Efficacy of a novel treatment serum in the improvement of photodamaged skin.

A novel treatment serum formulated to target multiple pathways in the anti-ageing cascade was tested both in vitro and in clinical settings. In vitro testing was performed to assess the ability to stimulate key proteins and genes fundamental to the anti-ageing cascade. The antioxidant potential of the formulation was studied in a UV-irradiation clinical study. A 12-week, open-label, single-centre study was conducted to determine whether this uniquely formulated topical treatment serum could improve visible signs of facial photodamage. Clinical evaluations showed statistically significant reductions in fine wrinkles and coarse wrinkles and improvements in skin texture, tone and radiance starting at week 4 with continued improvements at weeks 8 and 12. Subject self-assessments confirmed that the beneficial effects of the treatment serum were readily observed by the users. The treatment serum was well tolerated with no treatment-related adverse events reported during the 12-week study. Use of this novel treatment serum produced significant improvements in the visible signs of facial photodamage.

Spectrum of angiographic findings in aortoarteritis.

Angiographic appearances are characteristic, distinctive and a major basis of established criteria in the diagnosis of aortoarteritis. We present a pictorial review of digital subtraction angiography imaging in patients with proven aortoarteritis, based upon 16 years' experience in our institution. Understanding of these angiographic appearances is important for definitive diagnosis, and for evaluation of the extent of the disease in order to plan appropriate further management.

Intercellular adhesion molecule-1 suppression in skin by topical delivery of anti-sense oligonucleotides.

We topically applied 20 nucleotide phosphorothioate intercellular adhesion molecule-1 anti-sense oligodeoxynucleotide in a cream formulation. It effectively inhibited tumor necrosis factor-alpha-induced expression of intercellular adhesion molecule-1 in human skin transplanted on severe compromised immunodeficient mice. The effects were concentration dependent, sequence specific, and resulted from reduction of intercellular adhesion molecule-1 mRNA levels in the skin. Intravenous administration of the drug did not show pharmacologic effects, probably due to insufficient drug concentrations in skin. Topical delivery, however, produced a rapid and a significantly higher accumulation of oligodeoxynucleotide in the epidermis and dermis. The results strongly suggest that topically applied anti-sense oligonucleotides can be delivered to target sites in the skin and may be of considerable value in the treatment of psoriasis and other inflammatory skin disorders.

Permeability of antisense oligonucleotide through porcine buccal mucosa.

Antisense oligonucleotides (AONs) that can modulate malfunctioning genes have a great potential to become future therapeutic agents. In this study, we investigated the feasibility of buccal delivery of AONs using ISIS 3082 as a model compound. An isocratic HPLC method was developed to quantify ISIS 3082. The permeability coefficient of this AON at 37 degrees C, determined by using side-by-side diffusion cells, was 1.05x10(-9) (cm/s). The flux of ISIS 3082 across buccal mucosa was dependent upon its concentration in the donor chamber. The permeation of ISIS 3082 was increased when 100 mM of sodium glycocholate was used as a permeation enhancer. The potential of delivering AONs via buccal route with the aid of permeation enhancers is explored in this study.

Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human beta-adrenoceptors.

