text:
|Publication number
|Publication type
|Application number
|Publication date
|Jul 21, 1998
|Filing date
|Feb 7, 1997
|Priority date
|Feb 7, 1997
|Fee status
|Also published as
|Publication number
|Stephen C. Jacobsen, Gaylen M. Zentner
|Original Assignee
|Sarcos, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (14), Referenced by (97), Classifications (9), Legal Events (7)
|External Links: USPTO, USPTO Assignment, Espacenet
1. Field of the Invention
The present invention relates to a method of automatic dosing of drugs. More particularly, the present invention relates to a method for using electromechanical mechanisms and micromachines for dosing of drugs to maximize the effectiveness of the drugs and to prevent the development of drug tolerance and resistance.
2. State of the Art
It is well known in the fields of animal husbandry and veterinary medicine that it is usually desirable and often necessary to treat farm animals with drugs for parasites. The parasites of concern will often vary depending on the farm animal concerned and may include both ectoparasites and endoparasites. To eliminate or control these parasites, farm animals are often sprayed with or fed parasiticides, injected with these drugs or sprayed with drugs which act as parasite repellents. To accomplish such control of the parasites, the farm animals typically must be rounded up and placed in a holding area so that each animal may be properly dosed with the drug(s). Once treated, the animal is released until the next dosing is required.
Unfortunately, rounding up the animals each month, etc., is time consuming and expensive. The animal must be located and then brought to a suitable location for administration of the drug. Because of the time and expense involved with such round-ups, the farmer is forced into a compromise of overdosing the animal with a very large dose of the drug to prolong the period during which the drug is present at levels which meet or exceed the minimum effective level, thereby decrease the frequency with which the drugs must be administered, or accepting the expense of frequent round-ups to repetitively doses the animals. For example, a topically applied drug may have an efficacy threshold which relates to a 750 milligram dose of a given medication. However, to extend the period between dosing, a significantly larger dose is typically used. In FIG. 1, there is shown a curve indicating a normal, exponentially declining (i.e., first-order) efficacy curve where the drug is provided by prior art diffusion devices, such as ear tags, at a very high initial dose in order to maintain drug levels above the efficacy threshold for a prolonged period.
Referring to FIG. 1, the initially high drug level 10 that is available early in the treatment period is typically much higher than the efficacy threshold 20. In the present example, the initially high drug level 10, is 3,750 milligrams, a drug level that would require a dose which is at least four to five times higher than the efficacy threshold for the drug used. Such large doses create several problems and negatively impact the animal by causing host toxicity, decreased weight gains, and loss of income to the animal handlers/owners.
An additional problem with the initial high dose is that high levels of the drug may still be present should the farmer desire to slaughter the animal within the time period correlated with the upper portion, indicated at 30, of the first-order declining kinetic curve. The high, persistent drug levels can limit the farmer's marketing response and potentially lead to adverse reactions in consumers.
In the FIG. 1 example, the drug, assumed to be a parasiticide for discussion purposes, which has been diffused onto/into the animal remains above the efficacy threshold for approximately 90 days. Once the amount of drug present falls below the efficacy threshold, the drug is present in insufficient amounts to adequately kill the targeted parasites. However, it is well known that the prolonged presence of subtherapeutic levels of a drug gives rise to the development of resistance to the drug within the targeted parasites. In a resistant parasite population, the efficacy threshold is shifted upward substantially. Therefore, due to use of prior art diffusion controlled dosage forms, numerous previously beneficial antibiotics and parasiticides are now of limited effectiveness because the target microbes and parasites have developed sufficient resistance to the drug to withstand even very high dosages that the host animal cannot tolerate. Drugs that are not biocides also are negatively impacted by this type of dosing pattern as manifested by enzyme down regulation and the clinical development of tachyphylaxis.
There have been numerous attempts to overcome these concerns. For example, it has been proposed to implant in farm animals devices which provide for the release of drugs at a time other than implantation. Examples of such devices are included in the U.S. Pat. Nos. 4,564,363, 4,326,522, 4,425,117, 4,439,197, 3,840,009, 4,312,347 and 4,457,752. Unfortunately, these devices tend to be expensive to use, typically they allow only for a one time (continuous) discharge of a single drug, and are otherwise disadvantageous. Thus, there is a need for a method of administering drugs which overcomes the disadvantages of the prior art.
It is an object of the present invention to provide an improved method for dosing animals which requires only a single application to the animal during a treatment period.
It is another object of the present invention to provide such a method which prevents or substantially reduces the development of drug resistance within the targeted parasite or microbe.
It is still another object of the present invention to provide a method which maintains an efficacious dose of the drug within the animal throughout the treatment period.
It is yet another object of the present invention to minimize the amount of drug necessary to stay above the drug's efficacy threshold by providing dosing events which are accurate and precise.
It is still yet another object of the present invention to enable the user to control the amount of the drug present in the animal's system to thereby enable the user to increase drug levels during traditionally high periods of parasite infestation.
Yet another object of the present invention is to provide such a method which provides electronic control over drug delivery, rather than depending on the chemical attributes of the drug being delivered.
Still yet another object of the present invention is to provide such a method which is independent of the drug.
Additional objects of the invention include the use of devices which may be used topically, ruminally or implanted, and which may be used in both human and animal applications.
The above and other objects not specifically enumerated are realized in specific illustrated embodiments of a method for automatic repetitive dosing of a single drug or alternate dosing of two or more drugs including a microdelivery system which has at least two containers for holding at least a first drug and a second drug to be dosed and which is attached to, implanted in, or orally administered to the animal. The microdelivery system is programmed to release an initial dose of the first drug to the animal. The initial dose is then followed by periodic doses of the first or second drugs to achieve an efficacious treatment of the animal.
In accordance with one aspect of the invention, the first dose is administered to the animal and the amount of drug is allowed to diminish in, for example, a first-order kinetic decline. Of course, those skilled in the art will appreciate that the present invention applies equally wells to any type of decreasing drug concentration.
Before the first drug is allowed to pass below the known efficacy threshold for the first drug, the microdelivery system releases another dose of the first drug, or an initial dose of the second drug is administered which is sufficient to bring the amount of the second drug in/on the animal above the efficacy threshold for the second drug. The dosing of the first and second drugs are then cycled to achieve a desired efficacy by always maintaining at least one of the drugs at levels above the efficacy threshold for that drug. This repetitive dosing approach maintains high-level efficacy with a minimum drug exposure for the host animal and the environment. For example, the first and second drugs may be administered shortly before the other drug drops below the efficacy threshold, or several doses of the first drug may be provided with an occasional dose of the second drug, or several doses only of the first drug may be provided
In accordance with another aspect of the present invention, the first and second drugs are delivered in such a manner that each drug remains present in the body in amounts above the efficacy threshold, or, the two drugs may be alternated to ensure that at least one of the drugs is always well above the efficacy threshold without introducing excessive amounts of either drug into the animal.
In accordance with yet another aspect of the present invention, the microdelivery system could be used to supply a plurality of different drugs with any desired sequence and timing during a designated period. Thus, for example, antibiotics or parasiticides could be delivered monthly as described above and other drugs, such as hormones which stimulate animal growth, could also be provided. The use of the microdelivery system allows a farmer to provide all of the medication needs for an animal for a prolonged period of time with a single administration of the programmed microdelivery system. Such a method can save considerable amounts of time and money by avoiding repetitive handling of the animals, avoiding doses which may induce toxicity in the host, and maximizing efficacy with minimal drug doses.
In accordance with still another aspect of the present invention, the amount of drug delivered during each dose may be correlated with the amount of drug required to address particularly high or low infestation patterns. Thus, for example, the amount of drug provided by a dose may be increased or subsequent doses may be delivered more frequently during periods, such as spring or summer, when parasitic infestations may be particularly common, and decreased to a level slightly above the efficacy threshold during fall and winter or other periods when parasite infestations are not as common.
In accordance with still yet another aspect of the invention, a plurality of different drugs for humans and animals may be automatically dosed during different periods. For example, concerns may be present about the use of two drugs because of their proclivity to interact and produce undesirable side effects. With the method of the present invention, a first drug may be delivered and allowed to fall below levels at which it is likely interact with the second drug. The second drug may then be administered and allowed to fall to a sufficiently low level before the first drug is reintroduced. Thus, medical personnel can ensure that a patient has his or her medication administered at appropriate times without requiring the medical personnel to be present each time one of the drugs is administered. Accurate, precise delivery of complex dosing regimens is thus achieved in an unattended and automatic fashion, eliminating patient compliance and practitioner administration errors from the overall therapeutic outcome.
