete suggestions are presented for the purpose of enhancing patient compliance and enabling the doctor himself to be more effective as a therapeutic agent.     

Topotecan: a new topoisomerase I inhibiting antineoplastic agent

OBJECTIVE: To review the pharmacologic, pharmacokinetic, therapeutic, and safety aspects of irinotecan, a new antineoplastic agent, and to assess its role in the treatment of colorectal and lung cancer. DATA SOURCES: English-language articles from the MEDLINE database, January 1990-March 1998; Pharmacia & Upjohn Company; published articles and meeting abstracts. STUDY SELECTION: Studies in humans with cancer, clinical case reports, and open clinical studies were reviewed. Efficacy studies were limited to trials with at least 20 evaluable patients. DATA EXTRACTION: Relevant data were extracted from published reports and abstracts. DATA SYNTHESIS: Irinotecan is an effective agent for the treatment of advanced colorectal cancer. It demonstrates significant activity as a first-line agent and in patients with disease that is refractory to fluorouracil-containing regimens. Activity against lung cancer has also been demonstrated. Limited data indicate activity against cancers of the ovary, cervix, stomach, and in non-Hodgkin's lymphomas. Major toxicity consists of myelosuppression and diarrhea. CONCLUSIONS: Irinotecan is a useful addition to the antineoplastic drug family and offers significant efficacy for treatment of patients with fluorouracil-refractory colorectal cancer.     

Determination of the active moiety of BX661A, a new therapeutic agent for ulcerative colitis, by studying its therapeutic effects on ulcerative colitis induced by dextran sulfate sodium in rats

Conventional hematopoietic stem cell cryopreservation methods use a DMSO concentration of 10%. However, cells manipulated ex vivo may require more refined freezing protocols adapted to the specific cell suspension. In this retrospective study, we evaluated the results obtained with CD34+ cells purified from peripheral blood of 39 patients on the CEPRATE SC System and frozen in 7.5% DMSO with a view to transplantation. The post-freezing recovery of progenitor cells was 89.4 +/- 27.87% for CD34+ cells, 59.13 +/- 36.93% for CFU-GM, and 53.49 +/- 40.71 for BFU-E. Neither the purity of the suspension nor the nucleated cell density during freezing was predictive of cell recovery. No difference was observed between cells stored in vials and bags. Thirty-seven patients transplanted with the concentrated CD34+ fraction received 4.46 x 10(6) CD34+ cells/kg and 33.04 x 10(4) CFU-GM/kg. The median time to granulocyte (>0.5 x 10(9)/l) and platelet (>50 x 10(9)/l) engraftment was 11 and 13 days, respectively. Only cell density and the infused number of CD34+ cells and CFU-GM were significantly related to hematological recovery. Our data suggest that purified CD34+ cells can be successfully cryopreserved in 7.5% DMSO and may represent a first step in establishing freezing parameters for selected CD34+ cells.     

Gemcitabine: a new chemotherapy agent for solid cancers

Gemcitabine, a new nucleotide analogue, is a promising chemotherapeutic agent for pancreatic, lung, ovarian and breast carcinomas. Its low toxicity (mainly hematologic) makes it a good choice for palliative treatment in patients who would otherwise be unable to tolerate aggressive therapy. The combination of gemcitabine with other anticancer agents such as cisplatin and anthracyclines appears to be associated with high response rates. Finally, gemcitabine is a potent radiosensitizing agent and should definitely be tested in combination with radiotherapy mainly in locally advanced disease.