The site of interaction for the 1-(3',4',5'-trimethoxybenzyl) group of trimetoquinol (TMQ) with beta-adrenoceptors (beta-ARs) is important for the rational design of highly potent and beta3-AR-selective analogs. 1-Benzyl ring-substituted TMQ analogs were evaluated for binding affinities and biochemical activities (cyclic AMP accumulations) in Chinese hamster ovary (CHO) cells expressing the rat and human beta3-AR, and for functional activities on isolated rat tissues. Binding affinities (K1 approximately 0.055 to 1.5 microM) for the rat beta3-AR and potencies for adenylyl cyclase activation (K(act) approximately 0.43 to 2;5 nM) of the 3'-monoiodo or 3',5'-diiodo derivatives with 4'-isothiocyanato-, 4'-amino, 4'-acetamido, or 4'-alpha-haloacetamido substitutions were higher than those of (-)-isoproterenol, and comparable to those of BRL 37344 [(+/-)-(R*,R*-[4-[2-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]ph enoxy]-acetic acid sodium]. A similar rank order of binding affinities (K(i) approximately 0.11 to 2.5 microM) and potencies (K(act) approximately 0.45 to 9.5 nM) was obtained for TMQ analogs on the human beta3-AR. The 4'-acetamido and 4'-alpha-chloroacetamido analogs of 3',5'-diiodoTMQ were more potent than (-)-isoproterenol in rat atria (beta1-AR) and rat trachea (beta2-AR) and exhibited partial agonist activities, whereas full agonist activities were observed in rat esophageal smooth muscle (EC50 approximately 2-8 nM, beta3-AR). 4'-alpha-Chloroacetamido-3',5'-diiodoTMQ-mediated chronotropic responses in atria were sustained and resistant to washout. Further, the 4'-alpha-chloroacetamido and 4'-alpha-bromoacetamido analogs of 3',5'-diiodoTMQ demonstrated significant concentration-dependent irreversible binding to the rat beta3-AR. Reversible beta-AR agonists such as (-)-isoproterenol, BRL 37344, and 4'-acetamido-3',5'-diiodoTMQ or nucleophilic 1-amino acids (lysine, glutathione, cysteine) did not protect against this irreversible binding. Thus, the lipophilic 1-benzyl ring of TMQ analogs interacts with a hydrophobic region of the beta-AR that may represent an exo-site or an allosteric binding site.

Development of a statistical model for the formation of poly [acryloyl hydroxyethyl starch] microspheres.

PURPOSE: To develop a mathematical model for predicting the molecular weight between crosslinks, Mc, of poly[Acryloyl Hydroxyethyl Starch] (Ac-HES) microspheres system and to identify and evaluate the key microsphere preparation parameters which affect the Mc of the formed microsphere structure based on the developed model. METHODS: Link probability generating functions (LPGFs) based on the classical branching theory were used to derive a model for the calculation of Mc for the Ac-HES system. Based on the developed model, simulation was made to study the effects of the microsphere preparation variables on Mc of the formed microspheres. The process variables were the degree of derivatization (DD) of the Ac-HES, the molar ratio (MR) of the Ac-HES to acrylamide monomer, the fractional conversion of the unsaturation (alpha), the initiator efficiency (f), the molar concentration of initiator (I), the fraction of intramolecular cyclization (c), and the total weight of the reactable monomer and polymer (s). RESULTS: A model to describe the crosslinking reaction of Ac-HES system and predict Mc was developed. Simulation based on the model showed that Mc decreased as alpha increased and reached a limiting value before total conversion. At constant alpha, Mc initially decreased with MR to a minimum and then increased with MR; while Mc decreased monotonically with DD. I and c affected Mc only at very low alpha and changes in s and f had no effect on Mc. CONCLUSIONS: Simulation based on the model suggested that the most important microsphere preparation parameters influencing Mc of the Ac-HES system are the number of functional groups on the Ac-HES (DD) and the stoichiometry (MR) of the crosslinking reaction.

Evaluation of a statistical model for the formation of poly [acryloyl hydroxyethyl starch] microspheres.

PURPOSE: To characterize the network structure of Poly(Acryloyl Hydroxyethyl Starch) (Ac-HES) microspheres and test the theoretical model and the hypothesis that the rate of swelling of microspheres is inversely related to the extent of crosslinking. METHODS: Microspheres were prepared with varying degrees of derivatization (DD) and molar ratios (MR) and subjected to the characterization of matrix structure by dynamic and equilibrium swelling studies utilizing direct microscopic observation and the Flory-Rehner equation. The dependence of average molecular weight between crosslinking Mc, on DD and MR were compared to test the validity of the model. RESULTS: Study of the dependence of Mc on the microspheres preparation parameters, DD and MR, showed that at constant MR, the Mc decreased with DD, while at constant DD, the Mc initially decreased with MR to a minimum, and then increased with MR, complying with the model prediction. Dynamic swelling of microspheres showed a monotonical increase to equilibrium size featured by two time variables, Tp and Teq, that were dependent on Mc; this permitted a conceptual view of the general structure of the Ac-HES microspheres. The Mc, which was more accurately determined by the weight method (as opposed to volume method), was independent of the size of microspheres although there was evidence of variation among particles within a batch. CONCLUSIONS: The results validated the model in describing the polymerization/crosslinking reaction of the Ac-HES microsphere system and suggested that Mc is the principal factor in controlling release.

