text:
|Publication number
|Publication type
|Application number
|Publication date
|Jun 26, 1990
|Filing date
|Aug 26, 1988
|Priority date
|Aug 26, 1988
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|Michael Mezei, Adrienn Gesztes
|Original Assignee
|Mezei Associates Limited
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|Patent Citations (19), Non-Patent Citations (57), Referenced by (107), Classifications (8), Legal Events (9)
|External Links: USPTO, USPTO Assignment, Espacenet
1. Field of the Invention
The present invention relates to a method for providing local anesthesia using liposomal encapsulated anesthetic and analgesic drugs.
2. Description of Related Art
Liposomes are lipid vesicles composed of membrane-like lipid layers surrounding aqueous compartments. Liposomes are widely used to encapsulate biologically active materials for a variety of purposes, e.g. they are used as drug carriers. Depending on the number of lipid layers, size, surface charge, lipid composition and methods of preparation various types of liposomes have been utilized.
Multilamellar lipid vesicles (MLV) were first described by Bangham, et al., (J. Mol. Biol. 13:238-252, 1965). A wide variety of phospholipids form MLV on hydration. MLV are composed of a number of bimolecular lamellar interspersed with an aqueous medium. The lipids or lipophilic substances are dissolved in an organic solvent. The solvent is removed under vacuum by rotary evaporation. The lipid residue forms a film on the wall of the container. An aqueous solution generally containing electrolytes and/or hydrophilic biologically active materials are added to the film. Agitation produces larger multilamellar vesicles. Small multilamellar vesicles can be prepared by sonication or sequential filtration through filters with decreasing pore size. Small unilamellar vesicles can be prepared by more extensive sonication. An improved method of encapsulating biologically active materials in multilamellar lipid vesicles is described in U.S. Pat. No. 4,485,054.
Unilamellar vesicles consist of a single spherical lipid bilayer entrapping aqueous solution. According to their size they are referred to as small unilamellar vesicles (SUV) with a diameter of 200 to 500 A; and large unilamellar vesicles (LUV) with a diameter of 1000 to 10,000 A. The small lipid vesicles are restricted in terms of the aqueous space for encapsulation, and thus they have a very low encapsulation efficiency for water soluble biologically active components. The large unilamellar vesicles, on the other hand, encapsulate a high percentage of the initial aqueous phase and thus they can have a high encapsulation efficiency. Several techniques to make unilamellar vesicles have been reported. The sonication of an aqueous dispersion of phospholipid results in microvesicles (SUV) consisting of bilayer or phospholipid surrounding an aqueous space (Papahadjopoulos and Miller, Biochem. Biophys. Acta., 135: 624-238, 1968). In another technique (U.S. Pat. No. 4,089,801) a mixture of a lipid, an aqueous solution of the material to be encapsulated, and a liquid which is insoluble in water, is subjected to ultrasonication, whereby liposome precursors (aqueous globules enclosed in a monomolecular lipid layer), are formed. The lipid vesicles then are prepared by combining the first dispersion of liposome precursors with a second aqueous medium containing amphiphilic compounds, and then subjecting the mixture to centrifugation, whereby the globules are forced through the monomolecular lipid layer, forming the biomolecular lipid layer characteristic of liposomes.
Alternate methods for the preparation of small unilamellar vesicles that avoid the need of sonication are the ethanol injection technique (S. Batzri and E. E. Korn, Biochem. Biophys. Acta. 298: 1015-1019, 1973) and the ether injection technique (D. Deamer and A. D. Bangham, Biochem. Ciophys. Acta. 443: 629-634, 1976). In these processes, the organic solution of lipids is rapidly injected into a buffer solution where it spontaneously forms liposomes--of the unilamellar type. The injection method is simple, rapid and gentle. However, it results in a relatively dilute preparation of liposomes and it provides low encapsulation efficiency. Another technique for making unilamellar vesicles is the so-called detergent removal method (H. G. Weder and O. Zumbuehl, in "Liposome Technology": ed. G. Gregoriadis, CRC Press Inc., Boca Raton, Florida, Vol. I, Ch. 7, pg. 79-107, 1984). In this process the lipids and additives are solubilized with detergents by agitation or sonication yielding defined micelles. The detergents then are removed by dialysis.
Multilamellar vesicles can be reduced both in size and in number of lamellae by extrusion through a small orifice under pressure, e.g., in a French press. The French press (Y. Barenholz; S. Amselem an D. Lichtenberg, FEBS Lett. 99: 210-214, 1979), extrusion is done at pressures of 20,000 lbs/in at low temperature. This is a simple, reproducible, nondestructive technique with relatively high encapsulation efficiency, however it requires multilamellar liposomes as a starting point, that could be altered to oligo- or unilamellar vesicles. Large unilamellar lipid vesicles (LUV) can be prepared by the reverse phase evaporation technique (U.S. Pat. No. 4,235,871, Papahadjopoulos). This technique consists of forming a water-in-oil emulsion of (a) the lipids in an organic solvent and (b) the substances to be encapsulated in an aqueous buffer solution. Removal of the organic solvent under reduced pressures produces a mixture which can then be converted to the lipid vesicles by agitation or by dispersion in an aqueous media.
U.S. Pat. No. 4,016,100, Suzuki et al., describes still another method of entrapping certain biologically active materials in unilamellar lipid vesicles by freezing an aqueous phospholipid dispersion of the biologically active materials and lipids. All the above liposomes, made prior to 1983, can be classified either as multilamellar or unilamallar lipid vesicles. A newer type of liposomes is referred to as multivesicular liposomes (S. Kim, M. S. Turker, E. Y. Chi, S. Sela and G. M. Martin, Biochim. Biophys. Acta. 728: 339-348, 1983). The multivesicular liposomes are spherical in shape and contain internal granular structures. A lipid bilayer forms the outermost membrane and the internal space is divided up into small compartments by bilayer septrum. This type of liposomes required the following composition: an amphiphatic lipid with net neutral charge, one with negative charge, cholesterol and a triacylglycerol. The aqueous phase containing the material to be encapsulated is added to the lipid phase which is dissolved in chloroform and diethyl ether, and a lipid-in-water emulsion is prepared as the first step in preparing multivesicular liposomes. Then a sucrose solution is shaken with the water-in-lipid emulsion; when the organic solvents are evaporated liposomes with multiple compartments are formed.
For a comprehensive review of types of liposome and methods for preparing them refer to a recent publication "Liposome Technology" Ed. by G. Gregoriadis., CRC Press Inc., Boca Raton, Florida, Vol. I, II, and III 1984.
Liposomes, vesicles of phospholipid membranes, have been studied in recent years as a way of altering the pharmacokinetic properties of encapsulated drugs. A few studies have focused on their potential as drug carriers in topical preparations, for example involving corticosteriods, econazole, progesterone and methotrexate. Liposomal formulations of these materials were found which when applied topically delivered more of these drugs into the skin than conventional vehicles, (enhanced penetration) while at the same time localizing their effect at the desired site of action (enhanced localization) (M. Mezei in "Liposomes as Drug Carriers" ed. G. Gregoriadis, John Wiley & Sons Ltd., New York 1988, pages 663-677).
Topical anesthetics are agents that reversibly block nerve conduction causing numbness and cessation of pain even after major stimuli. A topical analgesic agent is a substance which relieves pain without necessarily causing numbness, or which can relieve topical pain of a minor nature, but not of a great degree (Fed. Register 44, 69768-69866, 1979). These drugs are therefore used to treat or prevent pain. For operations of a peripheral or minor nature involving the skin, like removal of superficial skin lesions and plastic surgery, or intradermal allergen testing, split skin grafting, treatment of painful ulcers, venipuncture--the ideal way of anesthesia would be the topical application of local anesthetics.
