The choice of compressor effects the aerosol parameters and the delivery of tobramycin from a single model nebulizer.

Recent U.S. Phase III trials of the aerosolized delivery of tobramycin to cystic fibrosis (CF) patients demonstrated a significant improvement in pulmonary function and in sputum bacterial density. These trials used the Pari LC Plus nebulizer and DeVilbiss Pulmo-Aide compressor. This compressor is not generally available in Europe, and its power requirements do not match the European power supply. Thus alternate compressors were evaluated, using the LC Plus nebulizer, in preparation for European clinical trials. Aerosol particle size distribution, nebulization time (min), and the respirable dose of tobramycin (mg within 1-5 mu) were obtained for seven compressor models. The respirable quantity delivered by each of the European compressors (240 Volts, 50 Hz) was compared to the LC Plus and PulmoAide compressor (120 Volts, at 60 Hz). The U.S. system delivered 71.4 mg of the 300 mg instilled dose within the respirable range; using the European compressors, between 63.0 and 74.8 mg was delivered. With a 97% confidence that the delivered tobramycin was within 20% of the standard, we conclude that the SystAm 23ST, MedicAid CR50 and CR60, Pari Master and the Pari Boy compressors are equivalent to the U.S. standard; the Hercules and the SystAm 26ST compressors were not statistically equivalent to the standard. Using the LC Plus nebulizer, five European compressors delivered doses of TOBI that are similar to the doses delivered by the DeVilbiss PulmoAide compressors, and thus may be expected to produce clinical results similar to those of the U.S. trials.

Development and use of a bipolar resectoscope in endometrial electrosurgery.

We conducted a prospective, blinded study to compare the tissue response and mechanical properties of a bipolar resectoscope with standard monopolar cutting and coagulation instruments. At the animal care facility of Tufts Medical School (Medford, MA), four surgeons blinded to instrumentation and distention media cut segments out of a rabbit uterine horn and desiccated the abdominal wall using either the bipolar device in 0.9% saline or the monopolar system in 1.5% glycine. Both systems used a Force 2 Valleylab radiofrequency generator at identical power settings. Cut and desiccated sections were fixed and stained with hematoxylin and eosin as well as Masson's trichrome to evaluate thermal damage. The pathologist was blinded to the system used to make the cut or desiccation. Both systems cut and coagulated tissue with similar properties. Most surgeons noted a longer delay from radiofrequency activation to actual cutting with the bipolar system. The depth of thermal damage when cutting or desiccating tissue was similar for the two systems. This disposable, inexpensive device allows for standard resectoscopic hardware to be transformed into a bipolar device. All current techniques of intrauterine cutting and coagulation may soon be performed in the presence of physiologic uterine distention media. Human clinical data remain to be gathered.

Determination of dolasetron and its reduced metabolite in human plasma by GC-MS and LC.

Both a GC-MS and an LC method have been developed for the simultaneous quantitation of dolasetron and reduced dolasetron in human plasma. The GC-MS method has been utilized in preliminary human pharmacokinetic studies of dolasetron mesylate. Selected ion monitoring was used in these initial studies to obtain the sensitivity and specificity required for quantitation. The GC-MS method has been used in the range of 1-120 ng ml-1 for dolasetron and 1-240 ng ml-1 for reduced dolasetron in plasma. The limit of quantitation for both compounds by GC-MS was 1 ng ml-1. Recently, an LC method has been utilized for quantitation of both compounds on a routine basis. This method utilizes essentially the same sample preparation procedure as the GC-MS method. The LC method has been used in the range of 5-200 ng ml-1 in plasma for dolasetron and reduced dolasetron. In addition, the relationship between the LC and GC-MS methods has been assessed using data obtained from human male volunteers following intravenous administration of 3.0 mg kg-1 of dolasetron mesylate monohydrate.

Healing after arterial dilatation with radiofrequency thermal and nonthermal balloon angioplasty systems.