Effect of processing parameters on the properties of peptide-containing PLGA microspheres.

The physico-chemical properties of biodegradable polylactide-co-glycolide (PLGA) microspheres containing the peptide salmon calcitonin (sCT) were affected by the processing parameters. The microsphere size increased with an increase in the viscosity of the polymer solution. Concentration of methanol and peptide in the dispersed phase had the most discernible effects with the combination causing external and internal porosity. Increasing sCT in the presence of methanol increased the surface area and porosity. The surface area also increased as the molecular weight of the polymer was decreased. At higher ratios of the dispersed phase volume to the continuous phase volume, the surface area and surface porosity were higher and the particle size was lower. Thus, the physico-chemical properties of the microspheres can be easily altered by varying the processing parameters allowing formation of microspheres with a range of properties. The microspheres may be used to evaluate the relationship between the properties and ultimate in-vivo performance.

Magnetization transfer magnetic resonance imaging: a clinical review.

Magnetic resonance imaging has traditionally used the T1 and T2 relaxation times and proton density (PD) of tissue water (hydrogen protons) to manipulate contrast. Magnetization transfer (MT) is a new form of tissue contrast based on the physical concept that tissues contain two or more separate populations of hydrogen protons: a highly mobile (free) hydrogen (water) pool, Hr, and an immobile (restricted) hydrogen pool, Hr, the latter being those protons bound to large macromolecular proteins and lipids, such as those found in such cellular membranes as myelin. Direct observation of the Hr magnetization pool is normally not possible because of its extremely short T2 time (< 200 microseconds). But saturation of the restricted pool will have a detectable effect on the mobile (free) proton pool. Saturation of the restricted pool decreases the signal of the free pool by transferring the restricted pool's saturation. Exchange of magnetization between the free and restricted hydrogen protons is a substantial mechanism for spin-lattice (T1) relaxation in tissues and the physical basis of MT. Through an appropriately designed pulse sequence, magnetization transfer contrast (MTC) can be produced. MT contrast is different from T1, T2, and PD, and it likely reflects the structural integrity of the tissue being imaged. A variety of clinically important uses of MT have emerged. In this clinical review of the neuroradiological applications of MT, we briefly review the physics of MT, the appearance of normal brain with MT, and the use of MT as a method of contrast enhancement/background suppression and in tissue characterization, such as evaluation of multiple sclerosis and other white-matter lesions and tumors. The role of MT in small-vessel visualization on three-dimensional time-of-flight magnetic resonance angiography and in head and neck disease and newer applications of MT are also elaborated.

Measure of magnetization transfer in multiple sclerosis demyelinating plaques, white matter ischemic lesions, and edema.

