Methods and Apparatus for Intraocular Brachytherapy
Methods and apparatus for intraocular brachytherapy are disclosed in which a cannula is introduced into the eye for delivery of radiation to a target tissue. Techniques for properly locating the cannula with respect to the target tissue, for protecting non-target tissue, for regulating heat generated by x-ray emitters, and for combining therapies are disclosed.
This application claims the benefit of U.S. Provisional Appln. Ser. No. 60/736,783 filed Nov. 15, 2005, and is a continuation in part of U.S. application Ser. No. 11/228,030, filed Sep. 15, 2005, which is a continuation in part of U.S. application Ser. No. 11/056,763, filed Feb. 11, 2005 and claims the benefit of U.S. Prov. Appln. Ser. No. 60/554,001, filed Feb. 12, 2004, all of which are incorporated herein by reference.BACKGROUND OF THE INVENTION
It has been proposed to treat age-related macular degeneration (AMD) by irradiating the choroidal neovascularization (CNV) underlying the retina that is associated with AMD with ionizing radiation (such as beta or x-ray radiation). See, generally, U.S. Pat. No. 6,875,165 and US Pub. Appln. No. 2003/0179854, both of which are incorporated herein by reference. Certain apparatus for the intraocular delivery of radiation, either epi-retinally or sub-retinally, and methods of their use are disclosed in the co-pending U.S. Applns. Ser. Nos. 11/056,763, filed Feb. 11, 2005 and 11/228,030, filed Sep. 15, 2005, identified above.
As noted in the above-referenced patents and applications, Beta radiation, and some forms of x-ray radiation, are advantageous for treating AMD because the dose delivered by such radiation sources decays roughly with the square of distance in materials with similar density to water (such as human tissue). Therefore, by accurately positioning the radiation source or emitter in close proximity to the target tissue (in this case the CNV, and/or taking steps to avoid irradiating non-target tissue by, e.g. the use of masks or attenuating substances and filters, a therapeutic radiation dose can be delivered to the target tissue, while delivering little or no dose to non-target tissues (such as surrounding ocular or non-ocular structures). The present application discloses a variety of methods and apparatus for accomplishing such accurate targeting of treatment.SUMMARY OF THE INVENTION
In one aspect of the invention, a device for local, directional intraocular delivery of radiation to a target tissue is provided. The device includes a cannula sized for insertion into an eye and having a proximal end and a distal end. A radiation-emitting source is adapted to be located in the distal end of the cannula, and an ultrasound transducer is also located in the distal end of the cannula. In one embodiment, the ultrasound transducer is located proximal to the radiation-emitting source, while in a second embodiment, the ultrasound transducer is located in the cannula distal to the radiation-emitting source.
In another aspect of the invention, a method for positioning a device including an ultrasound transducer as described above is provided. The method includes calibrating the ultrasound transducer in accordance with a predetermined spacing for the distal end of the cannula relative to the target tissue so as to generate a signal when the predetermined spacing is achieved. The cannula is then introduced into the interior of the eye through an access site in the surface of the eye and the distal end of the cannula is moved toward the target tissue until the signal generated by the ultrasound transducer is perceived by the user. In one aspect of the method, the signal generated by the ultrasound transducer is an audible signal, while in another aspect of the invention, the signal is a visual signal.
In another aspect of the invention, a method for positioning a first cannula having a radiation emitter in the interior of an eye by means of a second cannula with an ultrasound transducer is provided. First, the first cannula is introduced into the interior of the eye through an access site in the surface of the eye. Then, the second cannula is introduced into the interior of the eye through an access site in the surface of the eye. Then, the distal end of the first cannula is positioned between the ultrasound transducer associated with the second cannula and the target tissue. Then, the distal portion of the first cannula is moved toward the target tissue until a predetermined spacing between the distal end of the first cannula and the target tissue is achieved, at which time a signal is generated by the ultrasound transducer. Again, the signal may be either an audible signal or a visual signal.
In another aspect of the invention, a method for positioning a cannula for intraocular delivery of a therapeutic treatment to a target tissue on the interior of an eye is provided. First, a cannula is provided having an inflatable balloon that obtains a predetermined size when inflated to a predetermined pressure, the predetermined size corresponding to a desired spacing between the cannula and the target tissue for the delivery of the therapeutic treatment. The balloon may be either compliant or non-compliant. The cannula is introduced into the interior of the eye through an access site in the surface of the eye and the balloon is inflated to the predetermined pressure. Then, the cannula is advanced toward the target tissue until the target tissue is contacted by the inflated balloon. The balloon is preferably inflated with a fluid having a density lower than the density of the fluid displaced by the inflation of the balloon, thus resulting in a reduced treatment time. In another aspect, the balloon is selected to have a shape corresponding to the shape of the target tissue.
