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ABSTRACT: Despite the development of newer antifungal drugs, the polyene antifungals continue to be the most potent broad-spectrum fungicides available for clinical use. The incidence and severity of fungal infections are on the rise, underscoring the need for new and more effective antifungal drugs. Thus, the search for new polyene antifungals is ongoing. The limited solubility, polymorphic character, and inherent chemical instability of these compounds make their economical recovery and purification from mass culture challenging problems in biotechnology. This article provides a comprehensive review of the methods that have been developed for the recovery and purification of amphotericin B and nystatin, the two most important polyenes currently in clinical use.
Drug Development and Industrial Pharmacy 05/2001; 27(4):277-86. · 1.49 Impact Factor
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ABSTRACT: Adjuvants function by protecting antigens from rapid degradation or dispersal. The effectiveness of experimental adjuvants can be assessed by measuring antibody titers to the antigen of interest or, less frequently, by evaluating the retention and distribution of antigen at the application site. In this study, we used X-ray fluorescence (XRF) to monitor the release of an iodinated protein (I-bovine serum albumin) from several adjuvant formulations after its subcutaneous injection in rats. The interaction of the tagged antigen with an external Am-241 source leads to the emission of iodine X-rays from the application site; the number of these X-rays is proportional to the concentration of the protein remaining at the injection site. The disappearance of the iodine X-rays, and hence the antigen, from the injection site followed first-order kinetics for all adjuvant formulations tested; mean half-life values were as follows: in 50% Freund's adjuvant, 17.1 +/- 1.1 h; in 4-hour-old 25% Alum, 11.78 +/- 0.08 h; in 4-h-old 50% Alum, 13.2 +/- 2 h; in 3-day-old 50% Alum, 15.8 +/- 1.5 h; and in 240 mg/mL Pluronic F-127, 7.9 +/- 0.7 h. We conclude that XRF is an easy, reliable, noninvasive method to monitor the retention of antigens in these adjuvant solutions.
Pharmaceutical Development and Technology 02/2001; 6(2):241-6. · 1.36 Impact Factor
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ABSTRACT: A nitrogen gas-based foam fractionation method was employed to separate model proteins, bovine serum albumin (BSA) and hen egg white lysozyme, from each other. Fractionation was characterized by the separation ratio and by recovery of proteins in the retentate as a function of the nominal pore size of the gas dispersion frit and solution conditions (pH and ionic strength). For binary mixtures of the proteins at pH 7.4, and ionic strength (mu) of 0.18 M, the recovery of lysozyme and the separation ratio were both dependent on the frit size employed to generate the foam. At low ionic strength (mu = 0.01 M), separation was only somewhat greater with the small pore size frits, although at values significantly lower than those found for high ionic strength. The diminished separations appear to be due to the only slight changes in recoveries observed for BSA and lysozyme.%Separation ratios of lysozyme from BSA in solutions either of high or low ionic strength were maximal at pH values equal to or less than the isoelectric point (pI) of BSA. Separation ratios were lower when foaming was carried out under low compared with high ionic strength. The recovery of lysozyme was enhanced by foaming from solutions of low pH and high ionic strength. Recoveries of BSA were greatest when the molecule was negatively charged. Electrical interactions between the positively charged lysozyme and negatively charged BSA may explain the diminished separation ratios and enhanced recoveries. Enzyme activity studies of lysozyme remaining in the retentate showed no change from prefoam activity.
Journal of Pharmaceutical Sciences 07/2000; 89(6):693-704. · 3.06 Impact Factor
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ABSTRACT: The goal of this study was to photochemically bind 5'-[gamma-(32)P]-azido-ATP gamma-benzophenone ((32)P-ATP-BPA) to a polyurethane surface. Expandable balloon catheters composed of (32)P-coated polyurethane have the potential for preventing restenosis following percutaneous transluminal coronary angioplasty.