Thermal balloon angioplasty has been proposed as a means of reducing acute and delayed reclosure of arteries after percutaneous transluminal balloon angioplasty. A radiofrequency (rf) balloon catheter was used to perform thermal balloon angioplasty on canine arteries in vivo. The histologic appearance of rf-treated sites was compared with that of control sites treated by conventional percutaneous transluminal angioplasty. Acutely, rf-treated sites showed a reduced medial cellularity with preservation of internal elastic lamina except at the transitional zone between thermal injury and normal artery, where localized internal elastic lamina disruption was found. Nonthermal sites showed generalized disruption of internal elastic lamina and normal medial cellularity. Both thermal and nonthermal sites displayed a return of intimal cover commencing at 1 to 2 weeks and completed by 4 weeks. Diffuse myointimal hyperplasia appeared by 2 weeks after injury at breaks in the internal elastic lamina along the nonthermal vessels but was localized to the transitional zone in thermal injury sites. In rf-treated vessels, repopulation of the acellular thermally modified media had commenced by 4 weeks, and by 8 weeks the media was diffusely repopulated by spindle-shaped cells resembling smooth muscle cells lying between and aligned with preserved connective tissue laminae. Overall, the distribution and extent of the proliferative response after rf thermal balloon angioplasty were less than those seen after nonthermal balloon angioplasty. Thermal sites, which underwent reintimalization before medial cells returned, were considerably less prone to the development of myointimal hyperplasia. These results suggest that this modality may have beneficial effects on arterial healing after angioplasty.

Determination of terfenadine and terfenadine acid metabolite in plasma using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

This work describes the methodology for the analysis of terfenadine and the acid metabolite of terfenadine in plasma using high-performance liquid chromatography. The use of solid-phase extraction allows the use of robotic or manual sample preparation for the efficient clean-up of terfenadine and terfenadine acid metabolite from plasma. Additional selectivity is obtained through the use of fluorescence detection. For terfenadine, the validated quantitation range of this method is 10.0-84.2 ng/ml with coefficients of variation of 5.7-30%. For terfenadine acid metabolite, the validated quantitation range of this method is 8.2-500 ng/ml with coefficients of variation of 4.1-24%.

Potential of radio-frequency balloon angioplasty: weld strengths, dose-response relationship, and correlative histology.

Previous studies have established the feasibility of combining tissue heat generated by radio-frequency (RF) current and mechanical pressure to manage problems of percutaneous transluminal angioplasty (PTA) that are thought to cause postangioplasty restenosis (PARS). In the current in vitro study of normal and atherosclerotic human aortic layers (intima-media and media-adventitia) separated artificially, the purposes were to identify a dose-response relationship between the total RF energy delivered and the resultant weld strength between vascular tissues and to study the histologic correlates. Twenty-eight control and 100 experimental specimens were evaluated. The mean weld strength for all specimens with no RF current (at 0 J) was 4.1 g +/- 2.0; at 100 J, 5.9 g +/- 2.8; at 200 J, 28.5 g +/- 3.3; at 300 J, 50.0 g +/- 5.5; and at 500 J, 82.0 g +/- 8.2. Inspection of treated specimens revealed vascular molding (depression in the surface corresponding in dimensions to those of the electrode gap in the treatment chamber). Histologic examination revealed necrosis in the region underlying the electrode gap, a hypocellular fusion zone, indistinct boundaries between welded specimen parts, and transition zones to normal histologic characteristics at either end of each specimen. RF energy combined with mechanical pressure produces dose-dependent thermal welds in artificially dissected vascular tissues, molding of vascular tissue, and cellular destruction in the media. These findings may have clinical application in the management or prevention of all forms of PARS in humans and in the treatment of spontaneous aortic dissection.

Thermal compression and molding of atherosclerotic vascular tissue with use of radiofrequency energy: implications for radiofrequency balloon angioplasty.

The combined delivery of pressure and thermal energy may effectively remodel intraluminal atherosclerotic plaque and fuse intimal tears. To test these hypotheses with use of a non-laser thermal energy source, radiofrequency energy was delivered to postmortem human atherosclerotic vessels from a metal "hot-tip" catheter, block-mounted bipolar electrodes and from a prototype radiofrequency balloon catheter. Sixty-two radiofrequency doses delivered from a metal electrode tip produced dose-dependent ablation of atherosclerotic plaque, ranging from clean and shallow craters with histologic evidence of thermal compression at doses less than 40 J to tissue charring and vaporization at higher (greater than 80 J) doses. Lesion dimensions ranged between 3.14 and 3.79 mm in diameter and 0.20 and 0.47 mm in depth. Tissue perforation was not observed. To test the potential for radiofrequency fusion of intimal tears, 5 atm of pressure and 200 J radiofrequency energy were delivered from block-mounted bipolar electrodes to 48 segments of human atherosclerotic aorta, which had been manually separated into intima-media and media-adventitial layers. Significantly stronger tissue fusion resulted (28.5 +/- 3.3 g) with radiofrequency compared with that with pressure alone (4.8 +/- 0.26 g; p less than 0.0001). A prototype radiofrequency balloon catheter was used to deliver 3 atm of balloon pressure with or without 200 J radiofrequency energy to 20 postmortem human atherosclerotic arterial segments. In 10 of 10 radiofrequency-treated vessels, thermal "molding" of both normal and atherosclerotic vessel wall segments resulted with increased luminal diameter and histologic evidence of medial myocyte damage.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of radiofrequency-generated thermal energy on the mechanical and histologic characteristics of the arterial wall in vivo: implications for radiofrequency angioplasty.

