text:
|Publication number
|Publication type
|Application number
|Publication date
|Jul 16, 1991
|Filing date
|Mar 8, 1989
|Priority date
|Feb 27, 1987
|Fee status
|Publication number
|Robert Abra
|Original Assignee
|Liposome Technology, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (2), Referenced by (10), Classifications (15), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a continuation of U.S. patent application entitled AMPHOTERICIN B/CHOLESTEROL SULFATE COMPOSITION AND METHOD, Ser. No. 019,575 filed Feb. 27, 1987 now U.S. Pat. No. 4,822,777.
The present invention relates to an amphotericin B composition for the treatment of fungal infections, and in particular, to an amphotericin B composition which has both a high LD50 and therapeutic efficacy.
1. Holz, R. W., in F. E. Hahn, Ed., Antibiotics, Vol.2, Springer-Verlag, N.Y. (1979).
2. Trembley, C., et al. Antimicrob. Agents and Chemoth. 26(2):170(1984).
3. Mehta, R. T., et al. Infection and Immunity, 47(2):429 (1985).
4. Lopez-Berestein, G., et al. Cancer Drug Delivery, 1(1):37 (1983).
5. New, R.R.C., et al. J. Antimicrob. Chemoth. 8:371 (1981).
6. Graybill, J. R., et al. J. Infect. Dis., 145:5 (1982).
7. Lopez-Berestein, G., J. Infect. Dis., 150(2):278 (1984).
8. Trembley, C., et al. Invest. Opthalmol. 26:711 (1985).
9. Lopez-Berestein, G., et al. J. Infect. Dis. 151(4):704 (1985).
10. Juliano, R., et al. Biology of the Cell, 4(39) (1983).
11. Mehta, R., Et al, Biochem. Biophys Acta. 770:230 (1984).
12. Hopfer, R. L., et al. Antimicrob. Agents and Chemoth. 25(3):387 (1984).
13. Brockerhoff, H. et al. Biochimica Biophysica Acta 691:227 (1982).
14. Crowe, L. M., et al. Biochimica Biophysica Acta 769:141 (1984).
15. Remington's Pharmaceutical Sciences, Gennaro, A. R., ed., Mack Publishing Company (1985)
Amphotericin B (AMB) is an effective antifungal agent, and at present, is the drug of choice for most serious systemic fungal infections (reference 1). The drug is presently available for human use as a lypholized powder of AMB and deoxycholate ("Fungizone"). The drug binds strongly to ergosterol, a major sterol component of fungal membranes, forming pores in the membranes which allow leakage of solute molecules. The drug also has a strong binding affinity for cholesterol, a sterol present in most mammalian cell membranes, and is therefore capable of disrupting host cells.
When AMB is administered in free form (i.e., as a reconstituted AMB/deoxycholate complex) side effects resulting from red blood cell disruption are observed initially, followed by more serious cardiotoxicity, CNS and bone-marrow effects. Renal toxicity, resulting from the body's attempt to clear the drug, is also present.
Several studies have shown that AMB toxicity can be reduced by administering the drug in a liposome-bound form (references 2-12). Typically, the LD50 of the drug increases from about 2-3 mg/kg body weight for the free drug up to about 8-15 mg/kg when the drug is administered in liposomal form. One limitation of liposomal formulations, however, is the apparent size instability of amphotericin B/liposomal particles when stored in an aqueous medium. Typically, AMB-containing liposomes which have an initial size distribution between about 200-300 nm will spontaneously form large liposomal structures of up to several microns on long-term storage in an aqueous medium. Liposomes with sizes greater than about 1-2 microns are generally more toxic than smaller liposomes when administered parenterally, i.e., into the bloodstream. The toxicity of large liposomes in the bloodstream is related in part to liposome blockage of the alveolar capillaries. There are also indications that relatively large liposomes are more toxic to the liver, presumably due to liposome accumulation in reticuloendothelial cells. Co-owned U.S. patent application for "Amphotericin B Liposome Composition", Ser. No. 781,395, filed Sept. 27, 1985, discloses a novel method of preparing and storing AMB liposomes which largely overcome the size-growth problem mentioned above.
An amphotericin B composition formed by complexing AMB with a polyethylene derivative of cholesterol (PEG-cholesterol) has also been proposed (PCT application US84/00855). The formulation increased the LD50 of AMB to 10.0 mg/kg in mice, from 3.8 mg/kg for Fungizone, and was also less cytotoxic in cell culture. It is not known how and whether AMB complexing to PEG-cholesterol affects therapeutic efficacy against fungal infection in vivo, nor whether the complex can be stored in a size-stable form.
One object of the invention to provide an AMB i composition which has a substantially higher LD50 than AMB formulations reported in the prior art, and also is significantly more effective in treating fungal infections, in vivo.
Another object of the invention is to provide an AMB formulation which can be stored in suspension form over a several day period without significant particle size change, which can be stored long term as a lyophilized preparation.
Yet another object of the invention is to provide an improved method for treated fungal infections with AMB.
The invention includes an AMB composition containing particles of AMB and cholesterol sulfate, in a mole ratio of AMB to cholesterol sulfate of between about 1:1 to 1:4. When prepared in a suspension form in an aqueous medium, the particles have preferred sizes between about 100-400 nm. Osmotic swelling and solute trapping studies indicate that the particles are non-liposomal. A preferred composition, containing AMB and cholesterol sulfate in a mole ration of about 1:1 shows very little change in particle size when stored in solution form over a several-day period.
The composition is formed, according to one aspect of the invention, by dispersing an aqueous suspension of amphotericin B/cholesterol sulfate particles, in a molar ration of between 1:1 to 1:4, to optical clarity, where particle sizes are predominantly between 100-200 nm. The suspension is then lyophilized in the presence of a cryoprotectant, such as lactose. After reconstitution in an aqueous medium, particle sizes are predominantly in the range 200-300 nm.
The composition has an LD50 greater than 20 mg/kg. The therapeutic efficacy of the AMB/cholesterol sulfate composition, in treating fungal infections in vivo, is significantly greater than that observed for Fungizone.
The invention also includes a method for treating fungal infections with AMB, with substantially less toxicity and greater efficacy than has been achieved heretofore.
These and other objects and features of the invention will become more fully apparent from the following detailed description of the invention.
To prepare the AMB/cholesterol sulfate particle suspension of the invention, AMB and cholesterol sulfate are combined in dry or solution form at a selected mole ration of AMB to cholesterol sulfate about 1:1 to 1:4. In a preferred method, the two components are mixed in dry form, at the selected mole ration, than dissolved in a suitable solvent, and preferably an alcohol such as methanol. A combined molarity of AMB and cholesterol sulfate in methanol of 50 umole/ml, in the mole ratio range between 1:1 and 1:4 AMB to cholesterol, is suitable. For example, in a 1:1 formulation, both AMB and cholesterol sulfate would be present at 25 umoles/ml.
A cryoprotectant may be added to the AMB/cholesterol sulfate solution, to a final preferred concentration of between about 5-15%. The cryoprotectant serves two purposes in later processing steps. First, it provides a crystalline, water-soluble bulking agent on which the AMB and cholesterol sulfate components can form, when the solvent in the mixture is removed. That is, the dried crystals of cryoprotectant increase the surface area of lipid film formed on solvent removal, and this facilitates particle hydration when an aqueous medium is added to dried mixture. Secondly, where the hydrated particles are stored in a lyophilized state, as discussed below, the cryoprotectant may reduce particle damage which can occur on freezing, and thereby reduce size growth of the rehydrated particles. Suitable cryoprotectants are carbohydrates such as trehalose, lactose, maltose, cellobiose, sucrose, glucose, fructose, sorbitol, raffinose, myo-inositol, and glycerol (references 14) which have also been shown effective in limiting lipid membrane damage on freezing (reference 14). A variety of other water-soluble bulking agents, such as maltodextrin, salts and the like may be substituted for cryoprotectant where particle processing does not involve a freezing step, such as where the particles are dried for storing by spray drying.
The lipid solution of AMB/cholesterol sulfate is dried to a lipid film. As just indicated, the film is preferably formed from a solution containing a bulking agent, yielding dried particles of the agent coated with the lipid mixture. Solvent removal is by vacuum evaporation or under a stream of inert gas, e.g., nitrogen. The dried lipid film may be stored under an inert gas, preferably at 4� C. or less.
An aqueous particle suspension if formed by addition of an aqueous medium to the dried lipid mixture. The medium used in Example 1, containing 10 mM Tris-HCl, 0.1 mM EDTA, pH 7.4, is suitable. The amount of medium added is sufficient to produce a final AMb concentration of preferably between about 25-100 umole/ml.
Initially, the lipid material is crudely suspended by spatula or mechanical agitation until the lipid clumps are released into the aqueous medium, to form a slurry-like mixture. This material is now dispersed to a fine particle size by sonication, homogenization, French press or other high-energy input. The dispersion is carried out until a desire particle size, preferably between 0.1 to 1 micron is achieved. The suspension may be warmed during dispersion, and should be maintained under an inert atmosphere. In the method described in Example 1, the suspension is sonicated at 4� C. to optical clarity. Final particle sizes were between 0.1-0.2 microns. Here it is noted that formulations containing less than about 1 mole cholesterol sulfate per mole AMB do not sonicate to optical clarity, indicating that particle dispersion requires at least a stoichiometric amount of cholesterol sulfate.
The particle suspension may be treated such as any molecular sieve chromatography or dialysis, to remove traces of unincorporated AMB. The dialysis conditions noted in Example 1 are suitable The final concentration of AMB in the dispersed particle suspension can be determined by diluting an aliquot of the suspension in methanol, and measuring AMB spectrophotometrically at 406 nm. Typical AMB concentrations at various stages of the preparation of the dispersion are given in Table 1 in Example 1 below.