Still another aspect of the invention includes introducing the initial dose of a drug and allowing the drug to diminish, for example, in a first-order kinetic decline. Before the drug is allowed to pass below the efficacy threshold which has been established, the microdelivery system releases a second dose of the drug to maintain the amount of the drug in the patient above the efficacy threshold for the drug.
The microdelivery system is sufficiently small that it may be administered either topically, ruminally, or it may be implanted. If necessary, the dosages provided by the microdelivery system may be maintained within a single compartment for each dose, or larger doses may be achieved by using two or more compartments.
Still yet another aspect of the present invention is mixing two or more drugs within a compartment, or during application to achieve a desired balance of the two drugs which is available to the patient. The two drugs disposed in a single compartment may be selected to interact with each other, or may be simply selected on the basis that dosing of the two drugs is desirable at approximately the same time. When dispensed from separate compartments, the drugs will typically interact in a symbiotic manner to further improve the efficacy of the method of the present invention.
The above and other objects, features and advantages of the invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:
FIG. 1 shows a graph demonstrating a first-order kinetic decline of drug levels in/on an animal when the drug is delivered by a device that releases drug by the conventional diffusion method;
FIG. 2 shows a perspective view of a microdelivery system which may be used to practice the method of the present invention;
FIG. 2A shows a fragmented, side cross-sectional view of the microdelivery system of FIG. 2;
FIG. 3 shows an isometric, exploded, partially cutaway view of an alternate embodiment of a microdelivery system which may be used in accordance with the teachings of the present invention;
FIG. 4 shows a graph demonstrating a method of repetitive, alternating dosing in accordance with the principles of the present invention, along with a first-order kinetic decline for the delivery of each dose;
FIG. 4A shows a flow chart of the process used for implementing the dosing method demonstrated by the graph of FIG. 4;
FIG. 5 shows graph of another dosing procedure in accordance with the present invention;
FIG. 5A shows another graph of a dosing procedure performed in accordance with the present invention; and
FIG. 6 shows a graph of yet another dosing procedure performed in accordance with the present invention.
Reference will now be made to the drawings in which the various aspects of the present invention will be described so as to enable one skilled in the art to make and use the invention. It is to be understood that the following description is only exemplary of the principles of the present invention, and should not be viewed as narrowing the pending claims.
Referring to FIGS. 2 and 2A, there is shown a microdelivery system, generally indicated at 100, which may be used to practice the teachings of the present invention. The microdelivery system 100 includes a housing 104 having a plurality of compartments 108 formed therein. Each of the compartments 108 has an open upper end 108a, over which a rupturable or removable cap 112 is placed. The caps 112 may be attached to the housing 104 so that one or two sides rupture when desired, or a plurality of score lines 116 can be made so that the cap 112 opens when forcefully contacted by medication disposed therein.
As shown in FIG. 2, the compartments 108 are arranged in rows to achieve maximum dosing volume in a minimum space. Positioned at one end of the two rows of compartments 108 is a utility compartment 120. The utility compartment 120 is used to house a battery 124, an oscillator 128, and a timing circuit 132. A receiver and antenna 136 may also be provided. The battery 124, the oscillator 128, the timing circuit 132 and the receiver/antenna 136 (if provided) are mounted on a substrate 140 which forms a floor of the utility compartment 120 and the other compartments 108.
Disposed in each compartment 108 is a drug containment sack 150 shown in FIG. 2A. The drug containment sack 150 has an upper opening 154 and a void 158 disposed within the sack 150 for holding medication. The upper opening 154 of each drug containment sack 150 is attached adjacent the opening 108a of a corresponding compartment. The drug containment sacks are provided for holding a drug dose to be delivered to an animal to which the drug delivery system is administered. The drug dose may be formulated as solids such as tablets, powders and granules, semisolids such as ointments and creams, or even solutions, suspensions, and emulsions.
The drug containment sacks will typically be made of material which is flexible and chemically inert. The exact material used to form the sack may vary depending on the drug to be administered. Several likely materials are set forth in U.S. Pat. No. 5,167,625, which is expressly incorporated herein.
Disposed at the bottom of each compartment 108 on the substrate floor 140 is a pyrotechnic gas generating element, typically a bead of material 162 which is responsive to heat resulting from an electrical signal applied to a heating element, thereby igniting and producing gas that fills and pressurizes the corresponding compartment. Alternatively, a non-toxic foam may be produced by an ignition material to similarly fill a corresponding compartment 108. As a compartment 108 fills with gas, the gas forces the corresponding drug containment sack 150 upwardly and the sack, in turn, forces the drug formulation contained therein against the cover 112 which ruptures and allows the drug formulation to be expelled as the sack everts. Sack 150b of FIG. 2A is shown fully everted from compartment 108b which ensures that all drug formulation initially contained in the sack, i.e. a dose, is administered to the patient.
The pyrotechnic gas generating material 162 might illustratively be a composition of nitrocellulose, nitroglycerine, hydrazine, or polyvinyl nitrate. Although not shown, a second or more pyrotechnic gas generating beads might also be included in each compartment to be activated after the first bead has been activated to thereby better ensure the complete release of drug formulation from each compartment.
The oscillator 128 supplies an oscillatory signal to the timing circuit 132 which is adapted to selectively connect the battery 124 to the pyrotechnic gas generating beads 162 in some preferred order (to activate the beads) and with a predetermined delay between activation of the different beads, to thereby discharge and administer doses of drug formulation to the patient (animal or human) over a period of time.
The timing circuit 132 operates in such a manner to selectively and sequentially connect the battery 124 by way of electrical conductors 166 to the pyrotechnic gas generating beads 162. While shown as being disposed underneath the substrate 140, the conductors can also be disposed in or on top of the substrate. Thus, the timing circuit is able to selectively trigger the release of numerous doses of therapeutic drugs over a prolonged period of time. For example, half of the compartments 108 could be filled with a first insecticide and the other half filled with a second insecticide. The timing circuit 132 could be programmed to activate release from a compartment having the first insecticide, and then activate release from a compartment containing the second insecticide after some predetermined delay. If necessary, a dose could be provided by the actuation of two or more compartments.
In such a manner, a single administration of the microdelivery system 100 can deliver a series of medication doses over a prolonged period of time. For example, if a parasiticide were released monthly, a single administration of the microdelivery system 100 would enable treatment of an animal for eight full months. Prior to the present invention, farmers would typically either round up their animals monthly to administer the medication, or would use a diffusion device which results in initially dangerously high drug exposures, followed by a prolonged period of sub-therapeutic levels as the drug diffusion device is depleted. Additionally, diffusion controlled devices are often problematic because the chemical structure and reactivity of the drug to be delivered can significantly impact the delivery curve.
The present invention offers the advantages of periodic administration of the drugs from a one time administration of the dosage form. The chemical structure of the drugs will have no effect on dosing because the microdelivery device 100 does not rely on drug diffusion or other drug-associated physicochemical phenomena to control the drug release pattern. Thus, considerable product development cost savings are achieved, in addition to improved drug efficacy.
Still another advantage of the method of the present invention is that the user can control when the microdelivery system 100 begins to administer the initial dose. A transmitter 170 can be provided to remotely transmit signals to the receiver and antenna 136. Signals from the transmitter 170 activate the timing circuit 132, thereby allowing the timing circuit to cause the drugs to be administered in a manner desired by the user. Thus, for example, a rancher could administer two microdelivery systems to each of his cattle, each of the microdelivery systems containing a six-month supply of antibiotics. One of the microdelivery systems would be activated to begin release of the antibiotics shortly after implantation. The other microdelivery system 100 could be activated approximately six months later by the transmitter 170. Thus, the rancher could reap the benefits of a one-year dosing regimen of antibiotics from a single administration of the dosage form. Annual administration of medication would save large amounts of time and money, by reducing animal handling and increasing the efficacy of the drugs. This method also provides a prolonged treatment period that can markedly exceed the duration of traditional diffusion devices, while eliminating concerns of host toxicity, subtherapeutic drug levels, development of parasite resistance, and tachyphylaxis.
The microdelivery system can be formed into numerous different embodiments. For example, in FIG. 3 there is shown a microdelivery system, generally indicated as 200, having an elongate tubular housing 204. Formed in the housing is a central compartment or vesicle 208, and a plurality of other vesicles 212 disposed in a circle about the central vesicle as shown. The vesicles 208 and 212 extend along a substantial length of the housing 204 generally in parallel with one another and include openings at the upper end 204a of the housing. A cover 216 with a plurality of rupturable portions 216a is disposed over the upper end 204a of the housing 204 to cover the openings of the vesicles, but to also rupture and allow discharge of the contents of a vesicle when adequate pressure is supplied to the cover from inside the vesicle. Although the vesicles 212 are shown to be generally the same size, different size and shape vesicles could be provided to allow for delivery of different amounts of a drug.