In another aspect of the invention, a method for positioning a cannula on the interior of an eye is provided in which the fluid in the interior of the eye is displaced with a known volume of a second fluid having a density different from the density of the first fluid so as to create a visual interface between the first fluid and the second fluid that is spaced a predetermined distance from the target tissue. The cannula is then introduced into the interior eye through an access site in the surface of the eye and advanced toward the interface of the first fluid and the second fluid until the distal end of the cannula contacts the interface. The cannula may optionally be provided with visible mark proximal to the distal, in which case the distal end of the cannula is advanced through the interface of the first fluid and the second fluid until the visible mark on the cannula is aligned with the interface. The second fluid may have a density either greater than or less than the density of the first fluid.
In another method according to the present invention, a method is provided for positioning a first cannula for treatment of target tissue on the interior of an eye in which the distal end of the cannula is in contact with the target tissue. A second cannula is introduced into the interior of the eye through an access site in the surface of the eye, the second cannula having a light source that projects a beam of light toward the target tissue. The first cannula is introduced into the interior of the eye through a second access site on the surface of the eye so that the distal end of the first cannula is between the second cannula and the target tissue so as to be within the beam of light projected toward the target tissue by the second cannula. This casts a shadow by the distal end of the first cannula that falls on the target tissue, with the shadow being observable through the lens of the eye. The distal end of the first cannula is then advanced toward the target tissue until the tip and the shadow cast by the tip coincide, thus indicating contact of the distal end of the first cannula with the target tissue.
In another aspect of the invention, device is provided for local, directional intraocular delivery of a therapeutic treatment to a target tissue that comprises a cannula, a therapeutic treatment source adapted to be located in the distal end of the cannula that is intended to be spaced a predetermined distance from the target tissue, and at least one source of light adapted to project two visible beams of light out the distal end of the cannula. The two beams of light form an intersection such that when the intersection is coincident with the target tissue, the treatment source is spaced the predetermined distance from the target tissue. The source of light preferably may either be a light pipe or a laser.
In another aspect of the invention, a device for local intraocular delivery of therapeutic treatment of a target tissue is provided that has a reduced surface friction. This reduced surface friction may be achieved by electro polishing the surface of the cannula, dimpling the surface of the cannula, applying a liquid lubricant, such as glycerin, to the surface of the cannula, or providing the surface of the cannula with a radiation-resistant, low-friction coating.
In another aspect of the invention, a method for delivering x-ray radiation to a target tissue in an eye from the interior of the eye is provided in which an x-ray probe with an x-ray emitter associated therewith is introduced into the interior of the eye through an access site in the surface of the eye. The probe is positioned with respect to the target tissue, and the x-ray emitter is intermittently activated until a desired radiation dose is delivered to the target tissue. The x-ray emitter may be activated and de-activated by a thermocouple located in the interior of the eye which is preferably associated with the probe. The x-ray probe may also have a heat exchanger associated therewith that includes flow path for receiving a cooled fluid. In addition, the heat exchanger may comprise a sheath that is preferably made of a material having a low coefficient of thermo conductivity.
In another aspect of the invention, a device for local, directional intraocular delivery of radiation to a target tissue is provided that comprises a probe sized for insertion into the eye with a radiation-emitting source having a predetermined length adapted to be located in the distal end of the probe. A filter is associated with the distal end of the probe that blocks a greater amount of radiation at the distal end of the radiation-emitting source than at the proximal end, resulting in a generally symmetrical dose profile delivered to the target tissue when the probe is oriented at an angle with respect to target tissue. In one embodiment, the filter is greater in thickness adjacent the distal end of the radiation-emitting source than adjacent the proximal end. Alternatively, the filter may have a higher density adjacent the distal end of the radiation-emitting source than adjacent the proximal end.
In another aspect of the invention, a device for local, directional intraocular delivery of x-ray radiation is provided in which a layer of high density metal is associated with the distal end of the cannula in proximity to the anode for attenuating x-ray radiation. The metal layer has an opening therein to allow x-ray radiation to pass therethrough substantially unimpeded, the opening being located in size to direct and confine the x-ray radiation to the target tissue.