According to one aspect of the invention, it has been discovered that the AMB/cholesterol sulfate particles of the invention can be stored long-term in dried form without significant increase in particle size or rehydration.
The dried particle formulation can be prepared either by lyophilization or spray drying. In the former method, the small-particle suspension is quick frozen and lypohilizied at shelf temperature of preferably 20� C. or less, as described in Example I. The effect of lyophilizing on particle size is seen in Table 2 in Example 2, for each of four formulations having AMB:cholesterol sulfate mole ratios between 1:1 and 1:4. In each case, mean particle sizes increased from about 100-200 nm before lyophilization, to between 200-300 after lyophilization and rehydration with water. The stability of the particles, pre and post lyophilization is considered in Section II below.
For spray drying, the particle suspension is dried in a conventional apparatus in which the particles to be dried are sprayed in aerosolized suspension form into a stream of heated air or inert gas, and the aerosolized droplets are dried in the gas stream as they are carried toward a plate collector where the dried liposomes are collected. An exemplary spray dry apparatus is a Buchi 190 Mini Spray Dryer.
The drying temperature is at least about 37� C., and preferably between about 40�-50� C. The temperature of the collection chamber is generally lower than that of the heated air, and typically about 37� C. The dried particles are collected and stored in dehydrated form, under an inert atmosphere.
This section examines the size stability of AMB:cholesterol particle suspensions under a variety of conditions relating to molar composition of the particles, suspension medium, and storage time.
In the first study, reported in Example 3, AMB: cholesterol sulfate particles having mole ratios of AMB:cholesterol sulfate of 1:1, 1:2, 1:3, and 1:4 were prepared and immediately after dialysis were stored for periods of up to 8 days at 4� C. The results are shown in Table 3 of Example 3. The 1:1 formulation was substantially stable over the 8-day test period, whereas the other formulations showed progressively greater size increases with increasing mole ratios of cholesterol sulfate.
The size stability of the same four formulations after lyophilization and rehydration was similarly studied, also as reported in Example 3. Size stability data for the eight day test is shown in Table 3. Interestingly, there was little difference in size stability amount the four formulations, and for each formulation mean particle sizes increased at most about 2 fold over 4 the eight day test period. The combined results from Tables 2 and demonstrate that (a) lyophilized AMB/cholesterol particles can be reconstituted with little increase in mean size and size distribution and (b) the particles in the reconstituted suspension are relatively stable on storage in solution over a several-day period.
The effect of physiological-strength saline and plasma on the size characteristics of the particles was also examined, as reported in Example 4. In a first study, the four post-dialysis AMB/cholesterol sulfate formulations from above were diluted in 0.9% saline, and the particle sizes examined immediately thereafter. As shown in the top row in Table 5, all of the particles showed a large size increase, although the 1:1 formulation was less aggregated. A similar study on post-lyophilization particles was also carried out, with the results shown in the top row of Table 6 in Example 4. A comparison of Tables 5 and 6 data shows that the 1:1 formulation is substantially more size stable in saline after lyophilization than post-dialysis. The other three formulations, having greater cholesterol sulfate mole ratios, showed large size increases in saline both pre and post lyophilization.
A second study was designed to examine AMB/cholesterol sulfate particle size in blood plasma, and the effect of subsequent dilution of the plasma medium with suspending buffer. Initially, each of the four samples (both pre and post lyophilization) were diluted 1:1 with human plasma, then diluted after a few minutes with suspending buffer containing 10% lactose. Size measurements were made immediately after dilution, and again 20 minutes later. The results are shown in the bottom two rows of Tables 5 and 6 in Example 4. Summarizing the data, plasma caused a size increase in all of the formulations. Smallest size increases were seen in the 1:1 formulation, where particle sizes were less than 1 micron (1,000 nm). The size increase produced on contact with plasma was at least partially reversible for all formulations except the 1:4 formulation, as evidenced by the significant reduction in particle size after 20 minutes incubation in dilute form in suspension medium. There was little difference in the size behavior of particles in pre- and post-lyophilization formulations.
The data above demonstrate that the AMB:cholesterol sulfate formulation of the invention can be stored in dried form long term, without significant increase in size, on rehydration, or significant change in size stability in plasma. One significant advantage of the dried particles which was observed was substantially greater size stability on storage in buffer. Within the range of AMB: cholesterol sulfate mole ratios which was examined, the 1:1 formulation, gave greatest size stability and smallest mean particle sizes under the various conditions examined.
It has been reported that cholesterol sulfate is capable of forming lipid vesicles or liposomes on extended (several hour) sonication (reference 13). It was therefore of interest to determine whether the AMB u cholesterol sulfate particles of the present invention are liposomal in form. For these studies, the 1:4 AMB/cholesterol sulfate formulation was selected, since a relatively high ratio of cholesterol sulfate is more likely to form liposomal structures.
One characteristic of liposomes is a continuous lipid bilayer capable of encapsulating water-soluble solute molecules. Many water-soluble molecules, such as sugars and other marker solutes, are readily encapsulated in liposomes by preparing (dispersing) the liposomal lipids in an aqueous medium containing the marker solute. Smaller marker molecules, such as sugars, also tends to pass through lipid bilayer membranes slowly, as evidenced by equilibration of the solute between encapsulated and bulk phase aqueous compartments over a several-hour to several-day solute-exchange period.
To test the ability of AMB/cholesterol sulfate (1:4) particles to encapsulate sucrose, the particles were prepared by dispersion in a medium containing 14 C sucrose. After sonication to optical clarity, the particles were separated from the suspending medium by molecular sieve chromatography, using a column sieving material which excludes particles in the size range of the AMB/cholesterol sulfate particles. Details of the test were given in Exmaple 5. Briefly, 95% of the AMB was associated with the particles eluted in the void volume, but no detectable peak of radioactivity was associated with the particles.
Based on this study, it appears that the particles do not form encapsulating (liposomal) structure, or alternatively, that the particles form very leaky structures. The latter explanation is unlikely, since (a) cholesterol tends to decrease permeability in liposomes to small water-soluble permeants, and (b) the pure cholesterol derivative liposomes which have been described (reference 13) have very low permeability. Studies on cholesterol hemisuccinate liposomes also show stable encapsulation of a variety of small water-soluble molecules (PCT patent application WO 05030).
Another characteristic feature of liposomes is the ability of isotonic liposomes to swell on injection into a hypotonic medium. Here the liposomes are acting as small osmometers in response solute gradients across the bilayer membranes. Isotonic liposome swelling has been observed in liposome prepared from a variety of cholesterol derivatives, including cholesterol-PEG and cholesterol sulfate (reference 13) and cholesterol hemisuccinate liposomes (PCT patent application WO 85/05030). Cholesterol-derivative liposomes show the expected increased absorbance when injected into increasingly dilute media, although these liposomes behave less like ideal osmometers than do liposomes formed from conventional phospholipid components.
Each of the above four AMB/cholesterol particle compositions from above (1:1, 1:2, 1:3, and 1:4 mole ratios) was prepared in 10% lactose. Both pre- and post dialysis particles were tested for osmotic swelling in distilled water, comparing particle size immediately after dilution with particle size 20 minutes after dilution. The results are shown in Table 7 in Exmaple 6. No swelling was observed in any of the particle formulations. The test supports the finding from the encapsulation studies above that the AMB/cholesterol sulfate particles of the invention do not form closed vesicle structures.
AMB is useful in treating a variety of systemic fungal organisms, including coccidiomycosis, cryptococcosis, systemic moniliasis, histoplasmosis, aspergillosis, rhodoptorulosis, sporotrichosis, phycomycosis, and blastomycosis, and is also effective against some species of Leishmania (reference 15). Because of the server side effects of the drug, in its presently available free form, it is generally administered only to patients with progressive, potentially fatal systemic fungal infections, and the patient must remain hospitalized during drug treatment for constant monitoring of renal function.
This section describes the increased toxicity and improved efficacy of AMB in the present formulation, and the potential therefore of wider drug use, particularly for prophylactic use in preventing opportunistic fungal infection in immune-deficient or immune-compromised patients, such as those receiving cancer chemotherapy, immunosuppressive drugs, or radiation therapy.
According to an important feature of the invention, it has been discovered that the AMB:cholesterol sulfate composition described herein is substantially less toxic than free AMB (Fungizone), as evidenced by a much higher LD50 value. Further, the composition is considerably less toxic than liposomal or lipid-complex forms of AMB which have been described in the prior art, as judged by a comparison with reported LD50 values. Toxicity studies to determine LD50 values for the composition of the invention are detailed in Example 7. An initial test examined the lethal toxicity of Fungazone and 1:4 AMB/cholesterol sulfate particles. Based on the data shown in Table 8, the LD50 of the free AMB (Fungizone) composition is between 1-4 mg/kg animal weight. This value is increased to between 15-25 mg/kg in the amb/cholesterol sulfate composition. LD50 value is substantially higher than values previously reported for liposomal or lipid-complex AMB formulations described in the prior art.
In the second test, also reported in example 8, the lethal toxicity of the four different mole ratio AMB formulation described above, at a dose of 20 mg/kg was investigated. Surprisingly, it was found that the 1:1 formulation was non-lethal at the 20 mg/kg in all six test animals, indicating an LD50 value of substantially above 20 mg/kg. The data show that the LD50 for the other three formulations is less than 20 mg/kg, and at least for the 1:4 formulation, therefore between 15-20 mg/kg.
The composition also enjoys the advantage that cholesterol sulfate is a natural cholesterol component found widely in animals. The cholesterol compound has no known toxicity, and is metabolized in the body by cholesterol sulfatase.
Finally, since toxicity is expected to increase with increased particle size, the stable and relatively small particles which can be injected may contribute to reduced toxicity.