After extensive preparation and cleaning of polyurethane disks, 10 microL of the radioactive ATP-BPA reagent (specific activity = 9.4 Ci/mmol) was applied to the surface. After drying, the membrane disks were exposed ultraviolet radiation (254 nm; 6,000 microwatts/cm(2)) for up to 2 h and subsequently washed. The amount of (32)P bound to the membrane disks was determined by Cerenkov counting in a liquid scintillation counter. The effect of the labeling solution composition (solvent, presence of potassium or manganese ions, addition of surfactants, etc.) on photobinding efficiency was determined.
The efficiency of attaching the (32)P-ATP-BPA reagent to the polyurethane surfaces was markedly dependent upon the cleaning and pretreatment conditions. Following detailed washing and rinsing steps, a photobinding efficiency of 36.4+/-3.6% was obtained with 10 min UV exposure time using (32)P-ATP-BPA solutions that were 95/5 methanol/water by vol. Increasing the concentration of the (32)P-ATP-BPA reagent did not improve the photobinding efficiency; however, the total amount of (32)P bound to the disks was increased.
Photochemical methods can be employed to attach beta(-)-emitting radionuclides to polymers that are employed as balloon catheters. The preparation of the polymeric material (washing, rinsing, and drying) is critically important in maximizing the amount of (32)P-ATP-BPA that can be bound to the polymer.
Journal of Biomedical Materials Research 02/1999; 48(5):669-74.
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ABSTRACT: Perfluorinated solvents are gaining popularity as pulmonary ventilation fluids, but they suffer from poor solvent quality in concurrent drug delivery applications. The present study examines the use of a hydrophobic solubilizing agent capable of interacting with model drug solutes by hydrogen bonding with the purpose of enhancing solubility in perfluorooctyl bromide (PFOB). A series of solubilizing agents containing a ketone carbonyl to act as a hydrogen bond acceptor and a perfluoroalkyl chain to maintain the solubility of the putative complex in PFOB are investigated. The solubility of phenol in PFOB is enhanced to the greatest extent by 1-(4-perfluorobutyl phenyl)-1-hexanone (III) where the ketone carbonyl is protected from the electron withdrawing effects of the perfluorobutyl chain by a phenyl ring. Experiments with solubilizers lacking the ketone group suggest that pi-pi bond interactions of III with phenol do not significantly enhance solubility. For a series of phenol derivatives, a rank-order correlation exists between the magnitude of solubility enhancement by III, as reflected by the calculated association constants, and the Hammett sigma parameter of the phenols. Because the O-methyl-substituted phenols do not have the ability to hydrogen bond, their solubility is not enhanced by the presence of III. The results of the present study indicate that solubility of model drug hydrogen bond donating compounds can be enhanced in PFOB by the presence of fluorocarbon-soluble hydrogen bond acceptors.
Journal of Pharmaceutical Sciences 01/1999; 87(12):1585-9. · 3.06 Impact Factor
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ABSTRACT: Purification is an important step in the production of pharmaceuticals from recombinant proteins. The characteristics of industrial-scale purification schemes, such as conventional chromatography, have a significant impact on the cost of production. Foam fractionation, a novel separation technique based upon the differences in affinities of components for the gas/aqueous interface of a foam, has the potential to be a cost-effective component in a purification scheme. This review covers some of the more recent studies in understanding the process and applications of foam fractionation in protein-containing systems with special attention to the requirements of pharmaceutical products.
Pharmaceutical Research 12/1997; 14(11):1511-5. · 4.09 Impact Factor
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ABSTRACT: A bioreactor consisting of the enzymes alcohol oxidase and catalase immobilized onto a hollow fiber membrane was used to convert [11C]methanol to [11C]formaldehyde. Using an alcohol oxidase:catalase ratio of 1:500 U, conversion yields of 90-95% were obtained allowing the production of up to 7400 MBq (200 mCi) of [11C]formaldehyde in 5 min. The hollow fiber bioreactor allowed for a convenient, rapid synthesis with yields significantly higher than the standard chemical procedures, has demonstrable advantages over glass bead immobilized systems (primarily due to convective flow), and was amenable to hot cell conditions.