In another aspect of the invention, a device for local, directional intraocular delivery of x-ray radiation is provided in which the distal end of the cannula and the anode have a hemispherical shape. Alternatively, the distal end of the cannula and the anode can be generally planar and oriented generally perpendicular to the longitudinal axis of the distal end of the cannula.
In another aspect of the invention, a method for treating target tissue on the interior of the eye with both radiation and an anti-VEGF pharmaceutical is provided. The administration of the two different types of therapies occurs within a period of time of fourteen days or less, and is preferably performed in a period of time of four hours or less, even more preferably during the same procedure. The pharmaceutical may be administered either prior to or subsequent to the irradiation of the target tissue. Follow-up doses of the pharmaceutical may be given, preferably two to eight weeks after the first treatment.
FIGS. 19 and 20A-C show means for shaping the dose profile of an x-ray radiation probe.
Various methods and apparatus for targeted delivery of a radiation dose are described in detail below.Positioning the Radiation Source
One way of properly spacing the radiation source from the target tissue is to use various distance feedback systems that are generally known in the art. For example, an RF (“radio-frequency”) or Ultrasound transmitter can be attached to radiation delivery probe/cannula disclosed in the above-referenced patents and applications. Specifically, with reference to
The transducer may emit ultrasound waves either toward the target tissue or toward the tip of the probe. If the prescribed dose is calculated assuming a space between the probe tip and the retina, the transducer is directed so as to emit ultrasound toward the target tissue, and calibration is required prior to treatment. Ultrasound distance calibration techniques are well known in the art, and will not be discussed in detail. As an example, and as schematically illustrated in
In certain circumstances, the transducer may emit ultrasound toward the tip of the probe, for example, when the radiation source is to be positioned by touching the probe against the surface of the target tissue. In such cases, calibration is optional. If the prescribed dose is calculated assuming contact between the probe tip and the retina, the surgeon can visualize the ultrasound output directly through the eyepiece and determine when contact is made. If the prescribed dose is calculated assuming some separation between the probe tip and the retina, the system will have to be calibrated either after manufacture or prior to treatment as described above. If the ultrasound is directed toward the tip, the tip may be made from a material with a lower density than the metal from which the probe is constructed, such as silicone or a fluid-filled balloon. This should prevent a shadow from the high density metal appearing in the ultrasound images, and is more atraumatic to the tissue.
In a further option (as shown in
In each instance, the output from the transducer provides the surgeon with real time position feedback so that the surgeon can adjust the position of the probe to ensure the prescribed dose of radiation is delivered. For example, a discrete tone or beep can be generated at one-second increments when the probe is distant from the target. The beep frequency increases as the probe gets closer to the target. If the probe comes in contact with the target, the beep tone sounds continuously. While the radiation exposure of the target tissue is occurring, a recording device collects data that describes the location of the probe over the duration of the treatment. This data may be used for post-procedure analysis of the dose delivered. The output may be analyzed to determine both the position of the source and the length of time it was in each position. When this information is combined with the dose rate of the radiation source, a precise dose delivered to the target tissue can be calculated.
Alternatively, the radiation source may be appropriately spaced from the target tissue through the use of a compliant balloon that forms a part of the delivery probe. Specifically, as illustrated in
The farther the radiation source is positioned from the tissue, the broader the treatment field and the longer the source must remain in position to achieve the prescribed dose. This phenomenon is illustrated in
As an alternative to the use of a compliant balloon, a non-compliant balloon made from a material such as PET may be attached to the distal tip of the radiation delivery probe. The non-compliant balloon is inflated to a pre-determined pressure with any of the fluids described above so as to be inflated to a known volume which cannot be adjusted. The known volume positions the probe a known distance from the target tissue. The procedure is the same as set forth above with respect to the use of a compliant balloon.