The commercially available topical anesthetic preparations however, are not completely suitable for this purpose. Studies of Dalili and Adriani (Clin. Pharm. Ther., 12: 913-919, 1971) provided the first experimental evidence that manufactured preparations containing local anesthetics intended for use on the surface of the skin often lack a desired degree of efficacy. The preparations were tested on normal skin and on ultraviolet light burned skin for the ability to block itching and pricking induced by electrical stimulation. The only preparation judged sufficiently effective was one containing 20% benzocaine. But even the effect of this preparation disappeared within 60 seconds after it has been wiped off the test site. The authors indicated several possible reasons for the lack of efficacy, including the low concentration of the active ingredient, possible chemical change or interaction, for example, with other components and the penetration-preventing effect of the vehicle formulation used (J. Adriani and H. Dalili., Anesth., Analg. 50: 834-841, 1971).
At present, the most successful commercially available preparation for dermal anesthesia is a lidocaine-prilocaine cream, first reported by Juhlin et al. (Acta Derm Venereol. 59: 556-559, 1979). The cream consists of an emulsion containing 5% by weight of the eutectic mixture of lidocaine and prilocaine bases (EMLA) in water, thickened with Carbopol� (G. M. E. Ehrenstrom Reiz and SLA Reiz., Acta Anaesth. Scand., 26: 596-598, 1982). An application time of 60 minutes under occlusion achieves complete anesthesia to pin-pricks, and the anesthetic effect lasts one to two hours (H. Evers et al., Br. J. Anaesth., 58: 997-1005, 1985).
In general, to achieve adequate local anesthesia of the skin using known preparations, a relatively excessive amount of drug, a prolonged application period or invasive methods are required. For adequate surgical anesthesia, the local anesthetic must be injected subcutaneously in order to reach sensory nerve endings lying in the dermis. When injecting a local anesthetic, pain is produced by the needle's penetration and by the deposition of the anesthetic solution. Distortion of the wound or performing the infiltration of large areas can also be problems in surgical cases (L. Juhlin, H. Evers, and F. Broberg., Acta Derm. Venereol., 60: 544-546, 1980).
In contrast to anesthetizing the skin, anesthesia of mucous membrane covered surfaces can be produced by topical application of local anesthetics quickly and easily. Unfortunately, rapid absorption of the local anesthetic through these surfaces into the circulatory system may reduce the duration of local anesthetic action, and since these drugs have low therapeutic ratios, may possibly cause systemic toxicity (J. A. Wildsmith, A. P. Rubin and D. B. Scott., Clin. Anaesth., 4: 527-537, 1986).
Thus, there is a continuing need in the art of local anesthesia for a preparation that is safe, yet effective on either unbroken skin, or on mucous membranes which provides a proper rate of drug permeation without discomfort or a risk of systemic reactions.
Local anesthetic agents previously have been encapsulated into liposomes. (Papahadjopoulos et al., Biochim. Biophys Acta, 394: 504-519, 1975). However, the liposome encapsulated local anesthetic was not used for producing local anesthesia or analgesia but rather was prepared as a way of studying the drug's mechanism of action, i.e. the interaction of the local anesthetic with the phospholipid bilayers, which in effect served as a model for a cellular membrane.
The present invention broadly relates to the use of liposomes for improving the effect on a mammal of topically applied preparations of local anesthetics and analgesics by enhancing the penetration (i.e. increasing cutaneous absorption) and localization (i.e. decreasing systemic absorption) of the anesthetic and analgesic agents.
The present invention may be used to provide local anesthetic and analgesic treatment for both human and veterinary purposes. Local anesthetics, as amphipathic agents, are good candidates for entrapment in the phospholipid bilayers of a liposome. Any anesthetic and analgesic agent or drug suitable for topical or local application can be used in the present invention including benzocaine, xylocaine, ketocaine, methyl salicylate, trolamine salicylate, lidocaine, prilocaine, tetracaine, pramoxine (tronothane) and dibucane. Tetracaine is a particularly useful agent because it is a potent topical anesthetic and owing to its relatively large hydrophobic moiety, it is easily encapsulated by phospholipid bilayers.
The amount of the anesthetic or analgesic agent or drug to be included in the liposomal preparation is not, per se, critical and can vary within wide limits depending inter alia on the particular agent, the intended application and the lipid used. Generally, the anesthetic or analgesic agent may be included in an amount of between about 0.1 to 10% by wt. of the liposomal preparation and more usually may be included in an amount of between 0.3 and 5.0% by wt.
Materials and procedures for forming liposomes are well-known to those skilled in the art and need not be described herein in detail. Reference is made to U.S. Pat. Nos. 4,485,054 and 4,761,288, which are hereby incorporated by reference, for a disclosure of preferred preparation techniques. Generally, the desired anesthetic or analgesic agent to be encapsulated is dissolved or dispersed in a lipid-containing organic solvent. Phospholipids are particularly useful, such as those selected from the group consisting of phosphatidylchloines, lysophosphatidylchloines, phosphatidylserines, phosphatidylethanolamines, and phosphatidylinositols. Such phospholipids often are modified using for example, a modifying agent selected from the group consisting of cholesterols, stearylamines and tocopherols. The solvent then is evaporated, typically under a reduced pressure, to yield a thin lipid film containing the anesthetic or analgesic. Afterwards, the film is hydrated, with agitation, using a aqueous phase containing any desired electrolytes and lipid vesicles entrapping the anesthetic or analgesic are produced. As recognized by those skilled in the art, while certain materials and procedures may give better results with certain drugs, the use of particular materials and procedures are not narrowly critical and optimum conditions can be determined using routine testing. Although some of the liposome formulations acquire a gel-like consistency upon cooling to room temperature in the absence of any adjuvants, the present invention contemplates the use of conventional thickeners and gelling agents to provide a preparation having any desired consistency for topical application. Additionally, a preservative or antioxidant often will be added to the preparation.
A particular feature of the present invention is that a more pronounced cutaneous anesthetic or analgesic effect is obtained in the patient with a smaller amount of the active anesthetic or analgesic agent than compared with prior topical preparations. While not wishing to be bound to any theory, it is thought that the lipid vesicles facilitate transport of the anesthetic or analgesic drug through the stratum corneum barrier. Thus, preparations containing from 0.1 to 3.0% by wt. of the anesthetic or analgesic agent may be useful. The low drug concentration should permit its use as a safe and effective over-the-counter medication for painful skin disorders. In most cases, the anesthetic or analgesic agent comprises from about 5 to about 25% by wt. of the lipid, i.e. the phospholipid, neutral lipid, surfactant or similar material having the amphiphilic character needed to form the lipid vesicles.
The amount of the liposomal preparation to be applied to the patient can vary within wide limits depending inter alia an the particular site of application and the desired duration of effect. Generally, application of between about 0.005 to 0.5 g of liposomal preparation per square centimeter of surface to be anesthesized should be sufficient, with an amount of between 0.01 to 0.05 g/cm2 being useful in many cases. Preferably, the liposomal preparations of the present invention are applied topically under occlusion to obtain enhanced effect.