Nuclear Medicine and Biology 02/1995; 22(1):105-9. · 3.02 Impact Factor
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ABSTRACT: An empirical mass-transfer model for enteric-coating dissolution that uses in vivo dissolution data to characterize the pH-dependent solubility properties of the polymer film and a mass-transfer coefficient determined from in vivo dissolution or disintegration studies is developed. Once the in vivo mass-transfer coefficient has been evaluated, it can be used in conjunction with in vitro dissolution data from other formulations to predict the in vivo time to disintegration and onset of drug release. Results of in vitro dissolution experiments using the USP basket dissolution apparatus and in vivo disintegration experiments using gamma scintigraphy with four enteric-coated pellet formulations are presented. The good agreement among the in vivo mass-transfer coefficients that were determined supports the validity of the model.
Pharmaceutical Research 03/1993; 10(2):233-8. · 4.09 Impact Factor
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ABSTRACT: We investigated the use of gamma scintigraphy to evaluate the temporal and spatial patterns of translocation of radiolabeled Escherichia coli from the porcine jejunum during and following hemorrhagic shock. Thirteen healthy mixed breed pigs (22-43 kg) were randomly allocated to two groups. Pigs were anesthetized with sodium pentobarital (30 mg/kg) and mechanically ventilated (100% O2). Each pig was instrumented for mean arterial pressure (MAP) and superior mesenteric artery (SMA) blood flow determination. A 25-cm loop of vascularly intact distal jejunum was isolated, and 10 mCi (10(11) cfu) of radiolabeled E. coli (99mTcO4-) was placed within the bowel segment. Consecutive 5-min scintigrams of the entire abdomen and thorax were collected for 6 hr. Pigs in the shock group (n = 7) were hemorrhaged such that MAP was maintained at 50-60 mm Hg for 5 hr. Pigs in the sham group (n = 6) were maintained without hemorrhage for 6 hr. The total radioactive counts in the translocation regions of the scintigram were plotted against time, and the slope of the regression lines was compared between groups. In the shock group, SMA blood flow decreased significantly (P < 0.05) during the hypotensive period but returned above baseline during reperfusion. The mean (+/- SD) slopes for translocation regression lines were 9.3 +/- 11.4 counts/min and 36.3 +/- 33.7 counts/min in the sham and shock groups, respectively (P < 0.05). Translocation was scintigraphically evident 50-100 min following induction of hemorrhage and did not require reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Surgical Research 02/1993; 54(2):102-6. · 2.25 Impact Factor
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ABSTRACT: X-ray fluorescence (XRF) has been used to determine in vivo the percutaneous absorption of 5-iodouracil (5IU) in dimethyl sulfoxide (DMSO) on female Sprague-Dawley rats. An average absorption rate constant of 122 +/- 34 micrograms/cm2-hr was obtained from the XRF measurements on four rats. A comparative study was performed with radiolabeled (125I) 5IU in which the absorption rate constant was determined to be 126 +/- 20 micrograms/cm2-hr. The XRF system described provides a simple, noninvasive means of measuring the percutaneous absorption rate of select compounds by the surface disappearance method.