Another important feature of the AMB/cholesterol sulfate composition is significantly enhanced drug efficacy in treating systemic fungal infection. One efficacy study performed in support of the present invention is detailed in Example 9. Here animals infected intravenously with C. albicans were treated with Fungizone, at doses between 0.3 and 0.9 mg/kg body weight, or with 1:4 AMB:cholesterol sulfate, at doses between 0.3 and 2.0 mg/kg. Drug efficacy was determined by survival at 25 days post-drug administration. The data, presented in Table 10, show that the AMB/cholesterol sulfate composition gives significantly higher survival rates at each dose level between 0.3 and 0.9 mg/kg. At 2.0 mg/kg, all of the animals treated with the formulation of the invention survived.
The present invention provides a dehydrated AMB composition which, when rehydrated after an extended storage period, forms a suspension of AMB particles having a selected size range less than about 1 micron. Because the particles can be stored in an anhydrous, inert environment, toxicity and lipid and drug breakdown problems related to oxidation and mechanical damage at a gas/liquid interface are minimized. For parenteral use, e.g., intravenous administration, the composition is preferably formed from AMB liposomes having sizes of between about 0.1 to 0.4 microns, such as can be prepared by the methods above. The AMB/lipid composition is hydrated typically to a selected AMB concentration between about 50 and 200 mg/ml, and administered at a concentration of between 1 and 5 mg AMB/kg body weight.
Where the drug is given intramuscularly, to provide slow drug release from the site of injection, the composition is preferably rehydrated to a more concentrated form, which can be conveniently localized in an injection site.
From the foregoing, it can be appreciated how various objects and features of the invention are met. The invention provides an AMP formulation which has substantially reduced toxicity and greater drug efficacy and free AMP or lipid/AMP formulations described in the prior art. The enhanced therapeutic index of the drug, particularly related to reduced toxicity, allows much wider use of the drug, for example, for prophylactic treatment of immune-compromised patients, and also provides greater therapeutic efficacy, in the treatment of active systemic fungal infections.
The composition is readily prepared, and the cholesterol sulfate component is relatively inexpensive in purified form, and naturally utilized when administered parenterally. The formulation is easily stored in dried form, and when rehydrated, yields a particle suspension with selected small sizes.
The following examples illustrate methods of preparing, characterizing, and using the AMB/cholesterol sulfate composition of the invention. The examples are in no way intended to limit the scope of the invention.
CHSO4 (cholesterol 3-sulphate, sodium salt) was obtained from Sigma Chemical Co., St. Louis, Mo.; AMB (amphotericin-B, Type 1) was donated by E.R. Squibb & Sons, Inc., (Batch No. 20-914-5978-001). All other materials are of reagent grade or superior from commercial sources.
AMB and CHSO4 in dry powder form were weighed out and combined to give one of the four AMB:cholesterol sulfate mole ratios listed in Table 1 below. The amount of AMB and cholesterol sulfate added was sufficient to produce a final AMB plus cholesterol sulfate concentration in the particle suspension of about 50 umole/ml.
Dry methanol was added to the AMB/cholesterol sulfate powder to a final AMB concentration of between 0.2-0.6 mg/ml, and the suspension was stirred until all of the powder dissolved. Lactose was added to this solution to produce a 10% (w/v) lactose solution in the final aqueous product. The solution was dried in vacuo, yielding dried lactose particles coated with a lipophilic AMB/cholesterol sulfate film.
A suspending buffer containing 10 mM Tris-HCl, 0.1 mM EDTA pH 7.4, 67 mOsm, was added to the dried mixture in an amount sufficient to produce a final AMB plus cholesterol sulfate concentration of 50 umole/ml. This suspension was sonicated with an Ultrasonic Liquid Processor (Heat Ultrasonics, Inc., Farmingdale, N.Y.), Model W-800, probe sonicator until the suspension becomes optically clear. (This process is facilitated if the suspension is warmed to 45� C. in a water bath.) Sonication was performed under nitrogen gas.
The sonicated AMB/CHSO4 particles were dialyzed to remove traces of unincorporated AMB, using 6000-8000 molecular weight cut-off dialysis tubing. The material was dialyzed against a buffer containing 10 mM Tris-HCl, 0.1 mM EDTA, 10% (w/v) lactose, pH 7.4, 300 mOsm. The clear suspension was dried by rapid freezing in a dry ice/isopropanol mixture and lyophilized overnight at a shelf temperature of -25� C., followed by a further two hours at 25� C. (15 SRC-X Lyophilizer; Virtis, Gardiner, N.Y.). Lyophilized samples were reconstituted by addition of an equal volume of water and gentle mixing. Table 1 below shows the AMB concentrations of the four compositions, at various stages of preparation.
TABLE 1______________________________________AMB Concentration (mg/ml) Post- Pre- Post- Lyophilization/Molar Ratio Theoretical Dialysis Dialysis Rehydration______________________________________1:1 23.10 20.66 24.20 21.521:2 15.40 10.80 16.46 15.191:3 11.55 11.02 12.19 11.601:4 9.24 9.49 10.12 8.79______________________________________
Particle sizes were determined by dynamic laser-light scattering using a Nicomp Model 200 sizer (Nicomp Instruments Inc., Goleta, Calif.). Samples were typically diluted to 0.3 umole/ml for this measurement using 10 mM Tris/HCl, 0.1 mM EDTA, 10% (w/v) lactose buffer, pH 7.4. The mean particle sizes and standard deviations (S.D.) for the four compositions from Example 1 are given in Table 2 below. As seen, all four compositions have mean particle sizes between about 130-180 nm prior to lyophilization, and between about 210-280 nm after lyophilization.
TABLE 2______________________________________ (mean � S.D. nm) Particle Diameter ParticlesMolar Ratio Particles Post-Lyophilization/AMB/CHSO4 Immediately Post-Dialysis Rehydration______________________________________1:1 138 � 54 268 � 1371:2 148 � 66 211 � 1051:3 172 � 89 265 � 1471:4 138 � 61 274 � 151______________________________________
The four samples from Example 1, each containing an AMB plus cholesterol sulfate concentration of about 50 umole/ml, were incubated at 4� C. for up to eight days. At days 0, 2, 6 and 8, an aliquot of each suspension was withdrawn, diluted to about 0.3 umole/ml, and examined for particle size distribution, as in Example 2, The results are shown in Table 2 below. It is seen that 1:1 composition is stable to particle size change, whereas the compositions containing higher molar amounts of cholesterol sulfate are progressively less table on storage.
TABLE 3______________________________________ Particle Diameter (mean � S.D. nm) as a Function ofDays of AMB/CHSO4 /Molar Ratio Post-Dialysis)Storage 1:1 1:2 1:3 1:4______________________________________0 138 � 54 148 � 66 172 � 89 138 � 612 193 � 98 336 � 194 527 � 299 334 � 1926 161 � 82 462 � 265 679 � 377 823 � 4818 179 � 95 512 � 296 968 � 551 1034 � 587______________________________________
A similar stability study was performed on the same compositions after lypohilization and reconstitution in distilled water, as in Example 1. The results, given in Table 4, show (1) relatively small size increases over the eight day test for each of the four compositions, and (b) little effect on size changes of the molar amount of cholesterol sulfate.
TABLE 4______________________________________ Particle Size (mean � S.D. nm) as a Function ofDays of AMB/CHSO4 Molar Ratio (Post-Lyophilization)Storage 1:1 1:2 1:3 1:4______________________________________0 268 � 137 211 � 105 265 � 147 279 � 1512 304 � 153 331 � 177 541 � 293 554 � 3036 340 � 171 418 � 224 515 � 283 478 � 2428 371 � 188 436 � 228 570 � 314 487 � 258______________________________________
The four samples from Example were diluted to approximately 0.3 umole/ml with 0.9% (w/v) saline and their sizes measured as in Example 2. The results are shown at the top line in Table 5 below. For each formulation, saline produced a more than tenfold increase in mean particle size. The size growth of the 1:1 composition was substantially less than for the three compositions with greater amounts of cholesterol sulfate.
The four samples were also diluted 1:1 (v/v) with human plasma and subsequently (within a few minutes of contact with the plasma) diluted with 10 mM Tris/HCl, 0.1 mM EDTA, 10% lactose (w/v) buffer pH 7.4, for sizing. Size measurements, reported in Table 5 below, were made immediately after diluting, and 20 minutes after diluting. The data indicate that the 1:1 formulation is least sensitive to size change, upon contact with plasma, and that for all formulations, incubation in the diluted medium for 20 minutes produced some size decrease.
TABLE 5__________________________________________________________________________ Particle Size (mean � S.D. nm) as a Function of AMB/CHSO4 Molar Ratio (Post-Dialysis)Treatment 1:1 1:2 1:3 1:4__________________________________________________________________________Dilute in saline 3328 � 1990 13209 � 8288 6789 � 4276 11072 � 6618Mix + plasma, 728 � 334 1200 � 628 4017 � 1951 1942 � 1043dilute + sus-pending buffer20 minutes 358 � 169 823 � 457 1745 � 1007 1667 � 942later__________________________________________________________________________
Similar size measurements, after mixing with 0.9% saline or plasma, were made on AMB/cholesterol sulfate particles after lyophilization and rehydration with distilled water, as in Example 1. The results are shown in Table 6 below. Size changes similar to those observed with pre-lyophilized particles (Table 5 date) were observed.