The following examples are illustrative of the present invention and are not to be regarded as limitating. In the examples, several anesthetic agents, e.g. benzocaine, lidocaine, prilocaine, lidocaine-prilocaine eutectic mixtures, tetracaine and dibucaine, were encapsulated into liposomes using the procedure described in Mezei et al. U.S. Pat. No. 4,485,054. In order to increase the effective concentration of the encapsulated drug, e.g. with benzocaine, lidocaine and dibucane, where a reduced solubility restricted, to some extent, the upper concentration, the multiphase liposomal drug delivery system described and claimed in Mezei, U.S. Pat. No. 4,761,288 was utilized. Most of the time the base (and not the salt) of the anesthetic agent was used for preparing the liposomal product. It should be understood that all of the parts, percentages, and proportions referred to herein and in the appended claims are by weight unless otherwise indicated. The following examples demonstrate the formulas and the activity of selected anesthetic agents in liposome form versus ointment or cream form.
______________________________________Formula:______________________________________TetracaCine (base) 0.5 gSoy phosphatidylcholine 7.0 gCholesterol 0.5 gStearic acid 0.7 gEthanol (95%) 10.0 mlPropylene glycol 7.0 mlSolution of sodium chloride 83.0 ml(0.45 wt. %) and sodiumbicarbonate (0.65 wt. %)______________________________________
The tetracaine base (pharmacopoeal grade), phosphatidylcholine (NC-95-H, American Lecithin Co., Atlanta, Georgia), cholesterol (Sigma Chem. Co.) and stearic acid (Fisher Scientific Co.) were dissolved in a chloroform:methanol (2:1 v/v) solvent solution in a pear-shaped flask, and small glass beads (100 g) were added. The solvent was evaporated to dryness in a rotary evaporator at 30� C. and under a reduced pressure, until a smooth, thin lipid film was obtained on the surface of the flask and the glass beads. The film then was hydrated with an aqueous phase prepared by mixing the aqueous solution of 0.65 wt. % NaHCO3, and 0.45 wt. % NaCl, the ethanol and the propylene glycol, by shaking for 30 minutes in a Lab-Line Orbit Environ-Shaker at 55� C. The liposomes were separated from the glass beads by filtering the hydrated preparation through a Buchner funnel without using filter paper.
______________________________________Formula:______________________________________Lidocaine 2.0 gSoy phosphatidylcholine 9.0 gTocopherol acetate 0.24 gHydroxypropylmethylcellulose 1.5 gAqueous solution of sodium 100.0 mlchloride (0.45 wt. %) andsodium bicarbonate (0.65 wt. %)______________________________________
The lidocaine, soy phosphatidylcholine and tocopherol acetate were dissolved in a chloroform:methanol (2:1 v/v) solvent solution in a pear-shaped flask containing 100 g of small glass beads. The solvent was evaporated in a rotary evaporator at 30� C. and under reduced pressure until a thin, smooth film of the lipid and lidocaine was obtained on the surface of the glass beads and the wall of the flask. The resulting lipid film was hydrated at 55� C. using the aqueous sodium chloride and sodium bicarbonate solution in an environment shaker for 30 minutes. The hydroxypropylmethylcellulose was added to the preparation within 5 seconds after the lipid film and aqueous solution were mixed.
______________________________________Dibucaine 1.0 gSoy phosphatidylcholine 8.0 gTocopherol acetate 1.0 gHydroxypropylmethylcellulose 1.0 g80een � 1.0 gCaCl2 solution 0.8 mM 100.0 ml______________________________________
The method of preparation was substantially the same as that described above for Example 2; Tween�-80 was added last to the liposomal product.
In a manner similar to the preceding examples, several other compositions were prepared using:
(a) different local anesthetic agents (e.g. benzocaine, prilocaine and a lidocaine-prilocaine eutectic mixture) with various concentrations of the active ingredient (i.e., 0.5 to 5 wt. %);
(b) phosphatidycholines of different origin and at various concentrations (i.e., 2-15 wt. %);
(c) cholesterol or tocopherol lipid vesicle modifiers in different concentrations (i.e., 0.5-5 wt. %);
(d) buffer solutions with various pH's and electrolyte contents;
(e) various viscosity inducing agents (e.g. methylcellulose, Carbopol�, etc.) and
(f) various preservatives or antioxidant agents (e.g. benzoic acid, methyl and propyl paraben butylated hydroxyanisole (BHA), benzylalcohol, etc.);
The efficacy of the various local anesthetic agent preparations were tested in liposomal form against a commercial cream preparation or an ointment prepared using the same drug.
A protocol for human experiments was approved by the Ethics Committee for Human Research of the Faculty of Health Professions of Dalhousie University, Halifax, Canada. Healthy adult volunteers with no skin disorders or previous history of allergic sensitivity to local anesthetics were asked to participate in the study. Twelve subjects in each experimental group having ages ranging from 25 to 60 years were investigated.
Liposomal preparation containing about 0.5 wt. % tetracaine base (formula as Example No. 1) and Pontocaine� cream (tetracaine hydrochloride cream U.S.P., equivalent to 1% tetracaine base, manufactured by Winthrop Laboratories Aurora, Ontario, Lot No. 120 BL) were compared. A 0.2 ml volume of the liposomal preparation was applied to a 10 cm2 area marked by ink on the volar surface of one forearm of each of the volunteers and covered with Blenderm� tape (3M Co., St. Paul, Minnesota) to form an occlusive dressing. The same amount of Pontocaine� cream was applied to the other arm of each volunteer in the same manner. The samples of the liposomal preparation and the commercial preparation were randomly numbered, and the number of applied preparations recorded for each subject. The identity of the preparations was not known for the subjects or for the evaluator so as to maintain the "double blind" study design.
The samples were applied for 30 minutes in the first group of volunteers and for 60 minutes in the second group. After each of these time intervals the covering tape was removed and the tested area wiped dry with a tissue paper. Onset and duration of anesthesia at the test sites were tested using the pin-prick technique, described in detail by Lubens et al. (Am. J. Dis. Child., 128: 192-194, 1974). At each test period, each skin test area was pricked ten times using a relatively blunt sterile needle, to allow each subject to discriminate between the perception of touch and pain. Ten painless pricks at the time of the test was indicative of complete anesthesia. Sensitivity for each subject was confirmed by pin-pricking near to the test site areas before applying the samples to be tested. Testing score indexes were obtained from each of the volunteers by noting the number of painfree pin-pricks out of the 10 in both test areas. Testing was done immediately after the preparations had been removed from the test site, and then at 30 min., 1 h, 2 h, and 4 h afterwards. Results are reported in Tables 1 and 2.
As shown by the results in Tables 1 and 2 the liposome preparation containing 0.5% tetracaine base was effective in producing dermal anesthesia. After the onset of anesthesia the perception of pain was greatly reduced, although the pressure could be felt. The perception of cold also was observed to disappear at the "numb" test sites (by testing with a cold metal rod). Sensitivity of nerve fibers conveying the sensations of pain, cold, warmth, touch and deep pressure to local anesthetic action is differential. This is correlated with the fiber diameter, that increases from the fibers conveying the sensation of pain to those conveying deep pressure. Pain fibers are the first to be blocked, followed by sensations of cold, warmth, touch and deep pressure. Apparently, the absorbed doses in these tests were high enough only to block the pain and cold fibers, having no or little effect on touch or pressure sensations.
The results also show that the duration of application influences the intensity and duration of the anesthetic effect. On removal of the preparation after 30 minutes of application, the anesthesia was less pronounced, than after a one hour period of application. In both cases, the anesthesia effect improved with time after initial application. Since the onset of anesthetic action is not necessarily immediate, the preparation can be dispensed for administration suitably in advance of any painful procedure. A maximum in anesthetic effect was reached in both the 30 minutes and 1 hour application time groups about two hours after removal of the preparation at an average painless score of 8.25 and 9.5 respectively. Approximately, this level of anesthesia was maintained until the end of the experiments. Tests were conducted only up to 4 hours after removal of the preparations, but the anesthesia provided by the present invention was reported by the volunteers to persist longer, from 5 to 8 hours, depending on the application time.