Abrupt reclosure of atherosclerotic vessels after percutaneous transluminal balloon angioplasty has been blamed on traumatic dissections and elastic recoil of the vessel wall. Thermal energy with compression produces fusion of separated arterial wall layers, and heat appears to alter the elastic recoil of the vessel wall. Radiofrequency (RF) thermal energy has been used to perform vascular anastomoses and thermal angioplasty. A simple in vivo experiment was designed to describe and quantitate vascular tissue weld strength produced by a range of RF thermal energy levels. Canine carotid arteries were compressed between a pair of modified bipolar forceps that applied RF energy, causing occlusive tissue welds between the apposed intimal surfaces. The strength of the welds was evaluated by measuring the perfusion pressure required to reopen the vessel lumen. A dosimetry range of 0 to 205 joules showed a typical dose-response curve for the relationship between energy applied and bond strength, plateauing at approximately 300 mm Hg. Light microscopy showed fusion of the inner surfaces of the vessel with preservation of vessel wall architecture. Additionally inflation of a bipolar RF balloon catheter in the normal canine carotid lumen produced an alteration of vessel profile angiographically and histologically. Results of these preliminary experiments suggest that balloon angioplasty with adjunctive RF thermal energy may have benefits in reducing the factors causing acute failure of conventional percutaneous transluminal balloon angioplasty.

Radiofrequency balloon angioplasty. Rationale and proof of principle.

Post-angioplasty restenosis (PARS) in atherosclerotic lesions of medium and small arteries occurs in about one-third of cases in the first year following percutaneous transluminal angioplasty (PTA) (early PARS). PARS includes acute spasm, dissection with reclosure, elastic recoil, fibrocellular proliferative response, and progressive atheromatous disease. Fibrocellular proliferation (possibly initiated by platelet derived growth factor) is felt to be culpable in many cases of early PARS (months). Pharmacologic regimens, stents, and thermal welding of the intimal-medial cracks of PTA are among the interventions being developed to deal with PARS. Radiofrequency (RF) current as a source of thermal energy may be useful in combination with balloon angioplasty to reduce PARS. Ideally, this combination would (1) weld intimal-medial cracks of PTA; (2) mold plaque and normal vessel to increase lumen diameters without creating intimal-medial cracks; and (3) destroy medial smooth muscle cells and multipotential cells (cellular substrate of PARS). Canine in vivo studies have established the feasibility of RF-mediated vascular tissue welding. Human aortic specimens (N = 28) were manually dissected into intima-media and media-adventitia layers. Bipolar RF energy (650 KHz, total 300 J) and mechanical pressure (1 atm) (experimental group, N = 24) or mechanical pressure alone (control group, N = 4) were applied to the reapposed specimen layers in a special chamber. The chamber was modified with a bipolar electrode designed to reproduce that planned for an RF balloon angioplasty catheter. Welding was demonstrated in normal and atherosclerotic treated specimens (23/24 or 96%) but not controls (0/4).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of subcutaneous and intramuscular butorphanol in dogs.

Butorphanol tartrate was administered intramuscularly and subcutaneously to adult male and female dogs at a dose of 0.25 mg/kg. No significant absorption lag time and no significant difference bwtween peak intramuscular and subcutaneous serum concentrations were observed. The mean peak serum concentration was 29 ng/ml at mean times of 28 min after subcutaneous administration and 40 min after intramuscular administration. There were no significant differences in the pharmacokinetics of butorphanol in dogs with either route. The serum half-life was 1.62 hr, and the serum clearance was 3.45 liters/kg/hr. The apparent volume of distribution of butorphanol was 7.96 liters/kg. Although considerable inter- and intraanimal variation in Cmax and AUC was observed, there was no significant difference in the area under the serum concentration versus time curves, and the two administration routes were considered bioequivalent.