PURPOSE: To define the percentage of magnetization transfer of multiple sclerosis (MS) plaques, ischemic white matter lesions, and vasogenic edema to determine whether this measurement can help differentiate these entities. METHODS: Findings were compared in 25 patients with proved MS, 20 patients with white matter ischemic lesions, and 72 patients with white matter edema (caused by tumors, infections, or acute/subacute infarctions) in the periventricular system, centrum semiovale, and subcortical white matter. Magnetization transfer was performed using an on-resonance binomial pulse. The percentage of magnetization transfer of the normal white matter was also calculated. RESULTS: Magnetization transfer was significantly higher in white matter ischemic lesions (range, 31% to 38%; mean, 34% +/- 0.6%) than in demyelinating plaques of MS (range, 19% to 28%; mean, 22.5% +/- 1%) and in edema (range, 29% to 37%; mean, 30.2% +/- 0.4%). No statistical difference in percentage of magnetization transfer was found among lesions in the periventricular system (34% +/- 0.6%), centrum semiovale (35% +/- 0.5%), or subcortical white matter (33% +/- 0.6%), or in vasogenic edema associated with tumors, infections, or infarction. CONCLUSION: Differences in magnetization transfer suggest less change of demyelination in white matter ischemic lesions than in MS plaques and are significantly different in this respect from similar MS plaques. Magnetization transfer of edema was less than that of normal white matter or fell between ischemic abnormalities and MS plaques. Percentages of magnetization transfer below the mid-20% range is highly suggestive of demyelination. Vasogenic edema, our surrogate for increased water content of white matter, caused a decrease in the percentage of magnetization transfer.

A comparison of the skeletal effects of intermittent and continuous administration of calcitonin in ovariectomized rats.

The study was designed to compare the skeletal effects of intermittent and continuous administration of calcitonin (CT) in ovariectomized (OVX) rats. Female rats were sham operated or OVX at 3 months of age and treated for 6 weeks with vehicle or salmon CT. Sham-operated control rats were injected subcutaneously with vehicle on alternate days. One group of OVX rats was treated with vehicle intermittently by subcutaneous injection or continuously via Alzet osmotic minipumps. The remaining OVX rats were treated with CT by either subcutaneous injections (16 U/kg) on alternate days or by continuous infusion via minipumps at a daily dose of 8 U/kg. OVX rats treated with CT continuously were mildly hypocalcemic compared with all other groups. The proximal tibial metaphyses of vehicle-treated OVX rats were osteopenic with a cancellous bone volume at only 28% of the vehicle-treated control level. This bone loss was associated with increased indices of bone turnover such as osteoclast surface, osteoblast surface, and bone formation rate. Cancellous bone volume in OVX rats treated with CT either intermittently or continuously was significantly higher than that of vehicle-treated OVX rats, but lower than that of vehicle-treated control rats. Treatment of OVX rats with intermittent or continuous CT significantly decreased all indices of bone turnover compared with vehicle-treated OVX rats. However, osteoclast and osteoblast surfaces of OVX rats treated with CT continuously were still significantly higher than those of vehicle-treated control rats. These results indicate that intermittent and continuous administration of CT had similar skeletal effects in OVX rats. Both treatment regimens depressed bone turnover and partially prevented cancellous bone loss in the estrogen-deplete skeleton.

Interaction of recombinant human bone morphogenetic protein-2 with poly(d,l lactide-co-glycolide) microspheres.

The combination of recombinant human bone morphogenetic protein-2 (rhBMP-2) with poly(d,l lactide-co-glycolide) (PLGA) porous microspheres provided for "sustained release" of the protein from the microspheres. Soaking 50:50 PLGA microspheres in a buffered rhBMP-2 solution for a sufficient period of time to permit equilibrium binding enabled quantification of "free" and "bound" protein. "Free" protein is defined as protein present within the porous matrix of the microspheres, whereas "bound" refers to protein adsorbed to PLGA surfaces. Kinetics of the rhBMP-2-microsphere association revealed that equilibrium was attained within 8 hr for two buffer systems (arginine/histidine, pH 6.50; and glutamic acid/sodium glutamate, pH 4.50). Increasing the concentration of the rhBMP-2 stock solution used for the interaction studies from 0.025 to 1.0 mg/ml increased the amount of rhBMP-2 adsorbed and the concentration of free rhBMP-2. Beyond a 1.0 mg/mL concentration, only free rhBMP-2 levels increased. Linearized Langmuir treatment of the adsorption data yielded values corresponding to monolayer coverage of the microspheres (Cm) and the equilibrium adsorption constant (K) of 0.17 microgram/cm2 and 7.57 ml/mg, respectively. Studies performed to determine the effect of ionic strength revealed that increasing NaCl and buffer concentration decreased the amount of protein adsorbed. rhBMP-2 release studies, conducted in an isotonic phosphate buffered saline, pH 7.4 vehicle, revealed that free rhBMP-2 was released during an initial period of 72-96 hr. Following this period, there was no discernible release of rhBMP-2 from the microspheres for up to 7 days, suggesting that the bound protein would remain at a defect site and release slowly upon erosion of the polymer. Mass balances performed by using an extraction buffer of high ionic strength confirmed this prediction.