Considerable inter-individual variations were observed in the onset time of action. Painless scores in the 30 minutes and 1 hour period of application time groups at the time of removal were, respectively, at or above 7 in 25% and 50% of all the subjects tested (N=12). Pontocaine cream, the control preparation, was found to be relatively ineffective over the entire test period, in agreement with findings of Dalili and Adriani (Cin. Pharm. Ther., 12: 913-919, 1971).
Statistical analysis of the data by paired t-tests indicated a statistically highly significant difference in favor of the liposomal tetracaine over the commercial preparation (See Tables 1 and 2).
Liposomes with about 2 wt. % lidocaine (preparation as Example No. 2) were compared to a placebo, which consisted of "empty" liposomes with the same composition as that of the active preparation but without lidocaine. A comparison of the 2 wt. % lidocaine liposomes also was carried out with a control, which contained 2 wt. % lidocaine incorporated in Dermabase� as the vehicle. In both groups, the length of application of liposomal and control preparations was one hour. The procedures of Example A were repeated and the results are reported in Tables 3 and 4.
The anesthetic effect of the 2 wt. % lidocaine liposomes compared to the placebo, as measured by the painless scores, is shown in Table 3. Similarly to the tetracaine liposomal preparation, lidocaine encapsulated in liposomes produced anesthesia in the intact skin after topical application.
TABLE 1______________________________________Mean painless scores at different times of observation after aninitial 30 minutes application period under occlusion of 0.5% tetra-caine liposome preparation and Pontocaine � cream.Number of volunteers = 12Statistical analysis by paired t-testsLipsomepreparaton Pontocaine � creamTime Mean SD Mean SD P______________________________________at removal 2.75 3.25 0.25 1.73 0.064430 Min 5.50 3.94 1.08 1.98 0.0117 1 hour 6.75 3.28 1.08 1.68 <0.0001 2 hours 8.25 2.45 1.08 1.31 <0.0001 4 hours 8.33 2.31 0.25 0.62 <0.0001______________________________________
TABLE 2______________________________________Mean painless scores at different times of observation after aninitial 1 hour application period under occlusion of 0.5% tetra-caine liposome preparation and Pontocaine � creamNumber of volunteers = 12Statistical analysis by paired t-testsLipsome preparation Pontocaine � creamTime Mean SD Mean SD P______________________________________at removal 6.25 3.65 0.08 0.29 <0.000130 min 8.08 2.27 0.41 0.99 <0.0001 1 hour 8.83 1.47 0.25 0.62 <0.0001 2 hours 9.50 0.67 0.33 1.15 <0.0001 4 hours 8.75 1.48 0.16 0.57 <0.0001______________________________________
The pain and cold sensations were greatly reduced, but not the perception of pressure. The intensity of the anesthetic effect again continued to increase after the removal of the preparation, and reached its maximum value one hour later. The differences between the placebo and the liposome-encapsulated lidocaine preparation were statistically significant at every time point (Table 3). Similar results to the placebo experiment and to Example A were obtained when liposomal lidocaine was compared to lidocaine in a Dermabase� vehicle (see Table 4).
Table 5 presents and compares the liposomal tetracaine preparation of the present invention with several other anesthestic preparations designed for topical application.
Thus, while certain specific embodiments of the invention have been described with particularity herein, it will be recognized that various modifications thereof will occur to those skilled in the art and it is to be understood that such modifications and variations are to be included within the purview of this application and the spirit and scope of the appended claims.
TABLE 3______________________________________Mean painless scores at different times of observation after aninitial 1 hour application period under occlusion of 2% lidocaineliposome preparation and placeboNumber of volunteers = 12Statistical analysis by paired t-testsLipsome preparation PlaceboTime Mean SD Mean SD P______________________________________at 4.08 4.42 1.08 1.51 0.0337removal30 min 6.08 4.14 1.33 1.92 0.0040 1 hour 7.25 3.86 2.08 2.23 0.0040 2 hours 6.16 3.35 1.58 2.81 0.0062 3 hours 5.33 3.17 1.16 2.04 0.0042______________________________________
TABLE 4______________________________________Mean painless scores at different times of observation after aninitial 1 hour application period under occlusion of 2% lidocaineliposome preparation and 2% lidocaine in Dermabase � (control)Number of volunteers = 5Statistical analysis by paired t-testsLipsomepreparation Dermabase � (control)Time Mean SD Mean SD P______________________________________at 6.2 3.56 1.8 2.49 0.103removal30 min 7.4 3.71 2.6 1.67 0.018 1 hour 9.8 0.45 3.6 0.89 <0.001 2 hours 8.6 1.14 3.2 1.30 <0.001 3 hours 4.6 3.13 2.2 2.17 0.051______________________________________
TABLE 5__________________________________________________________________________Comparison of liposomal tetracaine preparation with other formulationsfor topical anesthesiaReference Drug Vehicle Onset time Duration Dosage Side__________________________________________________________________________ EffectMonash, S. 5% tetracaine ointment 1.5 h 3.5 h additional oint-Arch. Dermatol. ment hourly76:752-56, 1957.Lubens, H. M. 30% xylocaine "acid mantle cream" 2 h-- 0.5 h "liberal amount"Sanker, J. F. 4 h-- 3 hAnn, Allerg. (application)22:37-41, 1964.Brechner, V. L. et al. 5-33% tetracaine dimethyl sulfoxide 0.5 h 3 h 1 ml to 5 � 5 pruritisAnn. N.Y. Acad. Sci. (DMSO) area hypersensitivity141:524-31, 1967.Ohlsen, L. 10% ketocaine isopropranol 1-10 h several hours 5.3 ml to 8 � erythemaEnglesson, S. glycerol cm area oedemaBrit. J. Anaesth. water52:413-16, 1980.Evers. H. et al. 5% lidocaine- oil in water 1 h 1 h 1 g to 6.25 cm2Brit J. Anaesth. prilocaine (EMLA) emulsion area58:997- 1005, 1985.This Invention 0.5% tetracaine liposome 0.5-1 h at least 4 h 0.2 ml to 3 � 3 preparation cm area__________________________________________________________________________
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|U.S. Classification
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|International Classification
|Cooperative Classification
|European Classification
|Oct 18, 1988
Owner name: MEZEI ASSOCIATES LIMITED, A CORP. OF CANADA, CANAD
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Owner name: LIPODERM PHARMACEUTICALS INCORPORATED, CANADA
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text:
In a September 15 letter to U.S. Citizenship and Immigration Services (USCIS) Director León Rodríguez, Senator Chuck Grassley (R-Iowa) expressed his concern about a USCIS memorandum published on August 17, 2015 (and going into effect on August 31) that purports to "reform" the L-1B nonimmigrant visa category.
We've heard of so-called white privilege. Now there's supposedly "male privilege" as well. And some Americans are apparently willing to tax all men because of it.
A new report highlights several gross abuses of civil asset forfeiture law by Oklahoma law enforcement.
The Mississippi Highway Patrol has witnesses who confirm that a silver car swerved toward the SUV driven by Black Confederate activist Anthony Hervey, 49, causing his death as the SUV ran off the highway and rolled over multiple times.
Three groups filed suit against the Transportation Security Administration last week over its controversial body scanners, claiming that the agency has forged ahead with the use of the machines without the required regulations.
Despite days of advance publicity in the mainstream media, apparently only a handful of protesters representing the group Disarm NYPD showed up at Brooklyn's Fort Greene Park the evening of July 1 to burn a Confederate flag and an American flag.
The Confederate Flag BattleWritten by Warren Mass
Flags have always aroused the passions of the people. Like the heraldic emblems often emblazoned on them, flags have long been used in battle to identify the opposing combatants. But why all this fuss over an emblem that is 127 years old?
A former White House aide during the presidency of Bill Clinton was advising Secretary of State Hillary Clinton on the regime change in Libya while he was eyeing lucrative business deals with the transitional Libyan government.
The craving for combat by U.S. Senator Tom Cotton (R-Ark.) contradicts the counsel fo the Founders.
Aleksandr Dugin sought to inspire university students to support his Eurasianist "fourth political theory," but despite the controversy, almost no one showed up to hear him.