With reference to
A further technique for positioning the tip of the probe in gentle contact with the target tissue, illustrated in
In a further method for positioning the probe, illustrated in
Vitreoretinal surgery requires instruments designed for the unique environment of the eye that are also compatible with existing surgical instruments. The probe of the radiation delivery device used in the present invention preferably has a cross-section compatible with existing 20 gauge surgical instruments, including trocars. Probes sized larger than 20 gauge increase the likelihood for complications, such as retinal detachments, due to traction. This is due to the increased surface area of the probe and the volume displacement of the probe as it is inserted into the eye. To decrease the traction between the probe and the vitreous humor, the outer surface of the probe, if made of metal, can be electropolished to provide a smooth surface, thereby reducing the surface friction. Alternatively, the surface of the probe may be dimpled (similar to a golf ball) on either a micro or macro level using known surface finishing or machining techniques. The dimpling of the outer surface of the probe reduces surface friction under flow conditions (such as insertion and removal of the probe).
Additionally, a liquid lubricant, such as glycerin or Hinge Free instrument lubricant (available from Steris Corporation), can be applied to the outer surface of the probe to further reduce the friction at the probe/vitreous humor interface. Further, the probe can be provided with a low friction coating to achieve the same goal.Heat Regulation with X-Ray Emitters
The generation of x-rays within the eye could elevate the temperature inside the eye above the threshold for tissue damage. To limit the heat transmitted to the eye, several strategies could be employed. First, rather than being continuously on, the x-ray generator can be pulsed, with it automatically alternating between on and off at a known frequency. Additionally, the frequency of the pulsing can be regulated by a thermocouple inside the eye (either incorporated into the x-ray probe or inserted via a different port). Additionally, or alternatively, means for cooling the emitter can be employed. For example, with reference to
In addition, as shown in
Beta radiation and low energy x-ray radiation each have a rapid dose fall-off when traveling through water as compared to forms of gamma radiation. Other forms of external radiation can control the depth of penetration within a few centimeters; however, the dose distribution is less controlled than beta and low energy x-ray radiation. The probe of the present invention has the advantage of providing precise control over the dose distribution and depth of penetration over other radiation alternatives.
The use of a “targeted” radiation approach, with the masking of non-target tissue and/or attenuation of radiation other than that directed to the target tissue with filters and the like, allows a higher total dose delivered to the target tissue while lowering the risk of collateral damage to the surrounding ocular structures. When a targeted approach is not employed (such as with alpha or gamma radiation sources), the total dose is limited due to the risk to nearby ocular structures. Additionally, the risk for radiation retinopathy is lowered when a smaller volume of tissue is irradiated, and the healing response of the irradiated tissue is improved with a targeted approach.
Protecting the healthy areas of the retina is desirable because it lowers the risk of radiation-induced side effects. The dose distribution may be masked by placing a shaping filter 70 behind the radiation source 72 (as shown in
Because of the roughly hemispherical shape of the retina and the many angles of entry for the radiation probe, it may be desirable to have the ability to direct the radiation out of the probe. Beta radiation is blocked by thick and/or dense material. By using dense material, the emission of Bremstrahlung (secondary gamma radiation) is increased. By altering the density and/or thickness of the metals at the tip of the device, the shape of the beta dose field may be altered, as shown in
Alternatively, with reference to
Through the use of a magnet in the tip of the probe (e.g., where the transducer is located in
The low energy x-ray radiation can be blocked by a thin layer of high density metal 80, as shown in
Another method for protecting the non-target tissue from undue exposure to radiation is to more accurately define the boundaries of the target tissue. Pre-treatment diagnostic tests, such as color fundus photography and fluorescein angiography, provide a way to visualize the specific boundaries of the AMD lesion. Then, the focal nature of the dose distribution permits the surgeon to specifically target lesions or parts of lesions, rather than generically dosing the retina.
A color fundus photograph provides a picture or image of the retina showing similar anatomical features to what the surgeon sees through the surgical microscope. From a color fundus photograph, the surgeon can see drusen, major retinal blood vessels and other features. However, it is difficult to visualize the extent of the AMD lesion and leakage from these photographs (and during surgery).
To view the extent of the AMD lesion and leakage, a radio opaque dye is intravenously injected into the patient. As the dye circulates through the bloodstream and eventually reaches the retinal circulation, a photographer turns on an x-ray and captures frames of the dye as it perfuses the retinal and choroidal circulation. These x-ray images show boundaries of the AMD leakage that are not visible with fundus photography.
Using Imagenet software prior to surgery, the lesion boundaries can be located with respect to anatomy that can be visualized with the microscope, such as blood vessels, blood vessel branches, and the optic disc. With this information, a treatment planning strategy can be developed that includes determining, e.g., the spacing of the probe from the target tissue, the dwell time for the radiation source, the location of the center of the radiation source, and/or the type of shaping filter or window to use during surgery.