Biodegradable indium-111 labeled microspheres for in vivo evaluation of distribution and elimination.

Short-lived gamma emitting radioisotopes can be incorporated into polylactide/glycolide polymeric microspheres with various specific activities for possible use in understanding the in-vivo deposition, distribution and clearance of microparticulate drug carrier systems. The incorporated radiolabel is stable with negligible leaching out of the microspheres. These microspheres are suitable for studying the oral uptake of particles, lung distribution after inhalation delivery and evaluation of in-vivo fate following parenteral administration in systemic circulation or in specific tissue compartments.

Magnetization transfer MR of the normal adult brain.

PURPOSE: To establish a normal baseline of the percent magnetization transfer of gray (cortical and deep) and white matter structures in the brain in healthy adults and to determine whether there are adult age-related differences in these measurements. METHODS: Axial T1-weighted scans (800/20 [repetition time/echo time]) with and without magnetization transfer were prospectively performed on a 1.5-T MR imaging unit on 68 healthy patients (aged 20 to 76 years). Presaturation and postsaturation magnetization transfer images were obtained using an on-resonance binomial pulse. All patients had normal MR scans on all pulse sequences. A calculated "difference" image was used to calculate the percent magnetization transfer in multiple specific regions of the brain. In each hemisphere, 9 discrete areas of cortical and deep gray matter and 29 areas of white matter were measured in 68 patients to generate age-related changes in percent magnetization transfer in these anatomic regions. Ranges of normal percent magnetization transfer in each of the 38 measures were established. RESULTS: The percent magnetization transfer of the gray matter (28% +/- 2%) was lower than that of the white matter (36% +/- 2%). There was no statistically significant difference in the percent magnetization transfer in different areas of gray matter. Deep white matter in the different lobes (percent magnetization transfer, 31% to 38%) also showed no differences by age. Percent magnetization transfer was the highest in the genu of the corpus callosum (42%), and this was statistically significant compared with other white matter measurements. CONCLUSION: There were no statistically significant age-related variations in the percent magnetization transfer in healthy adults in gray or white matter. These percent magnetization transfer measurements provide baseline normative data, which can be used to measure the extent and severity of white matter changes in disease states.

Improved detection of enhancing and nonenhancing lesions of multiple sclerosis with magnetization transfer.

PURPOSE: To determine whether magnetization transfer imaging can improve visibility of contrast enhancement of multiple sclerosis plaques. METHODS: Fifty-nine enhancing and 63 nonenhancing lesions in 10 patients with multiple sclerosis were evaluated to calculate contrast-to-noise ratios on conventional T1-weighted and T1-weighted magnetization transfer images. The signal intensity of the lesion and the background (white matter) were measured on precontrast T1-weighted and T1-weighted magnetization transfer images (800/20/1 [repetition time/echo time/excitations]) and on postcontrast T1-weighted and T1-weighted magnetization transfer images. Mean contrast-to-noise ratios was calculated for all lesions. RESULTS: The contrast-to-noise ratio was significantly higher for enhancing and nonenhancing lesions on T1-weighted magnetization transfer images than on conventional T1-weighted images. For enhancing lesions, the contrast-to-noise ratio was significantly higher on postcontrast T1-weighted magnetization transfer images, 32 +/- 2 compared with 21 +/- 2 on conventional T1-weighted images. Fifty of the 59 enhancing lesions were seen on both the T1-weighted and the T1-weighted magnetization transfer images. Nine enhancing lesions were seen only on the postcontrast T1-weighted magnetization transfer images. In addition, of 63 nonenhancing lesions seen on proton-density, T2-weighted, and T1-weighted magnetization transfer images, 16 were not seen on the conventional T1-weighted images. Seven of the 63 nonenhancing lesions and 7 of the 59 enhancing lesions had high signal intensity on the precontrast T1-weighted magnetization transfer images suggestive of lipid signal, a finding not seen on the conventional precontrast T1-weighted images. CONCLUSION: Magnetization transfer improves the visibility of enhancing multiple sclerosis lesions, because they have a higher contrast-to-noise ratio than conventional postcontrast T1-weighted images. High signal intensity on both nonenhancing and enhancing lesions noted only on precontrast T1-weighted magnetization transfer suggests a lipid signal was unmasked. If magnetization transfer is used in multiple sclerosis patients, a precontrast magnetization transfer image is necessary.