TABLE 6__________________________________________________________________________ Particle Size (mean � S.D. nm) as a Function of AMB CHSO4 Molar Ratio (Post-Lyophilization/Hydration)Treatment 1:1 1:2 1:3 1:4__________________________________________________________________________Dilute in 1738 � 1007 8405 � 5549 13158 � 8625 9813 � 6265salineMix + plasma, 955 � 466 1030 � 550 1766 � 976 2467 � 1233dilute +suspendingbuffer20 minutes 534 � 267 776 � 378 1147 � 643 2661 � 1374later__________________________________________________________________________
The ability of the AMB/cholesterol sulfate particles to encapsulate a radiolabeled marker was examined. CHSO4 /AMB, 4:1 molar ratio particles, were prepared as in Example 1, except that the Tris buffer medium used to suspend the dried AMB/cholesterol sulfate mix contained 1 uCi of 14 C-sucrose. The suspension was applied to a Sephadex G50 gel exclusion column equilibrated with 10 mM Tris/HCl, 0.1 mM EDTA, 10% (w/v) lactose buffer, pH 7.4, and the applied material was eluted with the same buffer. The particles were eluted in the void volume, which was monitored by UV absorption at 280 nm. The samples were collected and examined for radioactivity by conventional scintillation counting. It was found that 95% of the AMB was in the particle peak, whereas no detectable peak of 14 C-sucrose occurred in this region.
CHSO4 /AMB formulations containing the four different mole ratios of AMB and cholesterol sulfate were prepared as in Example 1, (in the usual suspension medium containing 10% lactose). These samples are designated as post-dialysis (P.D.) suspensions in Table 7 below. A portion of each sample (containing 10% lactose) was lyophilized and reconstituted in distilled water, and these samples are designated as lyophilized and reconstituted (L.R.) in the table.
The P.D. and L.R. samples were each diluted to 0.3 umole/ml with distilled water, and the size distribution of the particles immediately after dilution in the hyptonic medium, and 20 minutes after dilution was measured as in Example 2. The results are given in Table 7 below. As seen, there is no appreciable swelling, over a 20 minute incubation period, as evidenced by an increase in mean particle size, in any of the samples examined.
TABLE 7______________________________________ Sample Post- Dialysis (PD) or Post-Lyoph-Molar Ratio ilization/Rehy- Time Particle SizeAMB/CHSO4 dration (LR) (min) (mean � S.D. nm)______________________________________1:1 PD 0 109 � 42 20 114 � 451:1 LR 0 212 � 107 20 212 � 1051:2 PD 0 126 � 59 20 134 � 641:2 LR 0 170 � 81 20 184 � 891:3 PD 0 124 � 58 20 131 � 611:3 LR 0 205 � 117 20 204 � 1071:4 PD 0 161 � 86 20 185 � 1001:4 LR 0 228 � 116 20 236 � 122______________________________________
Outbred male Swiss/Webster mice were obtained from Simonsen Labs, Inc. The animals weighed approximately 15-45 grams on the day of treatment and were between 4-8 weeks old. The animals were quarantined for at least three days prior to the study, and only mice that remained healthy during the quarantine period were used. The animals were given food and water ad libitum.
In a first study, the animal groups were treated with either Fungizone (Squibb) suspended in sterile saline or 1:4 AMB/cholesterol sulfate composition prepared as in Example 1. In each case, the AMB concentration was adjusted such that the selected dose of AMB (given in Table 8) could be administered in a final volume of 0.2 ml. Forty-eight animals were employed for each dose group. The test material was administered by a single intravenous injection via the lateral tail vein. Each dose was administered over about 1.5 minutes.
The animals were observed for signs of toxicity and death at least three times (1, 2, and 4 hour post treatment) on the day of treatment. During the remaining observation period of five days, the animals were examined daily in the morning and afternoon. The test results, expressed as the ratio of number of survivors on day five:total number of animals treated, are given in Table 8. The LD50 value for Fungizone, calculated by conventional methods, is 3.2 mg/kg. The LD50 for the AMB/cholesterol sulfate composition between 15-20 mg/kg.
TABLE 8______________________________________ Number of Survivors on Day 5Treatment (Post-Injection/Total Animals Injected)______________________________________FUNGIZONE0.5 mg/kg 8/81.0 mg/kg 8/82.0 mg/kg 8/84.0 mg/kg 2/86.0 mg/kg 0/88.0 mg/kg 0/4CHSO4 /AMB (4:1)10 mg/kg 3/315 mg/kg 3/420 mg/kg 2/525 mg/kg 1/3______________________________________
In a second toxicity test, mice were treated with 20 mg/kg of one of the four AMB/cholesterol sulfate formulations from Example 1, with drug administration and animal monitoring being done as above. The results, presented below in Table 9, show that the 1:1 formulation has an LD50 value higher than 20 mg/kg.
TABLE 9______________________________________Treatment Number of Survivors on Day 5(AMB/CHSO4) (Post-Injection/Total Animals Injected)______________________________________1:1 molar ratio 6/61:2 molar ratio 0/51:3 molar ratio 1/51:4 molar ratio 0/5______________________________________
Crl:CFW (SW)BR mice weighing 20-25 grams were obtained from the Charles River Breeding Laboratories, and were given food and water ad libitum. C. albicans strain 30 was grown at 35� C. on SDA (Sabourand Dextrose A gas) for 18 hours, and the organism is harvested and diluted with sterile nonpyrogenic saline to yield about 7�108 colony forming units in a 0.2 ml volume.
Eight-ten animals were injected in the tail vein each with 0.2 ml of the above C. albicans mixture. Two days after the fungal injection, the animals were injected with graded doses of Fungizone or AMB/cholesterol sulfate (1:4) prepared as in Example 1. The AMB preparations were adjusted in concentration so that each animal received a total volume, administered intravenously through the tail vein, of 0.1 ml. The amount of AMB administered, expressed in terms of mg drug/kg body weight of the animal is given at the left in Table 10. The animals were followed for 25 days post-drug administration. The number of survivors at 25 days per total number of test animals is shown in the table for the two AMB preparations, and a buffer control.
TABLE 10______________________________________Survivors Post-25 Days/Total Animals InjectedDose Free AMB CHSO4 /AMB = 4:1 Control______________________________________0.0 mg/kg -- -- 0/110.3 mg/kg 2/10 5/10 --0.6 mg/kg 1/10 9/10 --0.9 mg/kg 3/10 9/10 --2.0 mg/kg -- 10/10 --______________________________________
Although the invention has been described and illustrated with respect to specific embodiments, uses and methods of preparation, it will be appreciated that a variety of changes and modifications may be made without departing from the scope of the invention.
|Cited Patent
|Filing date
|Publication date
|Sep 7, 1982
|Aug 28, 1984
|Eli Lilly And Company
|2'-N-Acylated and 2'-N-alkylated derivatives of 4-O-substituted-2-deoxystreptamine aminoglycosides
|Feb 27, 1987
|Apr 18, 1989
|Liposome Technology, Inc.
|Amphotericin B/cholesterol sulfate composition
|Citing Patent
|Filing date
|Publication date
|Jun 17, 1998
|Nov 9, 1999
|University Technology Corporation
|Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
|Apr 13, 1999
|Sep 2, 2003
|Universite De Montreal
|Low-rigidity liposomal formulation
|Dec 21, 2001
|Jan 6, 2009
|Nektar Therapeutics
|Pulmonary delivery of polyene antifungal agents
|Jul 22, 2005
|Mar 26, 2013
|Novartis Ag
|Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
|Mar 4, 2010
|Nov 11, 2014
|Lifecare Innovations Pvt. Ltd.
|Formulation for treating fungal infection
|Oct 10, 2007
|Mar 18, 2010
|Jina Pharmaceuticals, Inc.
|Aqueous Systems For The Preparation Of Lipid Based Pharmaceutical Compounds; Compositions, Methods, And Uses Thereof
|Mar 4, 2010
|Jan 19, 2012
|Lifecare Innovations Pvt. Ltd.
|Novel formulation for treating fungal infections
|Nov 8, 2006
|Aug 18, 2010
|CombinatoRx, Inc.
|Methods, compositions, and kits for the treatment of ophthalmic disorders
|Mar 5, 2009
|Mar 6, 2013
|Anacor Pharmaceuticals, Inc.
|Boron-containing small molecules as anti-inflammatory agents
|Jan 27, 2011
|Aug 4, 2011
|Anacor Pharmaceuticals, Inc
|Boron-containing small molecules
|U.S. Classification
|514/31, 536/16.8, 536/18.5, 536/6.5
|International Classification
|Cooperative Classification
|European Classification
|Jan 3, 1995
|Fee payment
Year of fee payment: 4
|Jan 4, 1999
|Fee payment
Year of fee payment: 8
|Nov 14, 2001
Owner name: ALZA CORPORATION, A CORPORATION OF DELAWARE, CALIF
Free format text: MERGER;ASSIGNOR:SEQUUS PHARMACEUTICALS INC., A CORPORATION OF DELAWARE;REEL/FRAME:012302/0282
Effective date: 20000317
Owner name: INTERMUNE PHARMACEUTICALS, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ALZA CORPORATION, A CORPORATION OF DELAWARE;REEL/FRAME:012302/0359
Effective date: 20010105
Owner name: SEQUUS PHARMACEUTICALS INC., CALIFORNIA
Free format text: CHANGE OF NAME;ASSIGNOR:LIPOSOME TECHNOLOGY INC., A CORPORATION OF DELAWARE;REEL/FRAME:012302/0434
Effective date: 19950706
|Apr 1, 2002
Owner name: INTERMUNE, INC., CALIFORNIA
Free format text: CHANGE OF NAME;ASSIGNOR:INTERMUNE PHARMACEUTICALS, INC.;REEL/FRAME:012745/0226
Effective date: 20010426
|Jan 14, 2003
|Fee payment
Year of fee payment: 12
|Jan 29, 2003
|Maintenance fee reminder mailed


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Hotels near Vienna Twin Tower
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Hotels within 0.5 miles of Vienna Twin Tower
- Most bookedAustria Trend Hotel Bosei
211 people looked at this hotel in the last hour
Most recent review
"This is in a good out of town location with good transport links to Vienna. Lots of parking and modern, clean and comfortable room. Staff were friendly and knowledgeable about the area."
A Traveller, Jun 2016, GB
122 people looked at this hotel in the last hour
Most recent review
"This hotel was very clean and hallways and room had a fresh scent, staff was excellent and helpful any time of the day or night, free computer and printer available for use in the lobby, free wifi in room worked without interactions, great and on time shuttle service. Fast food, gas station and o..."