The housing 204 also includes a bottom compartment 220 in which are disposed a battery 224, an oscillator 228 and a timing circuit 232. The compartment 220 is separated from the vesicles 208 and 212 by a floor or substrate 236 in which are located a plurality of pyrotechnic gas generating beads 240. The circuit components 224, 228 and 232 selectively and successively ignite the pyrotechnic gas generating beads 240 in the same manner as discussed for the embodiment of FIG. 2.
Disposed in each vesicle 208 and 212 near the bottom thereof are pistons or plungers 244. The side surfaces of the plungers 244 are shaped to conform to and snugly fit within the side walls of the corresponding vesicles so that as a plunger is forced upwardly in a vesicle by gas pressure, it pushes out of the housing a drug formulation contained in the vesicle. The plungers 244 are forced upwardly in the corresponding vesicles by the activation of the pyrotechnic gas generating beads (or other geometric shapes) 240. Of course, the plungers 244 need not be used, as the drug formulation can be forced out the vesicle 208 by the gas itself.
Advantageously, the plungers 244 are made of polyurethane, synthetic rubber, silicone greases, petrolatym, paraffin, bees wax or other material which will allow for a slidably tight fit within the vesicles. The housing 204 could illustratively be made of rigid molded polymers (polycarbonate, ABS, polyesters, or other nonelastomeric thermoplastics or thermosets) or formed metals.
The microdelivery system 200 is advantageous in that the large number of vesicles 208 and 212 can hold numerous doses of the medications to be administered. For example, if alternating dosages are desired on a monthly basis, the microdelivery system 200 could provide drugs for more than a year without the need for implanting or otherwise administering additional dosage forms.
Referring now to FIG. 4, there is shown a graph demonstrating a method of dosing in accordance with the principles of the present invention, along with a first-order kinetic decline after delivery of each dose. For illustration purposes, the amount of drug available on an ear tag device configuration that is available to kill flies is graphed.
An initial dose 300 of a first drug, represented by solid line 304, is provided to kill flies. While referred herein as an ear tag which is clamped to an animal's ear, those skilled in the art will appreciate that the devices could be implanted, placed in the stomach of the animal, or placed in other areas. Additionally, the reference to a first drug should not be viewed as to limit the contents of a compartment of the microdelivery device, as two or more drugs could be disposed in a compartment of the microdelivery device for simultaneous administration.
As shown in FIG. 4, the initial dose is about 1400 milligrams. However, those skilled in the art will appreciate that the amount provided will depend both on the drug used, the type and size of the animal, and the disease. For illustration purposes, treatment of a parasitic fly infestation will be discussed, as those skilled in the art will be familiar with numerous parasiticides which may be used for such a purpose. After approximately 30 days, the levels of the first parasiticide 304 drop to near the efficacy threshold. Rather than providing additional quantities of the first drug 304, the microdelivery system (FIG. 2 or FIG. 3) is programmed to activate expulsion of a second drug 310 from a compartment or vesicle to provide the dosage indicated at 312. As shown in FIG. 4, 1400 milligrams of the second drug are provided to kill any parasites which have not been killed by the first drug 304.
As the second drug 310 falls toward the efficacy threshold 308, a sufficient quantity of the first drug 304 is again provided by the microdelivery system to bring the levels of the first drug 304 back up to 1400 milligrams. The amount of the first drug 304 necessary to reach the target dose is less than needed for the initial dose because of the residue first drug from the first dose. Thus, the second and subsequent dosings of either drug can typically be in smaller quantities, or delayed a sufficient period of time to prevent drug build up to levels which risk host toxicity. As shown in FIG. 4, approximately 900 milligrams is used for each dose after the initial dose for each drug.
By cycling the drugs in the manner described, considerable advantages are achieved. Of primary importance is that the cycling prevents the development of resistance to the parasiticide in the targeted parasite. There is always at least one of the drugs which is sufficiently above the efficacy threshold to eliminate the parasitic infestation. The two cycling drugs prevent multigenerational parasite turnover in the presence of subtherapeutic drug levels which is typically associated with development of resistance to drugs. Thus, resistance is substantially eliminated.
An additional advantage of the cycling is that the repetitive replenishment of drug keeps the total drug exposure for the host to a minimum. As shown in FIG. 4, one device administration has provided effective treatment of the animal for approximately five months. To achieve a similar treatment pattern with conventional dosage forms such as prior art diffusion devices would require the farmer, rancher, etc., to round up and treat the animal with the first or second drugs during each of the five months or periodically reapply diffusion-type devices. When dealing with large numbers of animals, the time and expense involved with such procedures is prohibitive.
FIG. 4A shows a flow chart of the process used for implementing the dosing method demonstrated by the graph of FIG. 4. The initial step 320 is accomplished by administering the device to the animal. The device may be attached to a collar, ear tag or similar device to provide topical treatments, or may be conveniently implanted, such as in an animal's ear or orally administered for retention in the rumen of ruminant animals, to provide the drugs into the blood stream.
The second step 324 is accomplished by providing an initial dose of the first drug in a sufficient quantity to surpass the efficacy threshold for the drug. This is followed by the third step 328 of providing an initial dose of the second drug while the level of the first drug is above the efficacy threshold.
The fourth step 332 is performed by supplying a second dose of the first drug while the amount of the second drug in the animal remains above the efficacy threshold for the second drug. Those skilled in the art will appreciate that the efficacy thresholds for the first and second drugs will often be different. However, for ease of reference, the efficacy thresholds for the two drugs are shown to be the same.
As indicated at 336, the dosing pattern can continue for a predetermined period of time, such as for 6 months. The actual time during which the microdelivery system will typically be used depends on the parasite infestation patterns and the amount of the first and second drugs which may be held in the microdelivery system.
While the graph of FIG. 4 shows the first and second drugs alternatingly falling below their efficacy thresholds, those skilled in the art will appreciate that a desirable dosing pattern is to keep both drugs above their efficacy thresholds for the entire period of treatment. Thus, instead of alternating the first and second drugs on a monthly basis, dosing may occur on a biweekly basis or a larger dose may be supplied. Such a dose, however, will be well below the potentially dangerous doses which attend administration of diffusion-type devices.
While more compartments are used if biweekly dosing is selected, the overall quantity of each drug used is relatively similar because the second and subsequent dose of each drug will need to be substantially less to bring the drug level to that shown at the top of each first-order kinetic curve.
In accordance with the graph and flow chart of FIGS. 4 and 4A, permethrin and chlorpyrifos insecticides are disposed in the microdelivery system 100 of FIGS. 2 and 2A and attached as an ear tag onto the ear of an animal for control of ectoparasites such as horn flies. The insecticides are formulated in combination with solvents, polymers and other additives as necessary to retard depletion of an expelled dose over a one-month period. A first dose of permethrin is supplied in sufficient quantity to raise the amount of available permethrin above the efficacy threshold. Applying a first-order kinetic depletion curve to the amount of permethrin that is available, the permethrin is formulated to stay above the efficacy threshold for one month. Similarly, the microdelivery system 100 is programmed to release a sufficient quantity of chlorpyrifos to bring the level of the drug above the efficacy threshold for chlorpyrifos and maintain a level above the efficacy threshold for one month. The microdelivery system 100 actuates a compartment holding the largest dose of chlorpyrifos four weeks after the first dose of permethrin is released.
Four weeks after the first dose of chlorpyrifos is released, the microdelivery system again actuates a compartment containing permethrin to release additional quantities of that drug. Because of the residual quantity of permethrin from the initial permethrin dose, the second permethrin dose will be a fraction of the first permethrin dose. According to FIG. 4, the second permethrin dose would be approximately 65% of the initial permethrin dose.
Therefore, the microdelivery system will be programmed as to which individual compartment to release for the first and all subsequent doses.