The radiation dose rate is inversely proportional to the square of the distance between the source and the target, and the dose field broadens with increasing separation between the source and the target. These features of the radiation physics may be used to control the shape of the dose distribution. In collaboration with the compliant balloon discussed above, the dose distribution could be modified to specifically match the AMD lesion. Specifically, the extent of the lesion can be measured. A compliant balloon can be designed to provide a predetermined spacing of the radiation source for a given inflation volume. Thus, based upon the size of the lesion, the inflation volume to provide the designed spacing of the radiation source to provide a therapeutic radiation dose will be known, and the balloon can be inflated to that volume.
As set forth in our co-pending applications referenced above, there is a therapeutic range of doses which have the desired treatment effect on the target tissue without undue side effects. Doses below the therapeutic range are not sufficient to halt the CNV leakage. Doses above the therapeutic range halt the CNV leakage, but may cause side effects that make the treatment risk outweigh the treatment benefit. The therapeutic range is unique to intraocular brachytherapy with ionizing radiation. The therapeutic range would likely vary with other energy sources or delivery means. The therapeutic range for Beta radiation is approximately 7-50Gy (measured at the CNV). The preferred dose lies somewhere between 10Gy and 30Gy.Combination Therapies and/or Re-Treatment of Target Tissue
It may be advantageous to treat macular degeneration with the non-ionizing radiation in combination with other therapeutic substances that are currently in use or under development. For example, certain pharmaceutical substances are currently under development that act upon the vascular endothelial growth factor (VEGF) cascade. VEGF's are vasodialating and vasoproliferative. The vasodilation feature results in leaky vessel walls while the vasoproliferation feature results in the formation of new blood vessels. Anti-VEGF pharmaceuticals, such as Macugen®, Avastin®, and Lucentis®, bind to VEGF, thereby preventing vasodilation and vasoproliferation, and halting the CNV leakage.
Clinical trials with the anti-VEGF pharmaceutical Lucentis® have shown it to be efficacious not only in slowing the effects of vasodilation and vasoprofliferation, but in also reducing leakage very soon after injection. However, the effects are not permanent, and the drug must be injected monthly to obtain the maximum efficacy. In contrast, because radiation treatment works by inferfering with cell division at the DNA level, the effects of radiation treatment are not expected to be immediate. Indeed, clinical trials show a decrease in visual acuity at one week post-op, a small increase at four weeks, and a bigger increase at two months. Therefore, a combination treatment with an anti-VEGF and radiation therapy may have an early effect, mainly due to the pharmaceutical, and a late effect, mainly due to the radiation therapy.
The time inverval between the radiation treatment and the treatment with the anti-VEGF is preferably two weeks or less, more preferably five days or less, and even more preferably four hours or less. The most preferred time interval would be 15 minutes or less. That is, both the radiation and the anti-VEGF are administered during the same procedure. This could be done with a single device in which the cannula or probe for delivering the radiation dose also includes a separate lumen through which the anti-VEGF can be injected, as shown and described in the co-pending applications referenced above. The radiation source could be either a beta emitter or a miniature x-ray emitter, which preferably delivers a radiation dose to the target tissue of from 20 to 30 Gy at a dose rate of 5 to 30 cGy/sec, and more preferably at a dose rate of 8 to 15 cGy/sec. The anti-VEGF pharmaceuticals could be delivered prior to, after, or both prior to and after brachytherapy.
A subsequent dose of an anti-VEGF pharmaceutical may also be administered to the target tissue intraocularly to enhance the complimentary effects of the combination therapy. The second dose may be given from two to eight weeks after the first dose, preferably three to five weeks after the first dose, and more preferably 25 to 35 days after the first dose.
Other therapeutic agents or modalities may also be used in combination with radiation for the treatment of macular degeneration. By way of example and not limitation, these may include, in any combination, one or more of small interfering RNA (“siRNA”), photodynamic therapy (“PDT” typically with verteporfin as the photosensitizing agent), corticosteroids (such as triamcinolone acetonide and dexamethasone), angiostatic steroids (such as anecortave acetate), implants of encapsulated human ciliary neurotrophic factor (“CNTF”-NTC-201), VEGF Traps, dietary supplements (e.g., docosahexaenoic acid), anti-inflammatory medicines (e.g., infliximab, sirolimus, declizumab or ketorolac tromethamine), interferon, antimetabolite drugs (e.g., methotrexate), squalamine lactate (an aminosterol), ruboxistaurin mesylate (a protein kinase C beta inhibitor), fluocinolon acetonide implants, monoclonal antibodies (e.g., Sphingomab), and anti-oxidants. Such pharmaceuticals may be administered in a wide variety of ways, such as intravitreously, intravenously, subcutaneously (by injection), orally, topically (including eye drops), and by implantation.