subset: commoncrawl


text:
Lesson Plan
The War Relocation Centers of World War II: When Fear was Stronger than Justice - A Teaching with Historic Places Lesson Plan
- Grade Level:
- Fifth Grade-Twelfth Grade
- Subject:
- History, World War II
- Duration:
- Variable. Adaptable to teacher and student needs.
- Group Size:
- Up to 36
- Setting:
- indoors or outdoors
- National/State Standards:
- Relevant U.S. History Standards for Grades 5-12: Era 8 - Expansion and Reform (1929-1945) Standards 3A and 3C
- Keywords:
- lesson plan, Teaching with Historic Places, Manzanar War Relocation Center, Manzanar National Historic Site, Rowher Relocation Center Memorial Cemetery, Relocation Camps, World War II, Japanese Americans
OverviewThis lesson is based on the National Register of Historic Places files from Manzanar War Relocation Center and Rohwer Relocation Center Memorial Cemetery and other related materials. It includes historic maps, readings, drawings and photographs. With these materials, students will analyze why people of Japanese ancestry in the United States were removed from their homes and placed in relocation centers and examine the relocation centers themselves.
- To analyze the reasons why people of Japanese ancestry living in the United States at the onset of World War II were removed from their homes on the West Coast and placed in relocation centers.
- To examine the places where relocation centers were established.
- To describe the characteristic features of the centers.
- To examine the reactions of some of the residents.
- To research the local community to see if a perceived enemy was ever unfairly treated, and, if so, how that mistreatment might be acknowledged
BackgroundInformation on how to use a Teaching with Historic Places lesson plan can be found here.
- Two maps showing Japanese military successes in 1941-42 and the locations of the relocation centers;
- Three readings about the relocation program and the centers;
- One drawing of residential block layouts; and
- Seven photos of the centers.
The War Relocation Centers of World War II: When Fear was Stronger than Justice
Each Teaching with Historic Places lesson plan contains the following teaching activities: Getting Started (inquiry question), Setting the Stage (historical background), Locating the Site (maps), Determining the Facts (readings, documents, charts), Visual Evidence (photographs and other graphic documents), and Putting It All Together (activities). See Parts 2-7 for information about how to use these resources.
Click here to go directly to the lesson plan.
Getting Started
Begin this lesson by asking students to discuss possible answers to the inquiry question that accompanies the "Getting Started" image. Provide them with paper print-outs of the image and question, or direct them to the lesson plan website. To facilitate a whole class discussion, you may want to print or scan the image to make an overhead transparency or digital slide. The purpose of this exercise is to engage students' interest in the lesson's topic by raising questions that can be answered as they complete the lesson.
Rather than serving merely as an illustration for the text, the image is a document that plays an integral role in helping students achieve the lesson's objective. To assist students in learning how to "read" visual materials you may want to begin this section by having them complete the Photo Analysis Worksheet for one or more of the photos. The worksheet is appropriate for analyzing both historical and recent photographs and will help students develop a valuable skill.
Getting Started section for this lesson
Setting the Stage
This section is intended to be used, if necessary, as background material. Read this material aloud to students or summarize it, or provide them with paper print-outs, or direct them to the lesson plan website. If students have computers, you can direct them to the page on the website.
Setting the Stage section for this lesson
Locating the Site
Provide students with the maps and questions included in Locating the Site. You can give them paper print-outs or direct them to the lesson plan website. Have students work individually or in small groups to complete the questions. At least one map familiarizes the students with the historic site's location within the country, state or region. Extended captions may be included to provide students with information necessary to answer the questions.
Locating the Site section in this lesson
Determining the Facts
Provide students with copies of the readings, documents and/or charts included in this section or direct them to the lesson plan website. Allow students to work individually or in small groups. The series of questions that accompanies each of these readings is designed to ensure that students have gathered the appropriate facts from the material.
Determining the Facts section for this lesson
Visual Evidence: Images
Distribute the lesson's visual materials among students. Provide them with paper print-outs, or direct them to the lesson plan website. Have the students examine the photographs and answer the related questions. Note that two or more images may be studied together in order to complete the questions. Extended captions may be included to provide students with important information.
Rather than serving merely as illustrations for the text, the images are documents that play an integral role in helping students achieve the lesson's objectives. To assist students in learning how to "read" visual materials, you may want to begin this section by having them complete the Photo Analysis Worksheet for one or more of the photos.
Visual Evidence: Images section for this lesson
Putting It All Together
After students have completed the questions that accompany the maps, readings and visuals, they should be directed to complete one or more of the activities presented below. These activities engage students in a variety of creative exercises that help them synthesize the information they have learned and formulate conclusions. At least one activity leads students to look for places in their community that relate to the topic of the lesson. In this way students learn to make connections between their community and the broader themes of American history they encounter in their studies.
Putting It All Together section for this lesson
AssessmentAssessment is built into the lesson in the form of questions for all documents, including maps and images, and in the student products completed for Step 7, Putting it All Together.
Additional ResourcesStudents and educators who want to know more can find sources of additional information (with links) here: Supplementary Resources.
Experience More
on NPS.gov
Lesson Plans
Distance Learning
- "They Fought Like Tigers" African American Soldiers and American Indian Soldiers
- George Washington and the French and Indian War
- The Human Story
Field Trips
- Sweep Through History
- Great Smoky Mountains - Mingus Mill History and Culture
- Kansas Museum of History Tour


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Submit your surgical and clinical videos to the Academy's 2nd Annual Global Video Contest. The grand prize winner will take home an iPad mini or $350 in Academy Store credit.
Submit your video.
The Academy provides annual meeting presenters with the information they need to help create a best-in-class educational meeting.
Access tools, tips and resources for presenters.
Abstracts are examined through a peer-review selection process which ensures the quality and integrity of Academy educational programs and allows broader input from Academy Members.
Find out more about the selection process.
Abstract submissions are accepted in specific subject classifications. You are encouraged to choose from the topics suggested by previous meeting attendees.
Review the List of Course Topics.
Presenter Central is your one-stop location for AAO 2015 and Subspecialty Day presenter information.
If you need assistance, contact firstname.lastname@example.com.
Visit the Presentation Tool and Tips webpage to find:
Interact with attendees by using the Mobile Meeting Guide to start a discussion, post a message or create a survey or poll. Plus, you can view statistics about the session including the number of attendees that downloaded your handout or number of attendees that have saved the session to their Planners.
Login to see a list of your session(s).
Sands Expo/Venetian, Titian 2302Thursday: 1:00 - 5:00 PMFriday & Saturday: 7:00 AM - 6:00 PMSunday - Tuesday: 7:30 AM - 6:00 PM
To comply with the Accreditation Council for Continuing Medical Education (ACCME®) guidelines as well as create an environment free of perceived commercial bias and financial interest, representatives from commercial companies are not allowed in the Speaker Ready Room.
Sands Expo/Venetian, Titian 2301Saturday - Monday: 8 a.m. - 5:30 p.m.Tuesday: 8 a.m. - 3 p.m.
During AAO 2015 Academy volunteers can visit the Volunteer Lounge to relax, enjoy complimentary refreshments, access meeting information and the Internet. Academy volunteers include:
11: AAO 2015 Instruction Courses and New Skills Transfer Labs Online Abstract Submitter OpenAbstract submissions accepted Dec. 11, 2014 - Jan. 13, 2015 for AAO 2015 instruction courses and new Skills Transfer labs.
13: Submission Deadline: AAO 2015 Instruction Courses and New Skills Transfer Lab Abstracts
12: AAO 2015 Paper/Posters and Videos Online Abstract Submitter OpenAbstract submissions for AAO 2015 paper/posters and videos accepted March 12 - April 14.
14: Submission Deadline: AAO 2015 Paper/Poster and Video Abstracts
16: Retina Subspecialty Day Video Online Abstract Submitter OpenVideo abstract submissions for the Retina Subspecialty Day meeting are accepted April 16 - May 13.
23: AAO 2015 Video Submissions Accepted Submit videos online April 23 - May 12. Note: must have submitted a video abstract by the April 14 deadline and then notified to submit a video for review.
30: AAO 2015 Course Selection Notifications Course selection notifications are sent by email to Senior Instructors only.
12: Submission Deadline: AAO 2015 Videos
13: Submission Deadline: Retina Subspecialty Day Video Abstracts
14: ISRS/Refractive Surgery Subspecialty Day Online Abstract Submitter OpenAbstract submissions are ISRS/Refractive Surgery Subspecialty Day meeting are accepted May 14 - June 17.
21: AAO 2015 Course Scheduling Notifications Course scheduling notifications are sent by email to Senior Instructors only.
21: Retina Subspecialty Day Late Breaking Developments Online Abstract Submitter OpenAbstract submissions of late breaking developments for the Retina Subspecialty Day meeting are accepted May 21 - September 16.
17: Submission Deadline: ISRS/Refractive Surgery Subspecialty Day Abstracts
10: AAO 2015 Paper/Poster & Video Selection Notifications Paper/poster and video selection notifications are sent by email to Presenting Authors and Senior Producers only.
14: Print Program Change/Additions Deadline Submit instruction course changes or additions to the Final Program up to July 14.
31: AAO 2015 Paper/Poster Scheduling Notifications Paper/poster scheduling notifications are sent by email to Presenting Authors only.
16: Submission Deadline: Retina Subspecialty Day Late Breaking Developments Abstracts
13: Refractive Surgery Subspecialty Day meeting
13 and 14: Retina Subspecialty Day meeting
14: Subspecialty Day meetings: Cornea, Glaucoma, Neuro-Ophthalmology, Pediatric Ophthalmology