By continuing to alternate doses of the first and second drugs until each of the eight compartments 108 has been emptied, the microdelivery system 100 provides doses which prevent parasite infestations for approximately six months. This is accomplished with a single device administration, saving the farmer or rancher time and money, while allowing both drugs to be kept well below levels which might induce host toxicity. Additionally, tolerance development by the parasites is nearly eliminated because the continual replenishment and alternating of the pesticides precludes multigenerational parasite turnover under conditions of sub-lethal insecticide exposure that is required for tolerance to develop. It is important to recognize in accordance with the present invention that alternating, as used herein, may include a one to one sequence, e.g. A-B-A-B . . . , or some other combination, e.g. A-A-B-A-A-B-A-B-B . . . , as may be desired to most efficaciously minimize the threat of parasite, etc., infestation during a predetermined period of time, while minimizing the risk of toxicity to the animal.
Referring now to FIG. 5, there is shown a graph of another dosing procedure in accordance with the present invention. An initial first dose 400 is provided of a first drug, the level of which is indicated by line 404. The initial first dose 400 of the first drug is approximately 1400 milligrams. At such a quantity, the amount of the first drug on the animal or available on a device configuration such as an ear tag, remains above the efficacy level 408 for approximately 60 days.
Approximately one month after the first drug is released, an initial dose 412 of a second drug, indicated by the dashed line 416, is released. The amount of the second drug 416 which is released is also 1400 milligrams and will take approximately 60 days to drop below the efficacy threshold for the second drug. For ease of reference, the efficacy threshold for the second drug is indicated as being the same as the efficacy threshold 208 for the first drug. Those skilled in the art will appreciate that the efficacy threshold for each drug used must be considered when determining the quantity of that drug released and the time between dosing and the presence of subtherapeutic levels of the drug.
Unlike the dosing regimen in FIG. 4, the amount of drug delivered with each dose is kept the same. Thus, because the level of the first drug has fallen to 500 milligrams, providing a second dose of 1400 milligrams, as indicated at 220, results in 1900 milligrams of therapeutically available drug. Likewise, a similar increase in the level of the second drug is achieved by use of a full 1400 milligram dose of the second drug, indicated at 424.
FIG. 5 also shows a third dose, indicated at 428, of the first drug. The third dose 428 is also 1400 milligrams, thereby bringing the amount of the first drug to a peak of slightly more than 2000 milligrams. Each of the two drugs are eliminated or degraded with a first-order kinetic decline, as indicated at 432 for the first drug and 436 for the second drug.
The dosing of the drugs so as to create an increase in the drug level in the animal with each subsequent dose can be used advantageously in several ways. First, if the goal is simplicity in manufacturing the microdelivery system, the method allows the system to be manufactured with each compartment containing the first drug to have the same quantity. Likewise, each compartment containing the second drug can have the same quantity. Rather than requiring the microdelivery system 100 or 200 to be programmed to release the compartment with the first (higher) dose of each drug, the system must only ensure that the compartments containing the first and second drugs, respectively, are released in an alternating pattern. To prevent build-up of the first and second drugs, all doses after the second dose for each drug would simply be delayed.
In the alternative, the escalating quantity achieved by the dosing level as shown in FIG. 5 can be used to improve the correlation between dosing and infestation patterns. For example, if a particular parasite infestation is most common during a specific month or period, the microdelivery system can be programmed to release a compartment containing a particularly high quantity of one or both drugs during the infestation period. Doses subsequent to the infestation period would be modified to return the drugs to a level desired when high-level infestation is not a concern.
Of course, a single drug could be used in the dosing pattern. As will be apparent to those skilled in the art from FIG. 5, either of the drugs delivered could be administered periodically to keep the drug doses to a minimum while ensuring that the available amount of the drug remains above the efficacy threshold. In such a manner, the development of resistance would be greatly diminished, as the available amount of the drug remains above the subtherapeutic level needed for resistance to develop.
Referring now to FIG. 5A, there is shown a graph representing the use of a microdelivery device such as those shown in FIGS. 2 through 3. The device is used to selectively control the therapeutically available amount of each drug to correlate the same to an infestation period, indicated at 504. An initial dose 508 of a first drug, indicated by the solid line 512 is 1400 milligrams and the efficacy threshold 514 for the first drug is 700 milligrams. Thus, the first drug 508 falls to the efficacy threshold 514 after approximately 30 days.
A second drug, indicated by dashed line 516 is provided. The initial dose 520 is 1400 milligrams and the second drug 516 has a similar efficacy threshold 514 as the first drug. The initial dose 520 of the second drug 516 is provided approximately 15 days after the initial dose 508 of the first drug 512.
A second dose 524 of the first drug 512 is provided after thirty days. To achieve an available level of 1400 milligrams for the first drug 512, the second dose 324 is 700 milligrams.
On about the forty-fifth day, a second dose 528 of the second drug 516 is provided. The second dose 528 of the second drug 516 is also 700 milligrams, thereby bringing the available level of the second drug back up to approximately 1400 milligrams.
A third dose 532 of the first drug 512 is provided on the 60th day. Because the 60th day is also the approximate beginning of the typical infestation period 504 for a particular parasite, the third dose 532 of the first drug 512 is increased to 1400 milligrams, the same as the initial dose 308. The third dose of the first drug 512 achieves a level of approximately 2100 milligrams. The increase in drug level decreases the risk that the animal will become infested during a high-level infestation period.
The second drug 516 is also released in a greater amount during its third dose 536 to raise its level to approximately 2100 milligrams. The level for each of the drugs is raised up to approximately 2450 milligrams by providing a 1400 milligram fourth dose 540 and 544 for the first and second drugs, respectively.
To return to the preinfestation drug levels, the fifth dose 350 and 354, for each of the drugs is spaced approximately 60 days from the fourth doses 540 and 544 of the respective drug. It is important to note that while the first drug transiently falls below the efficacy threshold, the second drug remains fully therapeutic and covers the need. The fifth dose 550 for first drug 512 is 790 milligrams, as is the fifth dose 554 for the second drug 516. Any subsequent treatment is provided by doses of 700 milligrams.
Thus it can be seen that the method for using the microdelivery system 100 or 200 enables the user to control dosing patterns to correlate available drug levels with infestation patterns. By careful planning, the user is able to use the minimum amount of the drug to maximize efficacy. This can be achieved either by timing the release of each compartment to achieve desired dosing levels, or by adjusting the quantity of the first or second drug which is contained in each compartment and then actuating the delivery from the compartments in a predetermined pattern. When a first quantity of one of the drugs is delivered in the initial dose, maintaining the effective levels of the drug can either be done by applying a second, smaller quantity on the second and subsequent dose for that drug, or by providing the same dose and extending the time before the next delivery. Likewise, the delivered drug levels can be modulated to correspond with seasonal fluctuations in parasitic infestations by altering either the quantity of the drugs delivered and/or by changing the timing at which the drugs are delivered.
While discussed primarily with respect to the control of parasites in animals, those skilled in the art will appreciate that the present method has a variety of medical applications. Thus, for example, a microdelivery device 100 or 200 could be programmed to provide medications in patterns which maximize their efficacy while minimizing adverse reactions or other problems. Furthermore, because the microdelivery devices are implantable or attachable to the patient, the drugs may be delivered in the most efficacious cycling while allowing the patient relative mobility. Thus, the principles of the present invention are equally applicable to medical applications in humans as it is to parasite control in animals.
Referring now to FIG. 6, there is shown an alternate dosing procedure of the present invention. Each of three drugs 604, 608 and 612 are provided to an animal. However, if two or more of the drugs are simultaneously present in sufficient quantities, the animal being treated will suffer from adverse side effects. Those skilled in the art will appreciate that the type and extent of any side effects are dependant on the amount of drugs provided.
To prevent adverse side effects, the first drug 604 is supplied to the animal in an initial dose 620. Based on the dose provided, it is known that the systemic level of the first drug 604 will fall to a level at which the second drug 608 may be introduced without side effects after time period A. Thus, the microdelivery system 100 (FIGS. 2 and 2A) or 200 (FIG. 3) is programmed to release an initial dose 624 of the second drug 608 after time period A.
Following a first-order kinetic curve, the second drug 608 falls to a sufficiently low level after time period B to allow introduction of an initial dose 628 of the third drug 612. The third drug 612 also is eliminated until a second dose 632 of the first drug 604 may be introduced at time period C. The alternate dosing of the first, second, and third drugs 604, 608 and 612, respectively, can be continued until the drug delivery is no longer needed, or until the microdelivery system 100 or 200 has been fully depleted.
Those skilled in the art will appreciate that regardless of which microdelivery system is used, the practitioner responsible for assuring that drug therapy is provided can utilize established pharmacokinetic/pharmacodynamic principles and program the devices to deliver an optimal dosing regimen. Relying on this information, the programmer can determine not only when a drug should be released, he or she can selectively control compartments having different dosing levels to select an optimum dosing pattern for the particular use.