A Traveller, Jul 2016, US
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Hotels within 1 mile of Vienna Twin Tower
148 people looked at this hotel in the last hour
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"Free parking and a bus to the centre of Vienna. Good buffet breakfast. Used by tour groups."
D, Sep 2016, US
27 people looked at this hotel in the last hour
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"This was my first experience with an apartment rental and I must say I'd do it again in a flash! Petra identified an easy route to the apartment from the train station and there was a tram stop right across from apartment for an easy 10-15 minute ride into the city. Was easy to get into city for ..."
A Traveller, Sep 2014, CA
26 people looked at this hotel in the last hour
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"Getting to the apartments was fairly easy. Close promixity to tram stops, made it very easy for us to travel to and from the city centre which was a big bonus for us. There was no reception at the apartment, but the staff communicates very well via email. Petra handled our reservation and was ver..."
A Traveller, Nov 2014, NZ
12 people looked at this hotel in the last hour
9 people looked at this hotel in the last hour
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"It is way outside the city and the bus in takes about 40 minutes. The A/C wasn't working but other than that I had no complaints."
A Traveller, Jun 2015, US
7 people looked at this hotel in the last hour
View hotels near to Vienna Twin Tower on a map
- St. Stephen's Cathedral
- Vienna State Opera
- Stephansplatz
- Vienna International Centre
- Hofburg Imperial Palace
- Vienna City Hall
- Messe Wien Exhibition and Congress Center
- Wiener Stadthalle
- Schoenbrunn Palace
- Karlsplatz
- Wiener Prater
- University of Vienna
- Ernst Happel Stadium
- Spanish Riding School
- Gasometer
- International Atomic Energy Agency
- Schwedenplatz
- Naschmarkt
- Belvedere
- Viennese City Park
Best Cheap Vienna Twin Tower, Vienna Hotels
5 of our most popular choices are:
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2. Blue Danube Apartments
3. GoVIenna Modern Apartment
4. Rafael Kaiser Premium Apartments
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Our map based hotel search function can be accessed from the map image above (or via standard search results) clearly showing the location of each hotel around Vienna Twin Tower. You can also refine your search within Vienna based upon other nearby landmarks and neighbourhoods as well as transport options to help you get around.
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Things To Do Near Vienna Twin Tower - Vienna Travel Guides
Vienna shopping guide – where to shop and what to buy
Shopping is a favored past time in Vienna, so much so that many of its popular shopping streets have...
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The land locked country of Austria, comfortably sat in the middle of mainland Europe is home to a me...
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Golden Sun Hotel Zhuhai: Find photos, reviews, information, amenities and compare prices for 3 stars hotels in Zhuhai, China.
Golden Sun Hotel Zhuhai provides 3-star accommodation in Zhuhai. It also offers a tour desk and a swimming pool.
Hotel description
Those staying at the hotel can enjoy Chinese dishes at the on-site restaurant, suitably located for those who want to stay nearby at mealtime.
Zhuhai Sanzao Airport is a 55-minute drive from Golden Sun Hotel Zhuhai. Zhuahai Stadium and Xianglu Bay are just an easy drive from the hotel.
Hotel features
Swimming pool, Tour Desk
Availability and Prices
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Users who viewed Golden Sun Hotel Zhuhai also viewed these 3 stars Zhuhai hotels:
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2007 Yue Hai Zhong Lu, Gongbei, Zhuhai
2007 Yue Hai Zhong Lu, Gongbei, Zhuhai
Tenda Hotel
29 Bitao Road, Xiangzhou District, Zhuhai
29 Bitao Road, Xiangzhou District, Zhuhai
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13 m
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261 m
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607 m


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Cheery Cherry Romper
$ 24.50 $ 49.00
Product Details
This romper is simply fabulous! This romper is off the shoulder and has an extra layer for detail. This great for going out, all you need is your favorite boots and a leather jacket!
This item is on sale and will be FINAL SALE. We cannot return or exchange this item.
- This item fits true to size.
- Color: Red


text:
Counterfeit bills turn up in area
PARKERSBURG – Counterfeit $100 bills discovered at the Parkersburg Kmart on Tuesday and the Vienna Kmart on Wednesday are suspected to be part of a larger counterfeit operation coming to the Mid-Ohio Valley, officials said.
The Parkersburg Police responded to a call about a counterfeit $100 bill being used at Kmart, 1050 Division St., on Tuesday, said Sgt. Greg Nangle with the Parkersburg Police Department.
The Vienna Police responded to a call on Wednesday about three counterfeit $100 bills being used at Kmart in Vienna, 800 Grand Central Ave., to purchase electronics on Monday, said Sgt. Mike Pifer with the Vienna Police Department.
Parkersburg Police have no suspects in the case and an investigation involving the video surveillance at the Parkersburg Kmart is underway, Nangle said.
Vienna Police have determined the counterfeit bills came from a black female who purchased electronics with them on Monday, although their counterfeit status was not determined until Wednesday by BB&T bank employees, Pifer said.
It is unknown if the same suspect is responsible for both counterfeit uses in the area.
The local police are working with other agencies in the state to locate the counterfeiters and prevent the spread of counterfeit money, Nangle said.
In the meantime, businesses in the Mid-Ohio Valley should be aware that counterfeit $100 bills have been sighted in the area, Nangle said.
Counterfeit bills matching the one found at the Kmarts have also been reported in Kanawha County, Nangle said. These bills have been the older generation, rather than the newer ones with holograms installed, Nangle said.
"We believe we have a group who is passing counterfeit $100 bills in multiple counties," Nangle said.
It is believed that the counterfeiters are not from the Parkersburg area, Nangle said.
Area shop owners are advised to have their employees scrutinize all $100 bills carefully in the coming weeks, Nangle said.
Counterfeit pens, a commonly used method of checking for counterfeit bills, are showing that some of the modern counterfeit bills are real, Nangle said. Although the counterfeit pen is a good starting point for counterfeit search, shop owners should use additional methods on large bills, he said.
Employees should hold all $100 bills, even those that indicate as real with a counterfeit pen, up to the light to examine them, Nangle said. Check for security strips and watermarks that should be in the bill, Nangle said.
The newest version of the $100 bill has a large security strip in the bill that is dark blue. This blue strip has bells in the ribbon that will change to 100s as the bill is moved.
In the gold bell located to the right of the blue strip is a color-changing liberty bell shape.
These holograms, and the watermarks on the older style of $100 bills, are challenging for counterfeiters to copy and are absent from most counterfeits, Nangle said.
Employees should examine the texture and feel of the bill and compare it to how other $100 bills feel, Nangle said. They should also examine the white space around the bill's edges before the printing begins, he said.
The edges of a legitimate bill should appear even all around the bill, he said.
When dealing with multiple bills at once, examine their serial numbers, Nangle said. Each bill should have a unique serial number, he said.
Those who suspect they have received counterfeit bills are asked to call their local police department immediately. The Parkersburg Police can be reached at 304-424-8444 and the Vienna Police can be reached at 304-295-8563.


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Check in from 2:00 PM / Check out prior to 11:00 AM
Albro House: Find photos, reviews, information, amenities and compare prices for 2 stars hotels in London, United Kingdom.
Located just a brief stroll from Paddington Railway Station, Albro House provides guests with an ideal base when visiting London. It is situated a short walk from Edgware Road.
Hotel description
There are a range of facilities available to those staying at Albro House Hotel London, including a tour desk, luggage storage and an express check-in and check-out feature. It also offers a safe, parking and a wake-up service.
The hotel provides rooms equipped with ironing facilities, heating and tea and coffee making facilities, plus all the necessities to ensure an enjoyable stay. A private bathroom, an in-room closet and a radio can also be found in each.
Each morning, guests can sit down to breakfast provided by Albro House before venturing out to see what the surrounding region has to offer. There is also the added convenience of an on-site restaurant.
Albro House Hotel London is close to Lancaster Gate Tube Station, making it easy for guests to discover London and its surrounding areas. Guests can also easily visit Kensington Gardens, the Marble Arch and Hyde Park.