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Sheriff's Office offering free course combatting identity theft
To help combat identity theft, detectives in Collier County will be leading a class on Tuesday about current scams in Southwest Florida.
Lt. Chad Parker, of the Sheriff's Office's Financial Crimes Bureau, will teach the hour-long course, which is free and open to the public. Students will learn how to protect their identities and financial well-being.
Seating is limited, but residents can sign up by calling 239-252-0687. The course will be held Tuesday at 10 a.m. at the Sheriff's Office's Professional Development Center, 615 Third Ave. S., room 108, Naples.
Subscribe to the Naples Daily News
Ready to subscribe to the Naples Daily News? Choose between a Premium or Digital subscription below.
Need Help? Call us at 1-888-878-6842.
Monday-Friday: 6am-6pm / Saturday: 7am-3pm / Sunday: 7am-2pm


text:
Select Local Merchants
Goldensun TanRead MoreEstablished: 2002 Reservations/Appointments: Optional Handicap Accessible: Yes Staff Size: 2–10 people Parking: Parking lot Most Popular Service: Tanning Brands Used: Devoted Creations, Ed Hardy, ProTan, Designer Skin, and California Tan Pro Tip: If [you're] coming in at peak times (5 p.m. to 7 p.m.), call ahead and make an appointment.3100 Oakwood Blvd.Hollywood, FL US
Sincerely Yours Hair Nail and Tanning SalonRead MoreFor a pain-free and sunless tan, head to Sincerely Yours Hair Nail and Tanning Salon in Hollywood. The nail technicians at this salon can buff, clean and polish your nails to perfection. Even your skin tone with some tanning at Sincerely Yours Hair Nail and Tanning Salon's tanning salon, offering services like tanning beds, spray tan, and airbrush tan. Get a great bronze glow at Sincerely Yours Hair Nail and Tanning Salon and start the weekend off looking hot, hot, hot.6930 Stirling RdHollywood, FL US
Beach Babe TanRead MoreA tan often indicates a recent visit to an exotic locale, but with Beach Babe Tan, clients can darken their skin tone without leaving their homes. The mobile tanning company carts its organic airbrush-tanning equipment to locations around the area, instantly bronzing bodies to prepare clients for trips to the beach, weddings, or other events.33020 Johnson st 26dHollywood, FL US
E-Z Tan Professional TanningRead MoreJump on the treadmill or work on your weights — Hollywood's E-Z Tan Professional Tanning offers a full body workout. Parking is plentiful, so guests can feel free to bring their vehicles.2766 N University DrHollywood, FL US
Planet Beach Fort LauderdaleRead MoreA wildly successful alternative to traditional day spas—its more than 300 locations blanket 36 states and half a dozen countries—Planet Beach Contempo Spa is a futuristic relaxation station where state-of-the-art machines administer all the spa and tanning services. These friendly automatons sometimes replace familiar treatments, as in the Luminous facial, a light-based service that delivers blemish-busting results similar to those of a conventional facial. But other equipment maps out new spa territory entirely: the Hydro-Derma Fusion chamber moisturizes the whole body with nutrient-rich steam in order to offset the effects of a dry climate or a rear-end collision with a salt truck. Other machines whiten teeth, spray tan skin, and massage muscles. Planet Beach operates on a gym-style membership system, meaning that members purchase packages or pay flat monthly rates. As members spend more time at the spa, they get to know the helpful assistants who are always on hand to demonstrate how to use the equipment without activating its ability to cry.6240 N Federal Hwy.Fort Lauderdale, FL US
Sunny Girl Spray Tan, LLCRead MoreSunny Girl Spray Tan, LLC's mobile technicians know that it's possible for a spray tan to last up to 10 days. To help that happen, they offer various tips on their website, telling clients to exfoliate thoroughly before their tan and to shave their legs one day before. The airbrush experts also recommend avoiding taking baths and swimming in chlorine, as well as moisturizing frequently after the color has set for at least eight hours. For clients who are super dedicated to maintaining their color, Sunny Girl offers a tan extender that contains a touch of DHA.UnknownFort Lauderdale, FL US


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BTS - base transceiver station
Short for base transceiver station. In mobile communications, a BTS holds the radio transceivers that define a cell and coordinates the radio-link protocols with the mobile device. The BTS is the networking component of a mobile communications system from which all signals are sent and received. A BTS is controlled by a base station controller.
A BTS is also called a base station (BS) and is commonly referred to as a "cell phone tower."
Stay up to date on the latest developments in Internet terminology with a free weekly newsletter from Webopedia. Join to subscribe now.
From wacky alarm clocks to lecture hall tools and after class entertainment, these Android apps are a good fit for a student's life and budget. Read More »Sharing Threat Intelligence
A growing number of startups make the sharing of threat intelligence a key part of their solutions. Read More »Smiley Faces and Symbols
A text smiley face is used to convey a facial expression or emotion in texting and online chat conversations. This Webopedia guide shows you how... Read More »
The Open System Interconnection (OSI) model defines a networking framework to implement protocols in seven layers. Use this handy guide to compare... Read More »Network Fundamentals Study Guide
Networking fundamentals teaches the building blocks of modern network design. Learn different types of networks, concepts, architecture and... Read More »Computer Architecture Study Guide
This Webopedia study guide describes the different parts of a computer system and their relations. Read More »


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All Categories
Tale Of The Tape: Miami Dolphins At Chicago Bears
Head coach Joe Philbin has not been happy with Ryan Tannehill's play at the quarterback position, and there are no assurances he will remain the starter for much longer.
Tale Of The Tape: New York Jets At New England Patriots
The Jets are near the end of their rope with Geno Smith, because the second-year quarterback simply makes too many mistakes, lacks maturity and appears to have lost some confidence in his own ability.
Injured Calvin Johnson Or Broken Megatron Toy, Which Is Worse?
Calvin Johnson, the NFL's Megatron, is a little banged up. But is that worse than a broken Megatron Transformer toy?
Adrian Peterson Or Anakin Skywalker, Worse Fall From Grace?
Adrian Peterson's fall from grace has been epic. But does it measure up to that of Anakin Skywalker aka Darth Vader?
Tale Of The Tape: Jacksonville Jaguars At Tennessee Titans
At a certain point, Jacksonville quarterback Blake Bortles will find his comfort level and play well enough to give the Jaguars a legitimate chance at winning a game or two this season.
Tale Of The Tape: Indianapolis Colts At Houston Texans
The Colts have to feel comfortable with the quarterback matchup on an every-week basis with Andrew Luck.


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comComparing the free .NET implementations Mono and DotGNU
The Open Source projects Mono and DotGNU open Microsoft's .NET platform to Linux developers. This article investigates how well-suited these alternative implementations are for building simple GUI applications.
In 2002, Microsoft launched a new system for platform-independent development that they dubbed .NET (pronounced "Dotnet"). The .NET pro-ject aims to simplify the development of network and Internet applications. It supports object oriented programming and comes with a unique class library suitable for use with multiple programming languages, such as C# and VB .NET for example. In the course of launching .NET, Microsoft has discontinued support for its previous favorite, the MFC library for Visual C++. All future Microsoft products will be based on the new technology. Free .NET? Despite the platform-independent approach of the .NET framework, Microsoft is highly unlikely to release a Linux implementation, and this lack of Linux support has prompted two projects to step into the gap: Novell's sponsored Mono project [1] and the open source DotGNU [2] project. Both Mono and DotGNU are aiming to provide as complete an implementation of the .NET platform as possible. The goal of both projects is to allow developers to exchange software across operating system boundaries.
Buy this article as PDF
(incl. VAT)
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Read full article as PDF:Mono_DotGNU.pdf (288.57 kB)
Bugzilla Bug
Bug database has a bug of its own that could allow an intruder to create an unauthorized account.
US Launches New Strategy for Broadband Access
Report focuses federal resources on achieving universal Internet access.
RC4 Finally Gets the Fork
Leading browser makers say "no" to porous encryption algorithm
IBM Says TOR Network a Vehicle for Ransomware
Report from the X-Force group says attackers are using TOR to hide their crimes
Mozilla Announces new Firefox API
Future Firefox extensions will be compatible with Chrome.
Weird Security Flaw Affected Intel Chips for 16 Years
Better read this if you bought your computer before 2011
OpenSSH 7.0 Secure Shell Arrives
Users should upgrade to the new version as soon as possible
Qemu Flaw Lets the Guest Escape
Xen project announces a privilege escalation problem for Qemu host systems
Android Bug Threatens Millions of Users
Attackers can compromise an Android phone just by sending a text message
Lenovo and Canonical Announce Laptop Deal
PC vendor will pre-install Ubuntu on portables in India.