Adsorption of salmon calcitonin to PLGA microspheres.

PURPOSE: The interaction of salmon calcitonin (sCT) and poly (d,l-lactide-co-glycolide) was detected during preparation and evaluation of microspheres. The purpose of this study was to quantitate the extent and nature of the interaction. METHODS: Blank microspheres were prepared by an aqueous emulsification solvent extraction technique. Adsorption studies were carried out at six concentrations of sCT and three concentrations of microspheres. Adsorption isotherms were constructed using the Langmuir and Freundlich treatments. RESULTS: Adsorption at 1 mg/ml sCT concentration resulted in almost complete depletion of the peptide from the adsorption medium with the time to reach maximum adsorption decreasing with increasing microsphere concentration. At sCT concentrations below 100 micrograms/ml, a true equilibrium occurred in 1 hour or less while at higher concentrations (up to 350 micrograms/ml), a transient equilibrium was reached in 1 to 2 hours, followed by further adsorption of the peptide. The adsorption followed the Langmuir isotherm at concentrations below 200 micrograms/ml, indicating formation of a monolayer. Multilayer interaction, described by the Freundlich isotherm, occurred at higher concentrations and resulted in complete depletion of sCT from the adsorption medium. The affinity constant during monolayer formation was 0.09 and the plateau surface concentration was 5.1 micrograms/mg. The multilayer peptide-peptide adsorption showed a lower affinity (0.025) but higher capacity (24 micrograms/mg) than the monolayer peptide-polymer adsorption. CONCLUSIONS: The results show that poly (d,l-lactide-co-glycolide) microspheres have a high adsorption capacity for sCT which must be considered in formulating a controlled delivery product of this peptide.

Central nervous system tumor, infection, and infarction: detection with gadolinium-enhanced magnetization transfer MR imaging.

PURPOSE: To quantitatively measure the degree of contrast enhancement of central nervous system (CNS) tumor, infection, and infarction by means of magnetization transfer (MT) magnetic resonance (MR) imaging. MATERIALS AND METHODS: T1-weighted MR images obtained before and after administration of contrast material with and without MT in 14 patients with CNS tumors were evaluated by means of a contrast-to-noise ratio (C/N). Another 72 patients with a variety of lesions underwent contrast material-enhanced T1-weighted MR imaging prospectively with and without MT; C/N was also evaluated. RESULTS: All lesions had a higher C/N on T1-weighted postcontrast MT images than on conventional images. C/N was 65 +/- 5 (mean +/- standard error) for MT and 42 +/- 4 for conventional images. C/N improved by a factor of 1.6-2.1 in the three disease categories. In intracranial tumors, the MT technique itself did not contribute significantly (P < .001) to the increase in C/N in the absence of gadopentetate dimeglumine. In fact, the C/N was lower for nonenhanced T1-weighted MT images. CONCLUSION: Concurrent use of gadopentetate dimeglumine and MT results in a statistically significant (P < .001) increase in C/N in CNS tumor, infection, and infarction.