Pharmaceutical Research 12/1992; 9(11):1410-4. · 4.09 Impact Factor
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ABSTRACT: Helicobacter pylori is associated with chronic type B gastritis. Diagnosis can be made on gastric biopsy specimens and noninvasively using [13C]- or [14C]urea breath tests. Both breath tests require meticulous breath collection, and false positive results are possible from urease producing oral-pharyngeal flora. We used [11C]urea, a positron-emitting radionuclide allowing dynamic imaging, to measure metabolism of urea in the stomach of biopsy documented H. pylori-positive patients. [11C]urea was synthesized from 11CO2 produced using a Van de Graaff accelerator and administered with [99mTc]DTPA to control for loss of radioactivity via gastric emptying. Images were obtained externally by gamma camera every minute and 11CO2 was monitored in the breath continuously for 30 min. An H. pylori-positive patient exhibited a 99mTc/11C activity ratio of 2:1 in the stomach 10-20 min following administration, compared to a 1:1 ratio in a negative control, indicating metabolism of urea to 11CO2 with subsequent diffusion of 11C activity out of the stomach. The 11C activity in the breath peaked at 10-20 min in the H. pylori-positive patients. The short half-life of carbon-11 (20.4 min) alleviates radiation safety concerns and results in low absorbed radiation doses to patients.
Digestive Diseases and Sciences 05/1992; 37(4):618-21. · 2.12 Impact Factor
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ABSTRACT: Poly-L-lactic acid (PLA) microspheres containing neutron-activated 166Ho were investigated as potential agents for radionuclide synovectomy. Stable 165Ho, complexed to acetylacetone (AcAc), was incorporated into PLA spheres by the solvent evaporation technique. Spheres prepared with the optimal mean particle size of 7.2 microns (range 2-13 microns) containing 25.4% 165Ho-AcAc (9.1% 165Ho) were irradiated in a high neutron flux to produce 31.1-36.0 mCi 166Ho. In vitro human plasma studies showed that the irradiated spheres retained 99.0 +/- 0.01% of the 166Ho at 314 hr. In-vivo retention studies were conducted by administering irradiated PLA spheres with 257-591 microCi 166Ho into the joint space of normal rabbits (n = 6). Biodistribution analysis and gamma camera analysis showed 166Ho retention in the joint space after 120 hr of 97.7% +/- 0.8% and 98.2% +/- 2.4%, respectively, with no uptake by the lymph nodes. The ease with which the PLA spheres can be made in the optimal size range for later irradiation and their ability to retain the 166Ho make them attractive agents for radionuclide synovectomy.
Journal of Nuclear Medicine 04/1992; 33(3):398-402. · 6.38 Impact Factor
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ABSTRACT: The solvent evaporation technique was employed to prepare poly(L-lactic acid) (PLA) microspheres with 165Ho acetylacetonate (Ho-AcAc). Particle size, percentage Ho-165, percent residual solvent, and retentive ability of the spheres were found to be strongly affected by preparatory conditions. Differential scanning calorimetry (DSC) thermograms suggested that the Ho-AcAc existed in the PLA matrix as a molecular dispersion. High neutron flux irradiations of the PLA spheres in a nuclear reactor produced Ho-166, a therapeutic radionuclide that emits high-energy negatrons (Emax = 1.84 MeV; half-life = 26.9 hr). The gamma radiation dose (53-75 Mrad) from the core of the reactor provided an overkill of all bioburdens in the PLA spheres. Gel permeation chromatography (GPC) analysis showed that these irradiations caused a reduction in PLA molecular weight. Infrared spectra, 13C NMR spectra, 1H NMR spectra, and DSC thermograms further confirmed the presence of lower molecular weight PLA but proved the overall maintenance of PLA structure.
Pharmaceutical Research 02/1992; 9(1):149-54. · 4.09 Impact Factor
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ABSTRACT: Biodegradable Poly(L-lactic acid) microspheres containing neutron-activable 165Ho were designed for internal radiation therapy of hepatic tumors. Spheres composed of Poly(L-lactic acid) (PLA) were prepared with excellent reproducibility containing up to 36% of a holmium complex. The prepared spheres were irradiated in a high neutron flux converting 165Ho to 166Ho (Emax = 1.84 MeV, half-life = 26.9 hr). Thus, these microspheres can be prepared under conditions that do not require the handling of a hazardous radionuclide, and then irradiated just prior to administration. In vitro studies in plasma (n = 6) revealed 97.3% (+/- 1.9) retention of 166Ho in the microspheres after 240 hr. PLA spheres administered via the portal vein in rabbits (n = 6) show 94.5% (+/- 3.4) retention of the original 166Ho activity in the liver after 6 days.