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- Andachtsorte
- Educational places
- Einkaufen
- Freizeit & Unterhaltung
- » Animal camps and shows
- » Concert venue
- » Cultural Show, Cultural Performance
- » Fereizeitsparks
- » Golf course
- » Kino
- » Outdoor activity and adventure sites
- » Parks & Gärten
- » Sportveranstaltungen
- » Theater
- » Zoo & Aquarien
- Kunst, Kultur & Erbe
- » Archaeological
- » Historische Häuser
- » Historische Sehenswürdigkeiten & Monumente
- » Kunstgallerien
- » Landzeichen & Denkmale
- » Museen
- » Thailändische Königspfalz
- Städtisches Leben
- Thailändische Natur & Tierwelt
Attraktionen Pattaya
Profil von :
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Introducing Admirallica, this grand pirate ship is now available in Pattaya for day and night cruises, parties, private charters or any special events. The mighty galleon offers a truly unique experie...Weitere Details
We are pleased to present you a great invention in the field of water and extreme activities called Flyboard! This unique design was created in France, in 2012 and immediately gained a crazy popu...Weitere Details
Mermaids Dive Center has operated since 1990 in Jomtien Beach, just South of Pattaya, Thailand. Now we feature 2 locations in Pattaya – one in Jomtien Beach and one on Pattaya Beach Road and a n...Weitere Details
There are several paintball battlefields in Pattaya as it has been a popular sports for locals and tourist who love exciting activities. The enclosures are well designed to create the atmosphere as if...Weitere Details
Pattaya Dolphin World & Resort has become a Pattaya new attraction since 2011 features the fascinating dolphin shows and other outdoor activities such as rope jumps as well as other entertaining p...Weitere Details
The only full time skydiving drop-zone in S.E. Asia We have 25+ years skydiving experience. Open since November 2009 we're a UK, US, Thai run operation with a full staff of western instructors and pil...Weitere Details
Located approximately 10 kilometers off of Sukhumvit Road, Horseshoe Point Club offers horse riding at all levels of proficiency, as well as dressage, cross-country jumping and polo. Opening hours: 8...Weitere Details


text:
UNC Charlotte is on YouTube
University Awarded Grant to Aid Student Success
UNC Charlotte's retention rates for first-year students have steadily increased during the past five years, and now University leaders look to build upon that success through a special grant from EDUCAUSE.
The University is one of 24 recipients of a three-year, $225,000 Integrated Planning and Advising for Student Success (IPASS) grant funded by the Gates Foundation and the Helmsley Charitable Trust. EDUCAUSE is a nonprofit association comprised of IT leaders and professionals who are committed to advancing higher education.
According to EDUCAUSE, IPASS recipient institutions will research how to utilize current software and/or technology to improve educational planning, counseling and advising to promote an integrative approach to student success through "shared ownership for educational progress among students, faculty and staff."
Annual Faculty and Mentoring Competitions Underway
The Graduate School is pleased to announce the 2016 competitions for the First Citizens Bank Scholars Medal and the Harshini V. de Silva Graduate Mentor Award are now underway.
The First Citizens Bank Scholars Medal recognizes outstanding scholarship, creativity and/or research among senior full-time faculty members. Each year the University, with support from First Citizens Bank, present this award in order to recognize and foster the advancement and diffusion of knowledge and creative endeavors. Nominations focus on the excellence and importance of sustained contributions in research and creative activities, including work done over a substantial period of time at UNC Charlotte.
The Harshini V. de Silva Graduate Mentor Award was established in memory of Dr. Harshini de Silva, an associate professor of Biology, who was noted for her deep dedication to the academic and professional development of graduate students. Each year, the Chancellor's Office and the Graduate School present this award to a full-time member of the graduate faculty who evinces the qualities of outstanding graduate mentoring. For additional information and submission details, visit the Graduate School website.


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fabiano in MA
NiceRead All Reviews
Blaine in NY
Still going strong years later on rocky trailsRead All Reviews
Blaine in NY
Bushings are still going strong years laterRead All Reviews
Brian in CA
If you are at all handy, I highly recommend this kit and a few specialty tools. Fork job was a lot easier than I expected.Read All Reviews
TERRY in MI
Fit as they should and working well. I would buy them again.Read All Reviews
BARRY in OK
No problems with this product. Good fit and seems to be quality workmanship.Read All Reviews


text:
Hayley Hudson is a contributor to PoliceOne, writing primarily on the people and personalities in police work, focusing on how others might relate to and learn from them.
Survey: Citizens want cops on Facebook - 10/02/20124
Mastering the media: Saving your department's reputation - 10/01/20122
Sick and tired: How sleep deprivation harms cops - 10/01/20128
Wounded SC officer said 'Not Today' — and meant it - 06/29/201212
Machete takedown: A NY cop's good shoot - 05/23/201220
Less-lethal, but more painful: A clock that shoots you - 04/01/20129
Tip: Using social media to promote your PD - 03/28/2012
PoliceOne Columnists:
PoliceOne's team of expert writers provides our readers with valuable insight from both on-the-job and classroom experience.
To submit articles or become a columnist click here and include your background/CV and a sample of your writing.
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Today's Top Stories
|Wednesday, October 14, 2015
|All of Today's News
Officer Down
Veteran Cherokee officer dies from injuries Anthony Lossiah - 10/09/2015
[ Cherokee , North Carolina ]
[ Cherokee , North Carolina ]
SC cop shot, killed by suspect in mall Greg Alia - 09/30/2015
[ Forest Acres , South Carolina ]
[ Forest Acres , South Carolina ]
Tenn. deputy sheriff dies in single-vehicle crash Rosemary Vela - 09/29/2015All Officer Downs Submit an Officer Down
[ Tennessee ]
[ Tennessee ]
Featured Columnist
Klugie's Corner
with Gary T. Klugiewicz


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Mary Dyann's BadgesExpertiseGreat Outdoors - Level 2
Welcome to the Great Outdoors!
Tree-rific! You've been to 5 different outdoor spots. Visit 5 new places to unlock Level 3.
Mary Dyann unlocked the Great Outdoors badgeMarch 8, 2012
Download Foursquare for your smart phone and start exploring the world around you!


text:
RC4 Low Profile Rect. Rapid Connect Adapter w/410PL Plate
DESCRIPTIONSupplied with 1/4'' and 3/8'' camera fixing screws. Fixing 1/4'' and 3/8'' thread. 410PL plate included. Equipped with 2 built-in spirit levels.
Warranty Manfrotto Photo Pro/Amateurs Products
This products is warranted to be fit for the purpose for which it has been designed, and to be free from defects in materials and workmanship. This guarantee does not cover the product against subsequent damage or misuse. The period of validity of the Standard Limited Warranty is defined by the law in force in the country, state or region where the product is sold. Please retain your receipt as proof of purchase to repair your product under warranty.
How to get an extra warranty coverage
Beyond the standard compulsory coverage outlined above, this product is eligible for a warranty extension valid up to 10 years from the date of purchase. The Limited Conventional Warranty Extension does not affect the standard compulsory coverage. To take advantage of the warranty extension scheme, you must register your purchase at warranty.manfrotto.com.
Attachment 3/8'' female thread attachment type 3/8'' female thread attachment type Attachment Number 1/4'' and 3/8'' screws attachment type 1/4'' and 3/8'' screws attachment type Bubble Spirit Level (No.) 2 number 2 number Color black color black color Material aluminum aluminum Plate Type 410PL 410PL Quick Release yes yes Secondary Safety System yes yes Weight 0.62 lbs 0.280 kg
- Name File Size Date of Publication
- 394_20030407.pdf 0.04 MB 2014-11-05
- 394_20050510.pdf 0.04 MB 2014-11-05


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Starring: Nikki Reed, Shelley Hennig, Jane Seymour
Running Time: 108 minutes
Director: Laurie Weltz
Languages: English
Rating: PG
Genre: Comedy / Drama
Quirky coming-of-age story about Scout, a 15-year old goth girl who convinces a wealthy but suicidal young man to accompany her on a road trip across Texas to find her little sister.
Rendez-nous visite
S'inscrire aux e-mails
© 2015 Emirates. Tous droits réservés.


text:
I'm a very outdoors kinda person. I love going to the beach, camping, hiking, surfing, biking, pretty much anything to do with nature. I have a dog, his name is charlie he is a pug and is the most important thing to me in my life. I work in the restaurant industry so I work late nights and weekends. It's a hard demanding job but I love it. I spend a lot of time working on my car, 71 vw bus, trying to get her in top top shape so I can take a few months off work and travel around the states. I'll sometimes take off to a city and crash on the side of the road, it's like a traveling motel. A lot of people at work call me a redneck hippy, I'm still not sure if that's a good thing or not but I just go with it. I like building things, my grandfather was a carpenter and I think his genes have seeped into me the older I get. One of my goals i would like to do is build a house, or at least buy a fixer upper and remodel it myself. I guess you could say I'm a very hands on type of guy.
Let me say Chivalry is not dead. I have been told I'm a pretty good example of it.