While the present invention will be desirable for a large number of insecticides, parasiticides and other drugs as listed in the Merck Index, the following drugs are currently viewed as being highly desirable for administration in accordance with the principles of the present invention which are set forth above:
pyrimiphos methyl
moxidectin and
insect growth regulators
Thus there is disclosed a method for automatic, alternate dosing of two or more drugs. Those skilled in the art will recognize numerous modifications which can be made without departing from the scope and spirit of the invention. The appended claims are intended to cover the scope of the invention.
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|U.S. Classification
|604/500, 604/891.1, 604/131
|International Classification
|Cooperative Classification
|European Classification
|Jun 11, 1997
Owner name: SARCOS, INC., UTAH
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JACOBSEN, STEPHEN C.;ZENTNER, GAYLEN M.;REEL/FRAME:008611/0131
Effective date: 19970602
|Jan 18, 2002
|Fee payment
Year of fee payment: 4
|Feb 13, 2002
|Maintenance fee reminder mailed
|Jan 20, 2006
|Fee payment
Year of fee payment: 8
|Oct 29, 2007
Owner name: SARCOS INVESTMENTS LC, UTAH
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SARCOS, INC.;REEL/FRAME:020024/0570
Effective date: 20071026
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Effective date: 20071102
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|Fee payment
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text:
I just moved to Marietta. It's alright so far.
I come off as nonchalant on many things, but only because I don't stress on things that aren't that important.
Keeping a straight face.
Some books: Blankets by Craig Thompson, Holidays on Ice by David Sedaris, A Scanner Darkly by Philip K. Dick, Wigfield by Amy Sedaris, Stephen Colbert, and Paul Dinello, and Nick Adams Stories by Ernest Hemingway.
Some music: The Features, Sam Roberts Band, David Bowie, Queen, Daft Punk, The Pillows, Beastie Boys, Franz Ferdinand, and Nick Cave and the Bad Seeds.
Some shows: on right now are Parks and Rec, Always Sunny, Friends, Superjail, Freaks and Geeks, Strangers with Candy, the Critic.

subset: commoncrawl


text:
Jacques Rogge says they can be proud of both their athletes and the way Canada has welcomed the world.
Canada's Olympians have won 13 gold medals in Vancouver and Whistler - more than any other nation. They've tied the record for the most ever won by a single country at a Winter Olympics.
But the gold medal that is more precious than all others to most Canadians is still up for grabs.
And the anticipation of this afternoon's men's hockey final between Team Canada and the rival Americans is palpable across the land where hockey rules.
Complete Coverage: Vancouver Olympics
For all intents and purposes, this country will grind to a halt this afternoon as Canadians glue themselves in front of their TV sets.
The puck drops at 12:15 p.m. PT (3:15 p.m. ET) for an event that's expected to produce a record audience for a Canadian sports event.
The North American neighbors played the most competitive game of the Olympic hockey tournament a week ago on a day dubbed Super Sunday. It was a 5-3 U.S. victory, which convinced the Americans they were the best team, and awakened the Canadians to the fact that an Olympic gold medal in their national sport wouldn't be a walkover.
"There were no expectations for us, from the media or the fans, no expectations for us other than ourselves," U.S. defenseman Jack Johnson said. "I think we had higher expectations for ourselves than anyone. Our expectations were to win a gold medal, we've put ourselves in a position to do that and I think we've earned that, absolutely."
Canada is the hockey superpower that always was supposed to play for the gold medal, on home ice, in the very country that claims the game as its own.
The U.S. hasn't won a hockey gold outside of its own borders but has been the best team in the Olympics so far.
Beating Canada once was difficult enough for the U.S., but they'll have to do it again if they don't want to leave with the silver for the second time in three Olympics. Canada also beat them in Salt Lake City eight years ago.
"It's hard to beat a team twice in a tournament like this," U.S. coach Ron Wilson said. "But we've beaten Canada, and we'll play better than we did the last time we played against them."
Last Sunday's win by the Americans over Canada was the first in the Olympics for 50 years. On Sequel Sunday, the U.S. will try to become Olympic champions on in the 50th anniversary year of their gold medal in Squaw Valley, California, in 1960.
"We all talked, `Wouldn't it be nice?' and now we have the opportunity," said U.S. goaltender Ryan Miller, who has arguably been the games' best goalie. "We have the talent. We have some youthful excitement, we have the right kind of veteran players."
A decidedly young U.S. team also has a chance for the gold that the now-eliminated Russians, Swedes, Czechs and Finns don't have. The U.S. is the only team to win every game in regulation in Vancouver, and it owns two of the most impressive victories by beating Canada and 2006 silver medalist Finland 6-1 in the semifinals.
Team Canada has been beaten only once in Vancouver - to the Americans - and have been very good since losing to the U.S., blowing out Germany 8-2 and Russia 7-3, but they've also shown some vulnerability. The Americans' speed confounded them, and they barely held on to beat Slovakia 3-2 in the semifinals Friday night as Roberto Luongo gave up two late goals.
"We've got to jump on them early," American forward Ryan Kesler said Saturday. "The Russians and Slovaks sat back and we're not going to do that, we're going to go right after them from the puck drop. We're going to have to get in his (Luongo's) face."
Canada's confidence apparently wasn't shaken by last Sunday's loss. Coach Mike Babcock was half-smiling after the Slovakia game when he said the U.S. should be favored, and defenseman Shea Weber said, "They did beat us, but now it's a whole different game."
Miller might represent the United States' biggest advantage; he has outplayed Luongo, who took over for Martin Brodeur following the loss to the U.S.
"We were too easy on Miller last time," Babcock said. "We won't be this time."
Neither will the crowd, which has kept the pump-up-the-Canadians volume at rock-concert levels game after game.
"The Canadians view this as their game and they view this game as planting a flag on a peak," Burke said.
The player expected to be Canada's best, Sidney Crosby, hasn't scored in two games and his most significant contribution was beating Switzerland in a shootout. He has yet to dominate, but what better time to start than the gold-medal game? When Crosby last faced Miller in the NHL, on Feb. 1, he scored three goals.
"I feel like I've generated a lot of chances," Crosby said. "The puck hasn't gone in as easy for our line the last couple of games, but we've been right there and that's a good sign. Hopefully, this is the time we're going to break out here."
If there is one shared sentiment in the Canadian dressing room, it's this: We're not going to let the United States beat us twice.
"It doesn't matter who we play in the gold-medal game, we want it so bad," forward Jonathan Toews said. "It will feel good to beat the U.S., for sure."
The game, Toews said, is "an opportunity of a lifetime" for any player.
Canadadian forward Rick Nash said this "is going to be a fun day."
At the Vancouver Olympics, the U.S. squad has a perfect 5-0 record, including a 5-3 win over Canada in a preliminary round game a week ago.
In Toronto Sean Fleming says it's more than just a game, it's a battle between the two countries.
He says hockey represents Canada's national identity and there's always that special desire to beat the Americans at our game.
Bruce Arseneau of Moncton, New Brunswick predicts a tough game, but says Canada will win if it plays 60 minutes of good hockey.
The tickets still available for today's gold-medal hockey match between Canada and the U.S. are selling for thousands of dollars.
Showtimetickets.com wants $138,000 for a suite, or about $6,900 for a seat in the suite.
Tickets on eBay Canada are selling for as much as $15,000, but Renee Smith-Valade of Vancouver's Olympic organizing committee says buyer beware.
She says there's no guarantee the tickets are legitimate if they haven't been purchased through authorized ticket reseller.
Ticket prices from those resellers are capped at 10 times the original price - which ranged from $350 to $750 apiece.
The closing ceremonies take place this evening at 8:30 p.m. ET.


text:
Low Carb Lasagna
Recipe by Chef amfox
This recipe is a rendition of the classic favorite that uses zucchini instead of pasta and healthy alternatives to other fattening ingredients
Top Review by TrebleChef
Ok, well I modified quite a bit, but the whole family was so surprised that it was meatless! My youngest (age 10) was "afraid" to try it, but loved it and ate it all. Here is a quick list of my modifications:
1/2 the mushrooms and I chopped them.
We used more mozzarella then the recipe called for. Probably about 1 cup or more. Enough to cover each layer fairly well.
My tomatoes were a little under-ripe, so I added half a can of tomato paste during that step.
I added a layer from my favorite traditional lasagna recipe for more protein. The layer is 2 cups of lowfat cottage cheese, one egg, 2 tbsp finely grated parmesan, and 1 tbsp of dried parsley mixed together.