Hotel features
Restaurant, Coffee / Tea Maker, TV, En suite, Private Bathroom
Safe-Deposit Box, Photocopier, Luggage Storage, Express Check-In/Check-Out
Tour Desk
Internet Connection (wireless)
Private Toilet
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Users who viewed Albro House also viewed these 2 stars London hotels:
Kensington Manor
8 Emperor's Gate, London
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Travelodge Hotel Uxbridge Central London
Colham House Bakers Road, London
Colham House Bakers Road, London
Cromwell Crown Hotel
139-141 Cromwell Road, London
139-141 Cromwell Road, London
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text:
Wind Power Whiz Kid A Buzz Beaker Brainstorm
Written by Scott Nickel
Illustrated by Andy J. Smith
Part of the Graphic Fiction: Tiger Moth Series
Lovereading4kids Price £3.99
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Wind Power Whiz Kid A Buzz Beaker Brainstorm by Scott Nickel
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Book Info
40 pages
Interest Age: 8 - 10
Scott Nickel
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Publication date
23rd October 2008
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text:
Hotel Anfield, Liverpool
- Free WiFi
Main amenities
- 8 guestrooms
- Breakfast available
- Room service
- Self parking
- Arcade/game room
- Meeting room
- Concierge services
- Wedding services
- TV in a common area
Feel at home
- Private bathroom
- Iron/ironing board
- Hair dryer
- Coffee/tea maker
- Flat-panel TV
- Satellite TV service
What's around
- In Anfield
- Anfield Road Stadium (0.1 mi / 0.1 km)
- Liverpool ONE (2.8 mi / 4.6 km)
- World Museum Liverpool (2.2 mi / 3.5 km)
- St. George's Hall (2.2 mi / 3.5 km)
- Walker Art Gallery (2.2 mi / 3.5 km)
The owner was fantastic! We got in and they got us into the room right away. The Master…
I was scheduled a room and when i had gotten there they informed me that they had…
Hotel Anfield, Liverpool
Hotel Info: 866-539-8117from $81
- Suite (5 People)
- Suite, 1 Double Bed
- Junior Suite, 1 Double Bed
- Family Room
- Family Room
- Club Suite
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At a glance
Key facts
Hotel size
- This hotel has 8 rooms
- Check-in time 1 PM-11 PM
- Check-out time is 2 PM
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
- Minimum check-in age is 18
Travelling with others
- No cribs (infant beds)
- Pets allowed
- Specific rooms only *
- Free WiFi in public areas
- Free WiFi in rooms
- Self parking *
Nearby Four Star Liverpool hotels
In the hotel
- Continental breakfast (surcharge)
- Room service
- Arcade/game room
- One meeting room
- Concierge services
- Wedding services
- Television in common areas
In the room
- Coffee/tea maker
- Iron/ironing board
- Egyptian-cotton sheets
- Private bathroom
- Shower only
- Hair dryer
- Flat-screen TV
- Satellite TV channels
- Free WiFi
Top Liverpool hotels
Recently reviewed hotels in Liverpool
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"Easy short walk from train station. Close to center and a 5 minute walk to the University. Would stay again. "Dec 6, 2016
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"Literally a few steps from Hope Street, 'the best street in the UK', with its two cathedrals, theatre, philharmonic, and two universities. Walking distance from groceries and…"Dec 5, 2016
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"Firstly: be warned!! This hotel is a long (long!) way past it's best and is really very tired indeed and in desperate need of some investment ad upkeep...... Don't expect the…"Nov 30, 2016
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Hotel Anfield, Liverpool's small print
Also known as
- Anfield Hotel
- Hotel Anfield
- Hotel Anfield Liverpool
- Anfield Liverpool
- Anfield
Pet-friendly rooms can be requested by contacting the property at the number on the booking confirmation.
Optional extras
Self parking is available for an extra charge
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Good 3.1 /5 from 44 reviews
After traveling over 15 hours to get to the Liverpool, the last thing I needed was arriving at a hotel (more like a guesthouse) with an empty parking lot, doors locked, and no person in sight at the place. I waited an hour and a half (I arrived to the place on time at 1:00 pm) before giving up and finding another place. The only reason I booked the place was the location. Would not recommend, period.
The hotel and its staff were excellent!! The location was perfect. We were treated like family by everybody. For example, we needed to buy some products from a grocery store and we asked where to go. The owner of the hotel (his name is Warren), drove us to the nearest supermarket and walked with us throughout the entire store so we could find the things we needed. We've never had this kind of treatment in any hotel and at any country we visited. We are extremely happy with Hotel Anfield and its personnel. We felt like home in a foreign country!! Strongly recommend this establishment to anyone!!
At nearly £200 for a one night stay this was terrible. calling yourself a hotel when you have no one to help you and no breakfast offered is very misleading. Do not stay here unless you just want footie convenience
I booked this for my husband and friend. When they arrived they were told that the cleaner had gone off with the room key so they wouldn't be able to lock the room door but that their belongings would be safe? Waking up after a night out, they were freezing. There was no heating in the room and no way of filling the kettle for a hot drink as it wouldn't fit under the taps in the bathroom sink. The description of the hotel says all rooms have private bathrooms but they had to share theirs and to top it all the water from the shower was cold. They couldn't complain as, when they were leaving, there was no one in sight at reception. I am currently waiting for a refund
I woke up with bug bites all over, so bad i had to go to a pharmacist who actually recommend i go see a doctor, and no milk or coffee in our room. There was also no one at reception to help and no one to contact either. The area there is quite rough,would be best to stay closer to city centre. I really feel like we got no value for our money!!
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5550 N FRANSON LN Oakley, UT 84055
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Estimated Monthly Payment$5,051
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- Status: Active
Listing courtesy of Discovery Properties
Gorgeous 8,000 sq ft custom home in beautiful Franson Estates on the outskirts of Oakley, it has views for miles & is an easy walk to 29.5 Weber River front acres! 6 bed 4 bath, massive great room + covered deck with outdoor fireplace, office & living room. Includes 12 shares of pressurized irrigation. Fully finished walkout basement -too many custom features to list.
Interior Features Include:
Bath: Master, Closet: Walk-In, Den/Office, Gas Log, Jetted Tub
Basement Walkout
Fireplaces 3
Air Cond: Central Air; Electric
Heating: Forced Air, Gas: Central
Floor Type: Carpet, Natural Rock
Exterior Features Include:
Deck; Covered, Horse Property, Walkout
Acreage: 4.8000 Acres
Lot: Road: Paved, Terrain, Flat, View: Mountain, View: Valley
Landscape Landscaping: Full, Mature Trees
Roof: Asphalt Shingles
Exterior: Stone, Stucco
Garage/Parking: Attached, Extra Width
Driveway Asphalt, Concrete
Garage Capacity: 3
Other Features Include:
Water: Culinary, Irrigation: Pressure
Utilities Gas: Connected, Power: Connected, Sewer: Connected
Storage Garage, Basement
Taxes 5293
School District: South Summit
Information deemed reliable but not guaranteed accurate. Buyer to verify all information.The multiple listing information is provided by Wasatch Front Regional Multiple Listing Service, Inc. from a copyrighted compilation of listings. The compilation of listings and each individual listing are © 2014 Wasatch Front Regional Multiple Listing Service, Inc., All Rights Reserved. The information provided is for consumers, personal, non-commercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing.


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The Meaning of TTTS
You have found the definitive source for the meaning of TTTS. This page contains all the definitions of TTTS, crowd sourced, moderated and curated by real people who care about the true definitions of TTTS.
The Top Definition of TTTS
The most popular meaning of TTTS is: Twin to twin transfer syndrome
What Other Meanings of TTTS Are There?
There are no other definitions for TTTS at this time. Add your own definition of TTTS.
What is TTTS?
TTTS is Twin to twin transfer syndrome
TTTS Means
The definition of TTTS is "Twin to twin transfer syndrome".
TTTS Definition
The meaning of TTTS
TTTS means Twin to twin transfer syndrome.
Now you understand the definition of TTTS - TTTS means "Twin to twin transfer syndrome".
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Why Poetry Matters Review: Reasoning Rhyme
May 19, 2009 by Jack Marland
Filed under - Home, Reviews
WHY POETRY MATTERS, Wednesday 20th May, BBC2, 9pm Alert Me
We live in a country that has one of the richest traditions of poetry found anywhere in the world.
From Shakespeare, Milton and Spencer to the likes of Benjamin Zephaniah, Carol Ann Duffy and Simon Armitage, we are steeped in an astonishingly diverse range of verse which communicates ideas about the world.
Poetry is found in libraries, football terraces and at the hundreds of amateur poetry groups which take place across the country. We are hardwired to appreciate it, yet poetry continues to have the reputation of being either a soppy pastime or an elitist pursuit.
With this idea in mind, poetry enthusiast Griff Rhys Jones sets out to examine what exactly it is about poetry that makes us both love and fear it.
In short, Why Poetry Matters is a celebration of poetry and its ability to convey an extraordinary range of emotion, feeling and interest. Looking at the way children are drawn to incantation and nursery rhymes, Rhys Jones asserts that we're predisposed to appreciate poetry in its various forms. According to poet Simon Armitage the genius of well written poetry is that it taps into an aural subconscious and affects the parts that lesser art forms fail to reach.
The good news is that not only do the British public appreciate good poetry but a surprising number actually engage in it on a regular basis. Up and down the country everyone from schoolboys to grannies are putting down their own thoughts on paper and communicating them to the wider world. People like Dan le Sac and Scroobius Pip have brought performance poetry more mainstream credibility and performance poets also visit primary schools in an effort to teach children about the joys of language.
While clearly infatuated with poetry, Rhys Jones is unfortunately also rather fond of the sound of his own voice. For a show that features snippets from some of the finest verse around, you might think it apt to include readings by some of the finest British actors around. Not Rhys Jones, however, who demonstrates the full range of his oratory prowess to the extent that, for someone who finds his on screen persona a little bit grating, the words get lost under his dramatic warbling.
I left the viewing full of the wonder of words yet I couldn't shake the idea that merely talking about it is missing the point.
Jack McKay


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first edition
by Joseph Turquan
NY: Brentano's 1913 1st ed. 336p., 1913. A blue cloth hardcover book in very good condition. Cover foxed and endpapers discolored. Contains former owner's bookplate but otherwise clean and tight. Biography of the hostess of a salon during the Napoleonic era. Includes black and white plates. (Inventory #: 121755)


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-Book Addict -Cant spend a day without reading books ! -Writer -Artist
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@00Amr has 127 followers on Twitter.
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Ibis Chengdu Yongfeng: Find photos, reviews, information, amenities and compare prices for 3 stars hotels in Chengdu, China.
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THIS IS A DIRECTORY PAGE. Britannica does not currently have an article on this topic.
Learn about this topic in these articles:
3. Unpredictable drought involves an abnormal rainfall failure; it may occur almost anywhere but is most characteristic of humid and subhumid climates. Usually brief and irregular, it often affects only a relatively small area.


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Peter H - 2013-04-23
Excuse the basic question - but when I download a version (say 0.6.4) the contents of pcap.c are nothing like those of the latest version in cvs. I have found an error with the downloaded version in that pcap.c:3445 does:
free((char *) arg1);
when it should be:
from what I can tell. Otherwise I run out of bpf descriptors on Darwin when I use scapy.
However, this line does not exist in the CVS version of pcap.c, so I don't know where the error is coming from and whether it is known to be fixed - and therefore in which released version.