Re-irradiation of the target tissue may also be indicated. The tissue response to radiation is proportional to the dose delivered, and there are four general tissue responses to the radiation. At low doses (below the therapeutic threshold), there is little or no lasting tissue response. At doses above the therapeutic threshold, but below the toxicity threshold, the desired therapeutic effect is attained. At doses above the toxicity threshold, long-term fibrosis and scarring can occur. At doses significantly above the therapeutic threshold, acute necrosis and scarring will occur.
Fractionation studies with external radiation therapy for AMD have not shown any appreciable benefit. However, re-treatment of patients that show recurrence of AMD with radiation may provide a benefit without exceeding the threshold for toxicity. The literature provides some evidence of an accumulation effect in the tissue of radiation over multiple treatments (i.e. previously irradiated tissue may be more sensitive than virgin tissue to new radiation treatments). If this theory is proven, it may affect the first, second, and third dose strategies. Additionally, the tissue may recover with time between radiation treatments.
43. A device for local intraocular delivery of x-ray radiation to a target tissue comprising:
- a cannula sized for insertion into an eye and having a proximal end and a distal end;
- a cathode within the distal end of the cannula;
- an anode on the distal end of the cannula; and
- the distal end of the cannula and the anode being generally planar and being orientated generally perpendicular to a longitudinal axis of the distal end of the cannula.
44. The device of claim 43 wherein the distal end of the cannula comprises an x-ray permeable material.
45. The device of claim 44 wherein the distal end of the cannula comprises an x-ray blocking material for attenuating the x-ray radiation received by the target tissue.
46. A method for treating a target tissue located on the interior of an eye with radiation and a further therapeutic agent comprising:
- providing an intraocular probe containing an ionizing radiation source;
- introducing the intraocular probe into the interior of the eye in proximity to the target tissue;
- irradiating the target tissue with a prescribed dose of ionizing radiation; and
- selecting the further therapeutic agent from one or more of anti-VEGF pharmaceuticals, small interfering RNA, photodynamic therapy, corticosteroids, angiostatic steroids, implants of encapsulated human ciliary neurotrophic factor, VEGF traps, dietary supplements, anti-inflammatory medicines, interferon, antimetabolite drugs, aminosterols, protein kinase beta inhibitors, fluocinolan implants, monoclonal antibodies and anti-oxidants;
- treating the target tissue with a prescribed first dose of the further therapeutic agent; and
- wherein the irradiation of the target tissue and the treatment of the target tissue with the further therapeutic agent occur within a period of time of 14 days or less.
47. The method of claim 46, in which the period of time is 4 hours or less.
48. The method of claim 46 in which the further therapeutic agent is administered prior to the irradiation of the target tissue.
49. The method of claim 46 in which the further therapeutic agent is administered following the irradiation of the target tissue.
50. The method of claims 46, in which the radiation source is a beta emitter.
51. The method of claims 46, in which the radiation source is an x-ray emitter.
52. The method of claims 46, in which the radiation dose is 20 to 35 Gy.
53. The method of claim 52, in which the radiation dose is delivered at a rate is 5 to 30 cGy/sec.
54. The method of claim 52, in which radiation dose is delivered at a rate of 8 to 15 cGy/sec.
55. The method of claims 46, in which a second dose of the further therapeutic agent is given after the first dose.
56. The method of claim 55, in which the second dose of the further therapeutic agent is given 2 to 8 weeks after the first dose.
57. The method of claim 55, in which the second dose of the further therapeutic agent is given 25 to 35 days after the first dose.
Filed: Sep 5, 2012
Publication Date: Dec 27, 2012
Inventors: Richard A. Hillstead (Duluth, GA), Charles E. Larsen (Cumming, GA), Roelaf Trip (Sawanee, GA), Cory S. Anderson (Apharetta, GA), John N. Hendrick (Henderson, NV), Benjamin W. Woodward (Santa Clara, CA)
Application Number: 13/604,212
International Classification: A61M 36/12 (20060101);