I layered it differently and used the spinach mentioned in the recipe during the layering process (since I couldn't find out how to use it in the recipe.) 1/2 Zucchini, 1/2 spinach, 1/2 cottage cheese blend, 1/2 sauce, 1/2 cheese, repeat.
This recipe was A LOT of work, so I was so thankful the experiment was worth it. Don't know how often I'll go in for that long of a job again, but if you like to cook, you'd probably love this recipe.
See Discussion:3 Reviews
Ingredients Nutrition
- 3 large zucchini
- 1 tablespoon salt
- cooking spray
- 1 1⁄2 cups diced onions
- 2 minced garlic cloves
- 12 ounces button mushrooms
- 3 cups chopped tomatoes
- 1 tablespoon dried basil
- 1 teaspoon dried oregano
- 1⁄4 teaspoon ground nutmeg
- 1⁄4 teaspoon black pepper
- 1⁄2 cup fat free mozzarella cheese
- 3 -4 cups raw spinach leaves
Directions See How It's Made
- Slice the zucchini lengthwise into 1/8-inch thick strips. Place in a bowl and salt generously, tossing once or twice to coat well. Lay strips on paper towels on your work surface. Set aside 1 hour.
- Meanwhile, spray a large saucepan with nonstick spray and set over medium heat. Add the onion; cook, stirring often, until softened, about 2 minutes. Add garlic; cook 20 seconds.
- Add the mushrooms; cook, stirring often, until they give off their liquid and it reduces to a glaze, about 7 minutes.
- Stir in the tomatoes, basil, oregano, nutmeg and pepper. Cook, stirring occasionally, until the tomatoes start to break down and the sauce thickens, about 25 minutes.
- Position the rack in the center of the oven and preheat the oven to 350°F.
- Blot any moisture off the zucchini strips with paper towels. Use one third of the zucchini strips to line the bottom of a 9 x 13-inch baking pan, laying them lengthwise like you would lasagna noodles. Top evenly with one third of the sauce, then one third of the shredded cheese. Place half the remaining zucchini strips on top, as before, then top evenly with half the remaining sauce and half the remaining cheese. Repeat this process one more time: using the remaining zucchini, remaining sauce, and remaining cheese.
- Bake, uncovered, until bubbling, about 45 minutes. Let stand at room temperature for 10 minutes before slicing into 6 pieces; serve.


text:
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0.4 acres in Pope County, Arkansas
Water Front With Boat dock included! Beautiful views inside and out, updated home with new wood flooring, updated bathroom, and kitchen.
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In "Utah's STEM problem" (Opinion, May 25), Matt Berry, CEO of Sandy-based Orca Health, complains about the STEM problem in Utah that we do not have enough college graduates in science, technology, engineering and math who are legal residents of the U.S. to staff his company. He asserts we need more visas to allow immigration for foreign workers with these skill sets.
People do not graduate with a masters degree in engineering without first singing the alphabet song in kindergarten. People rarely do doctoral-level research in genetics or nuclear physics without first passing calculus in high school.
Which makes me wonder. When was the last time Berry wrote an impassioned article demanding that Utah significantly increase funding for public schools? When was the last time he went to the Legislature and demanded that his own taxes be increased, that we all make a bigger commitment to education, so we can have high school math and science classes with 15 students instead of 40?


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Crispin Lansdowne Cider
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- Size: 22oz
- Type: Hard Cider
- Country: United States
- Region: Minnesota
"..A full bodied, confident & imposing cider. Fermented from a premium blend of fresh pressed apple juice, not from concentrate, using Irish stout ale yeast. It produces a slight hint of butterscotch, balanced by a subtle fruitiness and slightly dry crisp finish.."
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Voting or Buying: Inconsistency in Preferences toward Food Safety in Restaurants
Consumers sometimes prefer stricter food regulations as voters than as consumers. A prime example is that battery-cage eggs were the most sold types of eggs in California in 2008 when 63% of voters supported the animal welfare proposition forbidding battery-cage eggs starting from from 2015. In this paper, we investigate whether a similar consumer-citizen duality might exist in willingness to pay for food safety standards in restaurants. Using a split sample willingness to pay survey we find that consumers have a higher willingness to pay for improved restaurant food safety standards when voting than when acting as consumers. The results are discussed in the light of the literature on trust, social choice and public choice theory.
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Mauviel Copper Beating Bowl
Need a special gift for the person in your life that loves to cook?! This beautiful, French Mauviel Copper Beating Bowl @williams-sonoma.com, is idea for mixing and the brass handle makes gripping and hanging easy. The bowl has a 5 qt. capacity and can be purchased for $99.00. Stand is extra.
Get in the mood for spring with this Le Creuset cast iron 9-piece set. Adds such a clean, happy aura to the kitchen there's definitely no need to stuff these beautiful pieces away in the cupboard!Tags: home, kitchen, cooking, kitchen tools, eating, dining, cast-iron, Le Creuset, Kitchen GadgetsAdded 9 Years Ago from Williams-Sonoma
an important first in eatting healthy, these salad servers will last forever and make the dinner table look good.Tags: home, kitchen, kitchen tools, home decor, dining, home accessoriesAdded 10 Years Ago from Williams-Sonoma


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You hear it all the time — someone says, "I want to work for a company with a good culture." Just what does that mean? What is a "good company culture," why is it so important, and how can you choose the best culture for you? • According to management.about.com, "company culture" is the sum of values and practices shared by a company's employees. It goes on to say that companies with adaptive cultures that are aligned with business goals outperform their competitors, some say by 200 percent or more.
So, what do these companies with adaptive cultures have in common?
• A specific mission statement that includes their values, their commitment to quality, integrity, their employees, their customers and their community.
• A plan to align that culture to business goals.
• The ability to change and modify quickly as necessary.
• Employees who are empowered, motivated, feel free to communicate, and have a stake in how well the company does.
• A willingness to communicate both good and bad news quickly and a commitment to implement a plan to overcome negative situations.
Yet, even the most progressive firms are aware that over time their company culture will change. Like a flowing river, circumstances, changing markets, leaders and key employees leaving and coming in, new products and services and increased competition all will affect company culture. How well the culture survives depends on how well it has been developed and nurtured and how strong it is.
Do your homework
Once you've decided, here are some tips that will help you link to a company with the best type of culture for you.
• Talk with people who work there.
• Read articles about the company and its leaders in print, online, in trade journals and in business publications.
• Check into the company's financials. Is it holding its own through this recession? Is it growing or slipping? What are its future projections?
• Is there a growing market for the company's products and services? Is it innovative and planning for future markets? How is competition affecting it?
• How well and how quickly does the company respond to negative news? BP's slow response to the oil spill, its seeming lack of understanding of the people directly affected, and its CEO's apparent disinterest will color its reputation and the reputation of people working for it for years to come.
Marie Stempinski is founder and president of Strategic Communication in St. Petersburg. She specializes in public relations, marketing, business trends and employee motivation. She can be reached at email@example.com.


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Janie Frost of Philadelphia, and Gary and Vicki Wolf of Worcester, Pa., announce the engagement of their children, Melissa Frost and Sam Wolf.
Melissa, a graduate of Pennsylvania State University, holds a Bachelor of Science degree in finance. She is an administrative assistant for a real estate company in Philadelphia.
Sam, a graduate of Abington Friends School, earned a Bachelor of Science degree at American University in management information technology. He is president of the Internet health-and-wellness website: Luckyvitamin.com.
Melissa is the granddaughter of Jerri Shafran of Annapolis, Md., and the late Joe Shafran. Sam is the grandson of Libby Singer of Wyncote and the late Seymour Singer; and Lois and Ed Wolf of Norristown, Pa., and Boca Raton, Fla.
Sharing in the couple's happiness are Melissa's sister, Beth, and Sam's brothers, Sean and Jeremy.
The couple is planning a summer 2012 wedding in Napa Valley, Calif.


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Stephanie Sugar FlameModel Female Los Angeles, California, US
My MM URL: http://www.modelmayhem.com/StephanieSugarFlame
Mayhem # 737447
About Me
Currently I am only accepting paid shoots (excluding photographers I have worked with in the past for TFP).