text:
"Just as the chytrid fungus has decimated frog populations, the results of our study suggest that ranavirus infection too could contribute to extinction of amphibian populations that are demographically isolated," said lead author and NIMBioS postdoctoral fellow Julia Earl.
Amphibians are already considered the most imperiled of vertebrates, and a third of amphibians are threatened or endangered, according to the International Union for Conservation of Nature, the main international body that assesses the conservation status of species.
Disease may be playing a role in amphibians' extinction. Since the 1990s, chytridiomycosis, which has been called the worst disease affecting vertebrate animals in recorded history, has caused massive die-offs and species extinctions across the world, particularly in Australia, the Caribbean, and North, Central, and South America.
Ranavirus infections in amphibians have been known since the 1960s, but it wasn't until the 1980s when they were associated with large-scale mortality and disease.
Once exposed to ranavirus, in susceptible species like wood frogs, mortality can be as quick as three days. Transmission can occur through water, direct contact and when tadpoles scavenge other dead and infected frogs. There is no cure or treatment for the disease.
|Contact: Catherine Crawley
National Institute for Mathematical and Biological Synthesis (NIMBioS)


text:
This item is currently
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HN-CSC017 Cosco Home and Office
Cosco White Speckle Blow Molded Folding Chair-4 PackItem # HN-CSC017
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A durable set of four lightweight seats, the Endura Folding Chair ensemble makes entertainment hassle-free. Guests enjoy a comfortable seat, then it folds away to conserve floor space. Available in a choice of attractive colors, these chairs providing fast seating at large family or company gatherings.Make sure your guests are comfortable at your social events by ordering this comfortable set of chairs.


text:
All Android applications categories
All Android games categories
by: Temple Media | 360
If the rumors are true, this ancient temple holds treasures beyond your wildest dreams.It houses many traps, puzzles and pitfalls along the way.But what kind of thing has never deterred you before has it?
How to Play:
Explore the tomb to search for treasure.Solve puzzles and beware of the many traps and pitfalls!Careful reflexes, puzzles to solve,gems to collect! If it wasn't for the skulls and that nasty smell, I'd never leave! Good luck!
Click the "I" sign to access your inventory!
Tags: mystery of ancient tomb escape , mystery ancient tomb escape , ancient tomb free books
from 360 reviews


text:
Coatings / Paint Fluid Dispensing Equipment Datasheets
from Ellsworth Adhesives
The TS350 dispenses low, medium and high-viscosity fluids accurately and consistently. The TS350 is immediately usable anywhere in the world with its accompanying tools, accessories and universal power supply. [See More]
- Application: AdhesiveSilicone (optional feature); CoatingPaint (optional feature)
- Container Size: 10
- Dispensing Equipment Type: Dispense Only
- Dispensing Type: Bead
from Nordson EFD
MicroMark spray marking valve systems can be used to color code similar components, indicate pass/fail, or show production or test status. MicroMark spray marking valve systems produce uniform round patterns and stripes from 5.0mm to 30.4mm (0.20" to 1.20") wide without clogging or overspray. The... [See More]
- Application: CoatingPaint; Inks
- Mounting: MachineMounted
- Dispensing Type: Spray Round
from Aervoe Industries Incorporated
Plastic cover and stirring device fits onto any standard gallon paint can [See More]
- Application: CoatingPaint
- Dispensing Type: Solid Stream; Pouring Spout
- Dispensing Equipment Type: Mix And Dispense
- Mounting: ContainerMounted
from Binks
Name: 98-3061 Pogo Plus Glue Outfit. Part Number: 98-3061. Gun: Model 2100. Pump: Pogo Plus Pump. Tank: no tank. Typical Application: Solvent based adhesives. Max Output Fluid Pressure: 2:1 200 psi - (Fluid Pressure range (0-300 psi (0-24.2 bar). Markets: Adhesive. General Industrial. Miscellaneous. [See More]
- Application: AdhesiveSilicone; ChemicalSolvent; CoatingPaint
- Dispensing Type: Spray Flat; Spray Round
- Dispensing Equipment Type: Dispense Only
- Dispensed From: CanPail
from Cammda Corporation
Designed specifically for aircraft exterior touch-ups, CAMMDA's Paint Pax ™ is a complete self contained system that stores, mixes and applies two-component paints and primers. Each Paint Pax ™ kit consists of a pre-filled two component cartridge, an applicator gun and a mixer. The... [See More]
- Application: CoatingPaint
- Dispensing Type: Bead
- Dispensing Equipment Type: Mix And Dispense
- Mounting: HandHeld
from Generic Fluid Systems
These ingredient wings contain 3- or 6-gallon conical bottom canisters to hold ingredients. They are typically combined with our Pump Train systems which mount to the bottom frame of the wing. This method of ingredient supply is convenient when materials are stocked in one-gallon cans or five-gallon... [See More]
- Application: CleanRoomLab; CoatingPaint; Colorants; FoodBeverage; HighViscosity; Lubricants; MedPharmaceutical; Water
- Container Size: 11356 to 22712
- Dispensing Equipment Type: Dispense Only
- Mounting: MachineMounted
from Hernon Manufacturing, Inc.
0-100 psi for spraying water like materials and primers. Excellent for alcohol and acetone based primers. 100% Solid State, six function timer [See More]
- Application: CoatingPaint; Spraying waterlike materials and primers
- Dispensing Type: Spray
- Dispensing Equipment Type: Dispense Only
- Mounting: Stand Mounted
from Nordson Corporation
Touch screen control panel, easy troubleshooting, alarm equipped (1500psi) [See More]
- Application: CoatingPaint; Paint/Coating Spray Applications
- Dispense Rate: ? to 16.01
- Dispensing Equipment Type: Mix, Meter and Dispense
- Metering Accuracy: 1
from T&C Industries, Inc.
Base holds three 1-gallon cans and one 5-gallon, stainless steel pump tubes [See More]
- Application: CoatingPaint; Colorants
- Container Size: 2177
- Dispensing Equipment Type: Dispense Only
- Shot Size: 0.1155 to 59.15


text: DDB Worldwide, YouTube Emotional Organ Donation Ad Will Bring on the Waterworks By TheFW Staff May 21, 2015 | TheFW The power of animals shows the power of organ donations in a new and incredibly moving ad. Read More|Comment Category: Animals, News Tags: organ Send to a friend! Share on Facebook Share on Twitter Pin it! Reddit This! Share on Tumblr!


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- Find a rental
- Manage your booking
- Taguig City rentals
- How to book
- Help Center
- Write a review
Breeze & views - Avant @ The Fort - Manila BGC
From $120 / night
Payment Protection
Description from the owner
Description from the owner
Bedrooms: 1/
Bathrooms: 1/
Sleeps: 2/
Type: Apt. / Condo
Located in the Golden Triangle adjacent to Manila Golf & Country Club.
Rated by Savills International Real Estate as one of the top 5 condos in the Philippines.
The Space
Designed with your comfort, privacy and security in mind this apartment comes fully furnished including:
• Television with full cable package including HBO, Bloomberg, CNN, NHK etc
• Queen bed
• Clean Bed Linens and Towels
• Multiple Water Heater
• Brand New Appliances including Elba Microwave, Samsung Fridge/Freezer Electric Kettle, Rice Cooker, Toaster, Blender
• Kitchenware including Utensils, Glassware, and Plates
* Spacious living area with landscape views ...Read more
About the owner
About the owner
- Response rate: 90%
- Response time: A few hours
- Calendar updated: today
Overall rating:
Additional Location Information
Avant at The Fort located on 26th Street Corner 3rd Ave. is the premium area of Fort Bonifacio Global City. Banks, coffee shops and convenience stores are just downstairs.
All the leading offices can be reached just by walking, as well as the restaurants area (Fort Strip, Burgos Circle & High Street) At two minutes walking, the fort bus stop, going to Makati (Ayala Ave) means down-town Manila is on your doorstep.
More About This Location
City vacations
Getting There
Nearest airport: NAIA
Car is not necessary
Show rates details
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