MR evaluation of vertebral metastases: T1-weighted, short-inversion-time inversion recovery, fast spin-echo, and inversion-recovery fast spin-echo sequences.

PURPOSE: To compare the detectability of vertebral metastatic disease on T1-weighted, short-inversion-time inversion recovery (STIR), fast spin-echo (FSE), fat-saturated FSE, and inversion recovery FSE (IRFSE) MR sequences using percent contrast and contrast-to-noise ratios. METHODS: Patients with proved metastatic disease underwent imaging on a 1.5-T MR system with sagittal T1-weighted (800/20/2 [repetition time/echo time/excitations]) (91 patients), STIR (1400/43/2; inversion time, 140) (91 patients), FSE (4000/180/2) (46 patients), fat-saturated FSE (4000/180/2) (16 patients), and IRFSE (29 patients) sequences. Percent contrast and contrast-to-noise ratio were calculated for the lesions. The number of metastatic lesions detected with each of the pulse sequences was also calculated. RESULTS: Mean percent contrast was, for T1-weighted sequence, -42.2 +/- 1%; STIR, 262 +/- 34%; FSE, 121 +/- 21%; fat-saturated FSE, 182 +/- 6%; and IRFSE, 272 +/- 47%. The mean contrast-to-noise ratio for T1-weighted was -4.63 +/- 1.7; STIR, 10.8 +/- .98; FSE, 4.16 +/- .76; fat-saturated FSE, 4.87 +/- .19; and IRFSE, 5.2 +/- .87. STIR and IRFSE showed the highest number of lesions, followed by T1-weighted, fat-saturated FSE, and FSE sequences. T1-weighted sequences showed 94%, FSE 55%, and fat-saturated FSE 78% of the lesions detected. Epidural metastatic lesions were better depicted on T1-weighted, FSE, and fat-saturated FSE sequences. CONCLUSION: STIR was superior to both T1-weighted and FSE (with and without fat saturation) for detection of metastatic lesions, in terms of both percent contrast and contrast-to-noise ratio and visibility. IRFSE was equal to STIR for the detection of metastasis by both subjective and objective criteria. T1-weighted, FSE, and fat-saturated FSE sequences were superior to STIR and IRFSE in the detection of epidural metastatic disease. IRFSE provided faster scanning time, which could be translated into greater resolution.

Sustained bronchodilation with isoproterenol poly(glycolide-co-lactide) microspheres.

An animal study was carried out to evaluate the in vivo bronchodilator action of isoproterenol (Iso) from poly(glycolide-co-lactide) (PGL) microspheres. Microspheres with a mean diameter of 4.5 microns and a drug load of 7% were administered intratracheally to Long-Evans rats. The microspheres released about 70% of the incorporated drug in the instillation medium before administration, which provided immediate action, and the remaining 30% was available for sustained release. A total of 120 animals was anesthetized, paralyzed, artificially ventilated, and divided into 15 groups (n = 8): 3 groups each for saline, blank microspheres, free Iso, blank microspheres with free Iso, and microencapsulated Iso. All instillations were made in a volume of 1 ml/kg and the dose of all Iso preparations was 0.1 mg/kg. At 3, 6, or 12 hr after the intratracheal instillation, a serotonin challenge (40 micrograms/rat) was administered intravenously to constrict the airways. Airway function tests were performed at each time interval on one group of animals by a maximal expiratory flow-volume maneuver. The heart rate in animals receiving Iso formulations was similar to that in the saline control group, indicating minimal systemic effect of the dose administered. The systemic serum levels were below 2 ng/ml in all the groups. Animals receiving encapsulated Iso resisted the serotonin challenge for at least 12 hr after intratracheal instillation, indicating that the drug was still present over this period of time. On the other hand, the serotonin-induced airway constriction observed in the animals receiving blank microspheres, free Iso, or free Iso with blank microspheres was similar to that in saline controls at all time points. The results clearly show that only a small fraction of the free dose is required in sustained-release form for a prolonged pharmacological effect, resulting in a 50- to 100-fold reduction in the total dose administered.