I am a Photographer, Makeup Artist, Dancer and most importantly a MOTHER! I am a completely free spirit who believes in living life to the fullest every single day. I am professional and very expressive (I know what a pain it is to attempt to photograph people who are not). I welcome projects that are outside of the box but am not interested in depicting violence against anyone or anything..namely women or animals. I am comfortable with nudity in the right situation (please inquire about my rates for shooting nudes) but reserve the right to bring a non-invasive, shadow of an escort to any shoot if I haven't worked with the photographer before. As stated, I am a Makeup Artist with a ton of experience and am comfortable doing my makeup but, in all honesty, I would rather not have to worry about it and prefer to let someone else get a credit for their port since I already have a solid one. When I work I like to focus on my main task at hand...in front of or behind the lens...wherever the day takes me. Please see my photography at MM # 481060.
-Accepting select TF*, content trade, paid assignments, and select wardrobe exchange.
To see my photography profile, please go here:
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NUHS Accreditations, Approvals, and Listings
NUHS is accredited by the Higher Learning Commission (HLC), of the North Central Association (NCA). Please review our Accreditation page for more details about our Notice status. North Central Association of Colleges and Schools was founded in 1895 as one of six regional institutional accreditors in the United States. The Higher Learning Commission accredits, and thereby grants membership in the Commission and in the North Central Association, degree-granting post-secondary educational institutions in the North Central region.
Instructions for Filing a Complaint with the Higher Learning Commission of NCA
Complaint Processes required by 34 CFR § 668.43 (Program Integrity Rule)
United States Department of Education Regulation 34 CFR § 668.43(b) requires institutions of higher education authorized under Title IV of the Higher Education Act to make available to enrolled or prospective students upon request documents describing the institution's accreditation and its State, Federal, or tribal approval or licensing. The institution must also provide its students or prospective students with contact information for filing complaints with its accreditor and with its State approval or licensing entity.
Most external grievance processes require that the student first exhaust internal processes. NUHS expects that any student complaint will be filed in accordance with the procedures currently in place at the institution before seeking a resolution from a state or federal agency or any of the University's accreditation bodies. In the absence of or unfamiliarity with a procedure, the complaint should be filed with the Office of Student Services in the Caruth HEC-Annex in Florida or Janse Hall on the Illinois campus.
NOTE: No student will be subjected to any form of retaliation as a result of an earnest, good faith filing of a complaint. See: NUHS Non-Retaliation Policy.
How to File an Internal Academic or Non-Academic Grievance
In order to ensure an effective response, initial complaints should be prepared in a typed or written format. Complainants should describe the issue in their own words; include their full name and contact information. Please include dates and any college officials that were involved or have been contacted. Any supporting documentation, such as emails or other correspondence, should be included in order to help others understand the nature, context, actions, or events that lead to the complaint. Finally, the complainant should state what, if any, remedy is sought.
Where to File an Internal Academic or Non-Academic Grievance
For Complaints Regarding the Financial Aid Program:
Marc Yambao
Director of Financial Aid
2nd Floor, Janse Hall, Illinois campus
For Complaints Regarding Programs within the College of Professional Studies - IL:
Dr. Robert Shiel
Dean of the College of Professional Studies - Illinois
Janse Hall, Illinois campus
For Complaints Regarding Programs within the College of Professional Studies - FL:
Dr. Daniel Strauss
Dean of the College of Professional Studies - Florida
For Complaints Regarding Programs within the College of Allied Health Sciences, Ungraduate Studies, and Distance Education:
Dr. Jerrilyn Cambron
Dean of the College of Allied Health Sciences and Distance Education
For Complaints Regarding Programs within the Lincoln College of Post-professional, Graduate and Continuing Education:
Dr. Jenna Glenn
Dean of Lincoln College of Post-professional, Graduate, and Continuing Education
For Complaints Regarding any Non-Academic University Issue (Discipline, Discrimination, Sexual Misconduct, Harassment, Disabilities, Privacy, Misuse of Computing Resources, Mental Health Concerns, Student Safety & Security, etc.)
Yesenia Maldonado
Dean of Students
Where to File a Complaint With a Program's Accrediting Agency
For the Chiropractic Program (IL and FL): The Council on Chiropractic Education (CCE) complaint process is located on the website www.cce-usa.org under the keywords "CCE Policy 64."
For the Chiropractic Program (only FL): The Commission for Independent Education, Florida Dept. of Education, has also licensed this program in FL. To file a complaint with this body contact the Commission at 325 W. Gaines St., Suite 1414, Tallahassee, FL 32399, 888-224-6684.
For the Naturopathic Medicine Program: In addition to the HLC, the ND program has been accredited by the Council on Naturopathic Medical Education (CNME). To file a complaint with this body contact CNME, 342 Main St., PO Box 178, Great Barrington, MA 01230, 413-528-8877.
For the Acupuncture & Oriental Medicine Program: The Accreditation Commission for Acupuncture and Oriental Medicine (ACAOM) complaint process is located on the website www.acaom.org at this address: www.acaom.org/students/.
For the Bachelor of Biomedical Science & the Associate in Applied Science in Massage Therapy Programs: The Higher Learning Commission (HLC), of the North Central Association of Colleges and Schools(NCA) complaint process instructions can be found at this link: Filing a Complaint with the HLC of NCA.
For the Massage Therapy Certification Program: Accredited by the Commission on Massage Therapy Accreditation (COMTA) the complaint procedure is located on the website www.comta.org under the keywords " Complaint Procedure."
Note: Also applies to programs on FL campus.
Illinois State Board of
100 N. 1st St., Springfield, IL 62777
866-262-6663 or 217-782-4321


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Jamaica wedding with family and friends: Carnival Liberty Cruise Review by mankato320
Overall Member Rating
Jamaica wedding with family and friends
Destination: Western Caribbean
Embarkation: Miami
We arrived in Miami very late but had little trouble finding the hotel shuttle. My review here is about the Liberty, however if you are looking for hotel info. we had so many problems with the Wyndham that I would highly recommend you stay elsewhere.
This was our first cruise; we loaded 13 people and enough gear for 30 people into 3 cabs ($24 per cab rate max 5 people), and headed to the Port of Miami. We arrived at the Port at around 11 AM and it was already a madhouse. Some of us had our bags tagged with our Carnival deck tags, some did not. I would suggest tagging your bags prior to getting there if you can. They do have very helpful Porters that are anxious to help you and do have extra More tags. Getting on the ship is a bit of a process and some waiting, but before we knew it we were walking onto the Liberty and the holy sh*t factor kicked in. We were amazed from step one onto the ship. The Liberty is a beautiful ship and well organized. For our family we had two Balcony Staterooms on level 6 starboard aft. Our rooms were spotless and perfect for us. Our room had 2 Twin Beds converted into a King, a single Convertible Sofa and an upper bunk. My wife and I and our two youngest were in this room and it worked very well. Every night while we were at supper the sofa bed and bunk were made up and every morning the bunk was stowed away for space. With two adults and two children in our room it often looked like a tornado touched down. Twice daily our room attendants made our room look spotless. Anything left out was picked up, folded, put away, and/or organized. We ordered room service every morning. We used room service as our alarm clock and had a small breakfast and coffee on our balcony. I must add, if your considering saving some money and going with an inside stateroom, DON'T! We had inside staterooms booked and changed our minds and will never regret it. With the sun rising, a hot cup of coffee in my hand, and in my Carnival robe, I stood on our balcony and watched us port in Cozumel, The Cayman Islands, and Ocho Rios and will not regret paying extra for the experience and view. Every day ended on the balcony reflecting and watching the waves in the glow from the ship lights. We went with the soda cards for the kids which are just stickers attached to your ID card. I believe it was $38 or $39 per child but well worth it if your kids drink soda. We thought about sneaking liquor on the ship but didn't only because our hotel wasn't near a liquor store. However, it would not have benefited us because our family hangout/meeting spot was next to a bar near the casino and there was no chance I was going back to our room to mix drinks. I drink beer or bourbon and rarely drank either on the ship. Since our excursion on Mexico I have become a Margarita fan. Speaking of excursions, DO NOT BOOK THROUGH THE SHIP!!(no offense Carnival). We booked on-line for Mexico and Grand Cayman.
On the ship we tried to take part in daily activities but there is indeed too much to do. We went to a comedy show, a musical production, and some other fun shows but we seemed so busy all the time we know we missed a lot. We simply were having too much fun in the sun, in the pool, eating, eating, eating, relaxing, drinking, meeting others. It was wonderful.