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Find It Friday - Playaway Launchpads
On a shelf in the children's area at both the DeRidder and Merryville branches are some bright orange empty cases. Each branch has its own different collection of titles.
However, if you take one of those cases to the circulation desk and check it out, the clerk will place in it a Playaway Launchpad tablet. These tablets have educational software aimed at young children. They cannot connect to the Internet and have rubber bumpers to keep children safe while they explore and learn.
Each comes with a charger as well, so that your kid can play for two weeks of exploring and learning. Give your child the active learning experience soon! They do circulate on a first come, first served basis, so you cannot reserve one, but from time to time, the two collections get mixed around so you can find new ones.
Staff Picks
Need a suggestion for something to read or watch from the library this weekend? Maybe you'd like to check out an ebook or audiobook? Try some of our Staff Picks, to find what some of the other people in our parish are enjoying.
We know that not every staff pick will appeal to every patron, but not to worry! If you need help selecting something, we have online tools like Book Browse and our Online Catalog, or you can ask one of our friendly staff members to help search for you.
Murder at the Courthouse by Ann H. Gabhart
Nothing ever happens in Hidden Springs, Kentucky. Nothing, that is, until a dead body is discovered on the courthouse steps. What a welcome to Hidden Springs. 'Murder at the Courthouse' written by A.H. Gabhart is a cozy mystery complete with charming and quirky characters. Small town America at its best. A few twists will keep you wondering "whodunit". I hope you will check this book out and enjoy it as I did. This is Book 1 of 'A Hidden Springs Mystery' Series. I have put in a request for the second book in this series and am looking forward to visiting Hidden Springs again.
If Murder at the Courthouse interests you, feel free to request or check it out.
Merryville and Singer Closing Early
The Merryville branch is closing early today (10:00) due to urgent maintenance needs.
The Singer branch is also closing early today (1:55) due to a large-scale power outage and subsequential lack of heat.
We sincerely apologize for any inconvenience this causes and expect to be back to our normal branch schedule tomorrow. If you need assistance, please call us at 337-463-6217.
♬The Music Minute♬
Free Christmas music from Freegal, the free and legal website that gives you 5 free downloads per week and 3 free hours daily of commercial-free streaming music paid for by the Beauregard Parish Library. Freegal has many of your favorite artists singing new music and old classics. There are also many albums with different artists for a varied Christmas play-list. Or you could make your own play-list by downloading songs or create a play-list on the Freegal website.
From Sing-Along with the Very Best of Christmas Music:
❄For a beautiful sacred carol try "The Star Carol" sung by Simon & Garfunkel. This soft and gentle song tells the story of the manger scene.
❄"The Little Drummer Boy" sung by The Harry Simeone Chorale-the song about the boy who had no gift for baby Jesus so he played his drums.
❄"Silent Night"- a powerful, exquisitely expressive version sung by Mahalia Jackson.
❄"O Holy Night" sung by the Ray Conniff Singers.
❄"Do You Hear What I Hear?" sung by Bing Crosby.
❄"Mary's Boy Child" sung by Harry Belafonte.
❄You can hear the traditional instrumental "Sleigh Ride" by Leroy Anderson or on this album try the Rockin' surfer sound of The Ventures.
❄"It's the Most Wonderful Time of the Year" sung by Andy Williams.
❄"Here Comes Santa Claus" sung by Gene Autry.
❄"White Christmas" sung by Rosemary Clooney. (The library owns the movie.)
❄"It's Beginning to Look a Lot Like Christmas" sung by Perry Como.
❄"We Wish You A Merry Christmas" sung by the warbling folk sound of The Weavers.
❄"It's A Marshmallow World" sung by Brenda Lee.
❄"Winter Wonderland" sung by Johnny Mathis.
❄"Happy Holiday" sung by Steve Lawrence & Edie Gorme.
❄"All I Want for Christmas is My Two Front Teeth" -a song where someone is imitating a child who whistles when he sings because he is missing his two front teeth-Spike Jones.
❄Elmo & Patsy's "Grandma Got Run Over By A Reindeer". The title says it all. I would like to describe the song but I can't, and I shouldn't, so I won't.
❄"Monster's Holiday" sung by Bobby "Boris" Pickett and the Crypt Kickers, a song of how the monsters want to rob Santa's sleigh. But before they can, Santa's down the chimney and giving them presents like werewolf fangs and bat wings and a new speed shaver for Wofman.
❄"I Saw Mommy Kissing Santa Claus" (scandalous) sung by Molly Bee.
Just Arrived
Did you know that there is an entire cookbook devoted to bacon? Many people avoid this delicious food because of its reputation as being "unhealthy". But recently several diet plans including the Atkins and Paleo programs have embraced it due to its high saturated fat content and omega-3 fatty acids, as well as its low carb protein. It will probably never be considered a health food, but it may not be as bad as previously thought.
If you are like the authors of one of the books we received last week and believe that bacon makes everything better, check out Bacon Freak: 50 Savory Recipes for the Ultimate Enthusiast by Rocco Loosbrock, Sara Lewis and Dawn Hubbard. This book shows how to use bacon in new and exciting ways for breakfast, lunch, dinner, dessert, and more. It even tells how to cure your own bacon, if you prefer that to buying it at the store. There are tips on how to cook bacon properly on the stove or in the oven or microwave.
And then there are the recipes! Check out: Bacon Weave Chorizo Breakfast Burrito, Candied Bacon, Bacon-Wrapped Fried Ravioli, Creamy Bacon Lasagna, Salted Caramel Bacon Pie Bites and even Bacon Apple Pie Nachos. Some of the dishes sound very unusual, but if you love bacon, and are a little adventurous, there is plenty here to keep you busy.
The book concludes with a section telling about how the bacon phenomenon has swept the country and gives a list of the many bacon-themed festivals that were held last year. There are also bits of "bacon trivia" and a guide to the types of bacon travelers might encounter on their journeys around the world.
DeRidder Branch Closed Tomorrow
The DeRidder branch of the Beauregard Parish Library will be closed Saturday, December 3, 2016 for the Miracle on Washington festival. All other branches of the Beauregard Parish Library will be open according to their regular Saturday hours.
Find It Friday - Columbia Granger World of Poetry
Columbia Granger's World of Poetry is a wonderful resource for finding wonderful words that just roll off the tongue! Even though it's listed on our Online Research, poetry can be a relaxing way to occupy your mind and even help improve your memory.
Some favorites include:
- Abou Ben Adhem by Leigh Hunt
- Song of Fairies Robbing An Orchard by Thomas Randolph (trans. by Leigh Hunt)
- Stopping by Woods on a Snowy Evening by Robert Frost
- Twilight Turns From Amethyst by James Joyce
- Jabberwocky by Lewis Carroll
- The Raven by Edgar Allen Poe
- Rime of the Ancient Mariner by Samuel Taylor Coleridge
See if you can find an old favorite of yours in their search engine. Try various song lyrics to find the poems the musicians used as inspiration!
WiFI at Home
Take WiFi Home for a Week!
Beginning Monday, December 5, BPL will have HotSpots available for checkout so you can take our WiFi home with you for a week.
A HotSpot is a device about the size of a deck of cards that uses T-Mobile's data network to provide unlimited wireless internet access for up to 5 devices at a time. While we cannot guarantee coverage everywhere in the parish, our tests show that most of the parish is covered by our provider's network.
Give the HotSpot a shot and, if it works in your home, use the free WiFi connectivity to prepare for important presentations or homework assignments, apply for jobs online, or just to enjoy online entertainment. Or, if you're taking the camper for a long-weekend trip or traveling for work, why not see if you can bring free internet access with you?
Supplies are limited as we test this new service and they are provided on a first-come-first-serve basis, so please be patient. Adults who have had their card 6 months or longer and have an account in good standing are welcome to checkout a HotSpot (one per household) for a week at a time. For more details, call us at 337-463-6217 or 800-524-6239 within Beauregard Parish or drop by your nearest Beauregard Parish Library branch.
Public Notice
Board Finance Committee Meeting
The Library Board's Finance Committee will meet at our DeRidder branch (205 S. Washington Ave.) on Wednesday, November 30, 2016 at 4:35 pm. This meeting is open to the public pursuant to La R.S. 42:14.
I. Call to order & roll call
II. Review, discuss, and adopt a capital expense budget proposal
III. Review, discuss, and adopt a budget proposal for FY 2017
IV. Adjourn
♬The Music Minute♬
Free Christmas Music
Start collecting your Christmas Music now! There is plenty of free Christmas music on Freegal, the free website paid for by the Beauregard Parish Library. You get 5 free downloads a week that are yours to keep on your computer or transfer to your devices. If you just want to listen, you also get 3 hours a day of streaming music commercial-free. You can even make your own play-list on Freegal without having to download. You can find Freegal on your library home page under the Electronic Library Icon.
Freegal has hundreds of Christmas albums and songs to choose from. Just put under Albums in the search bar the word Christmas and the artist name. For example: enter Christmas Elvis Presley and you will get several of his Christmas albums and his songs on albums with various artists. These albums include his hits "Blue Christmas" and "Holly Leaves and Christmas Trees".
You will find both sacred and secular music from your favorite artists like: Jackie Evancho's latest Christmas album Someday at Christmas, Loretta Lynn's new Christmas album White Christmas Blue, Barbara Streisand with her frantic syncopated version of "Jingle Bells", Mariah Carey's Merry Christmas with her 60's type hits "All I Want For Christmas Is You" and "Christmas (Baby Please Come Home)". Or maybe you would like the groovy version of "Jingle Bells" by The Partridge Family on A Partridge Family Christmas. Why are you laughing? It's a far out version of the song.
There are many other famous artists with Christmas albums like: Kelly Clarkson, Sara Evans, Martina McBride, Susan Boyle, Celtic Thunder, Dean Martin, Sean Kingston, Kenny Chesney, David Archuleta, Clay Aiken and R.Kelley.