Journal of Nuclear Medicine 12/1991; 32(11):2139-43. · 6.38 Impact Factor
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Pharmaceutical Research 12/1990; 7(11):1198-200. · 4.09 Impact Factor
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ABSTRACT: The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of 170Er2O3 (greater than 96% 170Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 mu Ci of 171Er. Dosage form position were reported at various time intervals. In five subjects the sustained-release tablet remained in the stomach and eroded slowly over 7-12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and Tmax were unaltered and Cmax was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.
Pharmaceutical Research 04/1990; 7(3):304-7. · 4.09 Impact Factor
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Progress in clinical and biological research 02/1989; 292:293-300.
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ABSTRACT: Compressed tablets containing various quantities of stable isotopes of Ba, Er, and Sm for use in neutron activation studies were evaluated for the effect of stable isotope incorporation on tablet hardness and disintegration times. At concentrations likely to be used in scintigraphic studies employing neutron activation as a radiolabeling method, no significant effect on in vitro parameters were observed. While the incorporation of stable isotopes influenced tablet hardness to a greater degree than disintegration time, irradiation of tablets in a neutron flux of 4.4 x 10(13) n/cm2 sec had a direct effect on tablet disintegration time. Thus, future neutron activation studies should focus on minimizing the amount of stable isotope to be incorporated with the formulation while using the shortest feasible irradiation time.
Pharmaceutical Research 01/1988; 4(6):524-30. · 4.09 Impact Factor
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ABSTRACT: External gamma scintigraphy was used to monitor the gastrointestinal (GI) transit of radiolabeled sustained-release tablets containing 800 mg ibuprofen in eight fasted healthy volunteers. Ibuprofen serum concentrations were determined from blood samples drawn sequentially over a 24-hr period. Serum concentrations and related parameters were correlated to the position of the dosage form in the GI tract from the scintiphotos. The sustained-release tablets were radiolabeled intact utilizing a neutron activation procedure, by incorporating 0.18% of 170Er2O3 (enriched to greater than 96% 170Er) into the bulk formulation. After manufacture of the final dosage forms, the tablets were irradiated in a neutron flux (4.4 x 10(13) n/cm2.sec) for 2 min, converting the stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). Each tablet contained 50 microCi of 171Er at the time of administration. The scintigraphy studies suggested that the greatest proportion of ibuprofen was absorbed from this dosage form while the tablet was in the large bowel. The dosage forms eroded slowly in the small bowel and appeared to lose their integrity in the large bowel. In vitro studies showed only minimal effects of the neutron irradiation procedure on the dosage form performance.
Pharmaceutical Research 01/1988; 4(6):486-9. · 4.09 Impact Factor
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ABSTRACT: A hydrocortisone suspension enema was radiolabeled with [99mTc]technetium sulfur colloid and administered to four normal subjects and eight patients with varying degrees of inflammatory bowel disease. The extent of enema spreading was monitored using external scintigraphy for a period of up to 4 hr after administration. Pretreatment of normal subjects with an evacuation enema resulted in spreading of the radiolabeled enema throughout the entire colon. In seven of the eight patients studied, the enema migrated a distance equal to or greater than the extent of disease involvement. An in vivo stability study with an indium-111-labeled enema, using the perturbed angular correlation technique, revealed that the enema retains its stability for up to 90 min after administration. These results indicate that the use of hydrocortisone enemas may not be restricted to distal bowel disease, but may also be effective in inflammatory bowel diseases involving proximal regions of the colon.
Digestive Diseases and Sciences 03/1986; 31(2):139-44. · 2.12 Impact Factor