I don't think we over packed but I did spend the majority of my time on the ship in swim trunks, a t-shirt, and flip flops. We did two formal nights and wore suits and ties for the guys and dresses for the gals. The guys in shirts without jackets looked under dressed and the guys in tuxedos looked over dressed. The food in the Silver Dining Room was very good and changed often. I must thank our waiters Valentine and Avito for making our evenings so memorable. They were so good to us, we will miss them dearly. I read about the Chocolate Melting Cake before we cruised; yes, I agree you must have the Chocolate Melting Cake! Harry's...wow what a meal. You must try Harry's one night and do dress formal for the meal. We agreed we would have eaten at Harry's more had we known how good it was. It's not free at $30 something per meal plus tips and drinks, but man is it good. The buffet was as good as we expected. I loaded up on my favorites every morning and always found a spot to eat next to a window for my family. Lunch was an all day thing. We found ourselves eating burgers and pizza (dang good pizza!) all day. We had a buffet supper one night because we were to lazy to get out of our flip flops. We regret that night because the dining room is so much better for supper. My advice; daily room service for something light before breakfast, buffet breakfast and lunch, and your schedule dining room (Silver or Golden-same food) or Harry's at night. We did the late seating and would recommend it. One night at Sea my son and I felt sick. It happened to be the first formal night and we believe it had a lot to do with the mass of people moving to both dining rooms at the same time. After that we took a daily motion sickness pill just in case but it really wasn't that bad. It got a bit rocky at times but we were on a ship not land so it was to be expected. We all miss the ship and know we will go back as soon as we can. We talked about the people on board; I read some comments about Carnival and "white trash", etc. The people we met and the kids met were such good people and it was so relaxed on board that I would be nervous about going on another ship. I hope those that complain of "white trash" go on another ship because I don't want to be around people that complain about other people. It seemed that everyone on board wanted to have fun and get sun and we did just that. Thank you Carnival Liberty! Less
Published 01/25/10
Cabin review: 8A6465 BalconyBalcony (8A) Reviews >>
Port and Shore Excursions
Read Cruise Critic's Carnival Liberty Review >>
Carnival; never again
Very fun and comfortable
Everything you want to know ab...
Fun Ship Liberty
More of a CIRCUS than a "Carni...
Fabulous time on Liberty!
Carnival Legend Alaska 8/8/17
Had a great time!!
Family Cruise
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Blue Anarkali with Red yoke. Beautifully embroidered with Zari
Kurta material: Georgette Yoke : SilkDupatta material: Net
Note:Washing instructions: Dry clean only.
While we make the best effort to capture the exact colour of the product for the visuals offered, varying screen resolutions may cause colour representations to vary slightly from the actual colour
Churidar: Length: 45 inches, Waist: 40 inches (fully stretched), Hip: 42 inches, Cuff: 10 inches
Dupatta: Length: 25 inches, Width: 95 inches
(Please note that Churidar and Dupatta measurements remain standard across all sizes)
For shipping charges to all other destinations, please proceed to checkout
© 2015 Big Indian Wedding. All Rights Reserved.


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The Kirk PZ-151 Camera Plate for Nikon D600 and D610 is a quick-release plate that's designed specifically for these Nikon cameras. Its dovetail fits Arca-Swiss-style clamps to enable a quick release from a tripod head.
The plate is machined in the U.S. from 6061 T6 aluminum, and it includes two stainless steel Allen screws for attaching it to the camera. The PZ-151 plate features a sensor-centering line on the side, and allows the use of the Nikon LCD screen cover. Two Allen keys are included with the camera plate.
|Packaging Infotdfuwyzxsseueeseafzyebzxvx
|Package Weight
|0.15 lb
|Box Dimensions (LxWxH)
|4.6 x 3.5 x 0.7"


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Medical Definition of Circumflex
Circumflex: Curved like a bow. In anatomy, circumflex describes a structure that bends around like a bow. For example, the circumflex branch of the left coronary artery.
In linguistics, a circumflex is a caret-shaped mark (^) used over a vowel to indicate the pronunciation, length or the omission of a letter formerly pronounced. In French, it is called "un petit chapeau" (a little hat).
From the Latin circumflexus, bent around, circumflex, past participle of circumflectere, to bend around : circum- + flectere, to bend.
Last Editorial Review: 5/13/2016
Back to MedTerms online medical dictionary A-Z List
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Each month, Rated People connects over 50,000 homeowners with quality tradesmen - simply enter your job details in the form above to get started.
We'll match your job to the relevant tradesmen in your area - those interested will pay to see your contact details and call you to quote.
As each tradesman expresses interest in quoting on your job, we'll send you their profile and ratings to help you choose the right one for you.
After the work is complete, return to the site and rate your tradesman based on their quality of work, reliability and value for money.
Window & Conservatory Specialist
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I have a loft room with two 2x3.5ft (est) wooden framed single pane windows. 1 window is cracked...
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I have just moved into a property which has upvc doors and double glazing all of which do open...
Window & Conservatory Specialist
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Replace old uPVC bay windows & two small windows
Darren provided a very competitive quote & excellent service, I would use his services again and have no hesitation recommending him to other people
An excellent job. Thanks to Carl and team.
As a single lady I was extremely worried about having my fascias and soffits replacing with no recommendation from friends. I needn't have worried, the sales manager reassured me throughout, the job completed fully to my satisfaction wouldn't hesitate to recommend.
CIVICON have dealt the project with an excellent commitment and professionalism. We are highly satisfied with their work. CIVICON have demonstrated a great attitude with customer orientation and customer satisfaction.
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Motorcycle Saved
Fits 1984-'17 HD®big twin engines, 1986-'17 HD® Sportster® models, and 1994-'02 Buell®. Our forged steel roller rocker arms were designed for superior strength and to eliminate the failure-prone stress areas found in some other rockers. S&S® roller rockers are forged from 8620 steel, heat-treated, and then shot-peened for additional strength and protection from fatigue. Our rockers also utilize 3/4" long bronze bushings, compared to the more common 1/2" long bushings or needle bearings. The end result is what we believe to be the finest rocker arm available anywhere, for any price. Extremely durable rollers reduce valve stem side thrusting with high lift cams. Superior wear and fatigue resistance even in the most demanding.(2 front and 2 rear rocker arms)
0% of customers would recommend this product (0 out of 0)


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Trees planted as far back as 1869, spacious lawns, and a range of facilities that border the Poudre River have earned Island Grove Regional Park a reputation as one of the most picturesque and versatile events complexes in the nation.
Island Grove is a multi-use events complex owned by the City of Greeley and Weld County. Located on 145 acres, there is plenty of space for all ages to play!
The Events Center features more than 60,000 square feet of versatile and unobstructed floor space that is ideal for exhibitions, conferences, sporting competitions, banquets, livestock shows or any type of large event.
Designed with a contemporary agrarian flair, plenty of sunlight streams into the spacious conference room, ticket office and lobby areas that are part of the 80,000-square foot facility that is easily transformed from casual to elegant.
425 N. 15th Ave
Affordable rates and flexible space keep the 4-H Building regularly booked for smaller events. Meetings, corporate parties, banquets, family reunions, wedding receptions and birthday celebrations are among the many types of events held in the 4-H Building.
Greeley's first city hall, now known as Island Grove's "Bunkhouse," provides an affordable and intimate setting for class reunions, weddings, birthday parties, Christmas parties and more. Guests will enjoy socializing on the covered patio.
Conveniently located near Island Grove's new Events Center and a large playground area, this attractive outdoor pavilion is surrounded by trees and plenty of green space. Completed in 2002, this covered and lighted space is used frequently for festivals, wedding receptions, family reunions, corporate picnics and more.
Located on the western edge of Island Grove Regional Park along the Poudre River, the Greeley Saddle Club Center is well suited for smaller equine events, clinics, dressage and gymkhanas as well as stock dog events, trials and tests.
Two arenas, bleacher seating, wash racks, RV hookups and an attractive shelter house are among the many amenities offered by the Greeley Saddle Club Center.
All event plans need to be made through our scheduling coordinator Kathy Dilbeck at 970-350-9392, firstname.lastname@example.com, or 425 N 15th Avenue Suite 101, Greeley, CO 80631 (south west side of the Event Center). Information on food, alcohol, and rentals is on our event planning page.
501 North 14th Avenue
Greeley, CO 80631
Monday - Friday 7:00 a.m. to 3:30 p.m.
970-350-9392 tel
970-336-4002 fax


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Call us 7 days a week
Item #: WBB169946
Usually ships in 7 to 10 days (ships from US) Estimated lead times do not include weekends or holidays. Transit time is determined by shipping method and destination. Orders requiring credit information might take additional time.
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These must be ordered in sets of 5. Is it possible to mix and match? For example 2 24 compartments, 2 18 compartment and 1 16 compartment? Thanks!
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