Just Arrived
Now that Thanksgiving is over, many of us are in the Christmas spirit. If you are in that frame of mind and are looking for a quick, fun, Christmas-themed book to read, we have some new ones that might interest you.
For fans of Inspirational Romance, check out His Holiday Matchmaker by Kat Brookes. Widowed builder Nathan Cooper's six year old daughter wants only one thing for Christmas – a new mother. But Nathan doesn't want to risk any more heartache for either of them. When interior designer Alyssa McCall comes to town, both he and his daughter are charmed. As they work together, Nathan and Alyssa form a connection, but Alyssa worries that she can't be the mother little Katie needs. Katie, and her handsome father, are determined to prove her wrong and this could be a Christmas to remember.
If mystery is more your style, try Feliz Navidead by Ann Myers. Chef Rita Lafitte of Santa Fe's Tres Amigas Cafe hopes that the twinkling lights and tasty treats of the season will charm her visiting mother. She has several fun activities planned, including watching her teenage daughter perform in an outdoor Christmas play. But she didn't plan on murder. When she discovers a dead actor during the premier performance, she vows to stay clear of the case. Sleuthing would really upset her mother and there is already a prime suspect, caught red-handed in his bloody Santa suit. When Santa's wife begs her for assistance and points out that the other actors, including Rita's daughter, could be in danger, Rita can't refuse. Will she be able to salvage her mother's vacation, unmask a murderer, and stop the festive season from becoming more deadly?
Perhaps you prefer a western. If so, A Colorado Christmas by William W. Johnstone with J.A. Johnstone is for you. At the Sugarloaf Ranch, Smoke and Sally Jensen prepare to welcome their friend Preacher home for the holidays. But all sorts of troubles are brewing. Preacher is being chased by a gunfighter out to kill him. Bounty hunter Luke Jensen is after a different criminal. Ace and Chance Jensen have rescued an old trapper from some ruthless outlaws and another criminal mastermind is gathering a vicious gang of cutthroats to extract his final revenge on his enemies. Now with a snowstorm coming and a showdown ready to explode, these friends will be drawn together to try to forge peace on earth. But they will have to fight for it with their guns drawn.
Closed for Thanksgiving
All branches of the Beauregard Parish Library will be closed Thursday, November 24, 2016; Friday, November 25, 2016; and Saturday, November 26, 2016 in observance of Thanksgivingl
For your convenience, no items are due during holiday closures, and no fines will accrue. All branches of the Beauregard Parish Library will return to their regular hours of operation Monday, November 28, 2016.
Do You Hear What I Hear
Are you dreading the "sounds of the holidays:"
the kids making a ruckus?
Uncle Jim talking politics?
Aunt Mabel's organ recitation?
Look no farther! We can help!
Stop by your library and check out a Playaway today and get a free kit including a lanyard, batteries, and card holder.
Playways are compact, self-contained audiobooks that are easy to use and even easier to check out at your library!
Branches are on their regular schedules today, so you can stop in and get help picking out your own sounds for the holidays.
Gobble Up Some Good Reads
The whole family is coming together this week. What could be better than a family story time?
Stop by your local branch or browse our e-book collection available here on our website.
We have children's books in a variety styles, formats, and reading levels. We even have Tumble Books which do all of the reading work for you as you follow along!
Tumble Books also offers games and puzzles to keep the family content and engaged.
And remember, the family that reads together waits patiently for turkey together!
♬The Music Minute♬
Thanksgiving/Autumn Free Music
Freegal, the free and legal music service that gives you 5 free music downloads a week and 3 free hours daily of commercial-free streaming music has some Thanksgiving songs and some Autumn music for your enjoyment.
There is the traditional Thanksgiving song "Over the River and Through the Wood" written in 1844 by Lydia Marie Child. Or the traditional Thanksgiving hymn "We Gather Together".
For a nice autumn song there is "Autumn Leaves" sung by Doris Day with Paul Weston & his Music from Hollywood on the album Day By Day or an instrumental version by Les Baxter on 14 Unforgettable Songs.
Or there is the old song "Autumn in New York" by many people such as Tal Farlow from Jazz Relaxing, Claud Williamson Trio on Autumn in New York, Harry Happel on Solo Piano: Jazz at the Pinehill, Jo Stafford on The Best Songs 1940-1950, Frank Sinatra on The Complete Hits 1943-1962 Vol.2, Ella Fitzgerald & Louis Armstrong from Ella Fitzgerald & Louis Armstrong: 15 Unmatched Songs.
There is the album Songs for Thanksgiving which has many old-timey food songs. Some of them take place during the war rationing when you had to have ration stamps or tickets to get certain things like butter. The album features various artists on songs like: "Home Cookin'", "Please Leave My Butter Alone"(that's right, someone keeps pinching her butter), "One Meat Ball" (a sad little blues song about a man with only .15 and all he can afford is one meatball), "Sunshine Cake", and"Everything Stops for Tea". There are also instrumentals that will bring a spring to your step as you cook (or defrost) those Thanksgiving pies such as "Shoo Fly Pie and Apple Pan Dowdy","Ma, I Miss Your Apple Pie", "Dunkin' a Doughnut", and "Let's Have Another Cup of Coffee".
There are plenty of Thanksgiving Day albums for kids that have a variety of activity songs (that don't have anything to do with Thanksgiving) that might keep the kids entertained.
Whatever your music needs or wishes try exploring Freegal and have a nice Thanksgiving.
Just Arrived
Even though it's not Thanksgiving yet, many people are starting to get in the Christmas spirit. The Hallmark Channel has started showing its many holiday themed movies that many of our patrons seem to enjoy. Each year we add to our collection of these heartwarming films on DVD. Check out a few that arrived this week:
Christmas With Tucker. George, a thirteen year old boy, struggles to deal with the death of his father. He develops a friendship with a dog named Tucker that helps him in this struggle. When he is afraid he might lose the dog, he makes a poor decision in his attempt to hold onto him. He feels guilty and attempts to correct his mistake, but this may cost him the best friend he has ever had.
A Christmas Melody. Single mother Kristin and her daughter Emily move from New York back to her hometown in Ohio in order to start over in her parents' old home. It's a difficult adjustment for both of them, made worse when Kristin's old high school rival makes trouble for them. With the help of the school music teacher and Kristin's aunt, along with some holiday magic and music, they soon discover that home is where the heart is.
A Crown for Christmas. After being fired from her job as a maid, Allie takes a job in Europe as a governess for a young princess who lives in a castle. The child's father, King Maximillian, tells Allie that his daughter tends to terrorize authority figures and has gotten worse since the death of her mother. Despite this, Allie and the princess manage to get along and become close. And soon a spark begans to develop between Allie and the king. But there is a countess who is expecting to marry the king. The king will have to stand up for his feelings if they are all to have a truly merry Christmas.
Find It Friday - The New Books Shelves
You're looking for that book that just came out a couple of months ago. Our card catalog computer says we have it, and that it's available for checkout at the DeRidder branch. You search the shelves top to bottom, but it's just not there!
Well, it's probably up in our New Books shelves, off to the side of the circulation desk. New books that the Library acquires are put there for 2-6 months, depending on the collection they belong in. They're also a nice place to just see what has shown up lately. Perhaps there's a new book by an author you adore that you didn't hear about!
Of course, you don't want to spend all of your time in the New Books shelves. There's a lot of hidden and forgotten gems in the regular stacks, just waiting to be discovered. You can find out about some of them from our Staff Picks, on this same blog.


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All quotes tagged Love - Plato
(20000 quotes found)
"The Bermuda grass stock has risen. Everyone we talked to in Baltimore loved the grass and had not encountered any problems with it."
"When you figure out the face beneath the mask, the mystery is gone. All that is left is to touch his soul, without notice.""
"To hear them sing, I couldn't stop crying. The tears just couldn't stop. I just love them so much."
"When the sun rises in the morning and sets in the night. When the moon comes into sight from the east and leaves unto the west. When the stars appear in the night and erase in the morning. One thing that will never leave, that will never move, is me."
"I signed here last summer to come here and (want) to stay as long as I can. I love it here, and I don't want to move. I'm not afraid to admit that."
"Conquering people's hearts through fear only lasts as long as they are afraid. Conquering people's hearts through love lasts a lifetime."


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Your puzzling request for "some ideas for jobs in America" sounds whiny. (And please don't tell me you expect scumbag government to produce "jobs".)
You've been here long enough to (hopefully) have learned that the answer is to get government out of Americans' faces, out their wallets, and out of their way, and let the market economy take care of producing "jobs". In other words, do exactly the opposite of what this selfish, scumbag Democrat union hack Hoffa says to do.
Well I don't think I'm whining when I say very sincerely we ALL need to be 100% for American jobs.
American jobs.


text:
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Learn about this topic in these articles:
effect on Spanish history
...emperors Rudolf II and Matthias, the ambassador Baltazar de Zúñiga organized an effective "Spanish" party. His successor, the conde de Oñate, negotiated the secret Treaty of Graz (1617) by which the Jesuit-educated archduke Ferdinand of Styria (later Emperor Ferdinand II) was designated as heir to Matthias. In return for giving up Philip III's claims to the...


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Showing results 1 - 20 of 1332
But how does it reach the doorbell?
Sneaky, sneaky
Here's how to play
And trying to save your rude photos.
You gotta catch them all... again.
Getting fat is getting a whole lot easier.
A new way to back up printed snaps
Most of them probably Poké clones
Rewarding whichever way you slice it
Goodbye Videos, hello TV
Going Live in 5…4…3…
Celebrate Sir David
Controversial data-sharing paused
Neil Young backs down
Siri could soon talk more proper like
Cheats beware, Google's on to you
Stranger Things have happened
It died as it lived - quickly
If you don't mind the odd bug
Sky Q on the go
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