WO2008055159A2

WO2008055159A2 - Flash photolysis therapy for regulation of physiological function

Info

Publication number: WO2008055159A2
Application number: PCT/US2007/083009
Authority: WO
Inventors: Rodolphe P. Katra
Original assignee: Medtronic, Inc.
Priority date: 2006-10-30
Filing date: 2007-10-30
Publication date: 2008-05-08
Also published as: WO2008055159A3; WO2008055159A4; EP2079523A2

Abstract

Flash photolysis therapy is used to enhance cellular function, such as abnormal myocardial or renal function. A photo-reactive compound is administered to cells requiring therapy. A light stimulus is applied to the photo-reactive compound to cause desired intracellular activity when the photo-reactive compound is activated. The activated compound can, for example, affect intracellular calcium concentration, to cause forced contraction or relaxation in the muscle tissue.

Description

FLASH PHOTOLYSIS THERAPY FOR REGULATION OF PHYSIOLOGICAL FUNCTION

STATEMENT OF INCORPORATION BY REFERENCE This patent disclosure incorporates by reference the appended 27-page document captioned, "Implantable Flash Photolysis Device for Forced Myocardial Relaxation: A Proof-of-Concept," (and labeled "Exhibit 1") the entire contents of which are hereby incorporated herein by reference.

CROSS REFERENCE BACKGROUND OF THE INVENTION

The present invention relates generally to the field of therapeutic photolysis devices, and more particularly, to a device for regulating physiological function via flash photolysis therapy.

Many disease conditions are caused by a disruption in normal physiological function that result in abnormal levels of specific ions or other molecules. Such conditions may cause, for example, abnormal myocardial or renal function.

Abnormal myocardial function, for instance, is a leading cause of mortality and morbidity in developed countries. This abnormality may manifest mechanically as reduced ejection fraction (EF), low cardiac output and poor diastolic function, or electrically as arrhythmias. These abnormalities are associated with an increased risk of death due to organ failure and cardiac arrhythmias, poor cardiac function, elevated heart rates, chronic fatigue, pulmonary congestion and diminished exercise capacity.

BRIEF SUMMARY OF THE INVENTION A therapeutic system modifies cellular function with a photo-reactive compound.

A drug delivery device administers photo-reactive compound to cells, and a light delivery device delivers a light stimulus to activate the photo-reactive compound. When activated, the photo-reactive compound affects cellular function.

The invention is useful, for example, to manage abnormal myocardial function.

The photo-reactive compound is a calcium sensitive compound which causes a change in intracellular calcium concentration when it is activated. Improved myocardial contraction, relaxation, or both, can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram illustrating a therapeutic system for managing myocardial function that includes an implantable drug delivery device and an implantable light delivery device.

FIG. 2 is a block diagram of the system of FIG. 1

FIG. 3 shows a timing diagram illustrating operation of the system of FIG. 1. FIG. 4 is a block diagram of another embodiment of a therapeutic system for enhancing myocardial function.

FIG. 5 and 6 show a system having an optical lead that provides scanning of light pulses delivered to myocardial tissue.

FIG. 7 shows a system having a multi-window optical lead.

DETAILED DESCRIPTION

As will be described in greater detail below, a flash photolysis device is used to regulate any of a number of physiological functions. In operation, a photo-reactive compound is administered to a patient. The photo-reactive compound is inert until exposed to light of a wavelength that activates the compound. A light source, which is typically implanted within the patient (but alternatively could be located externally), emits light at the wavelength that activates the compound. The activated compound regulates a physiological function by increasing or decreasing the concentration of ions or molecules in and around the area where the active compound is formed.

In their inert state, the photo-reactive compounds include a caging group that has either a high or low affinity for the ions or molecules. Once activated, the affinity of the caging group changes such that the level of ion or molecule decreases or increases. Table 1 includes examples of various caging groups that may be used with the present invention. TABLE 1

Use of some of the above photo-reactive compounds may require the addition of dithiothreitol (DTT). DTT is a reducing agent and may minimize a potentially cytotoxic reaction between amines and the 2-nitrobenzyl photolytic by-product.

FIG. 1 is a representative embodiment of flash photolysis system 10 as used to regulate abnormal myocardial function in heart H. System 10 includes drug pump 12 with delivery lead 14 and light delivery device 16 with optical lead 18 and sensing lead 20. Optical lead 18 further comprises light dispersion lens 22 and anchor tip 24. In this embodiment, drug pump 12 is a hermetically sealed implantable device.

Delivery lead 14 is shown inserted into the coronary sinus of heart H, but it may be inserted in other areas in or around the heart. Examples of suitable drug pumps are described in U.S. Patent Application Serial Nos. 10/407,996; 10/382,757; and 10/382,948. Light delivery device 16 is also a hermetically sealed implantable device with both optical lead 18 and sensing lead 20 being positioned within the right ventricle. In other embodiments, optical lead 18 and sensing lead 20 may be placed in other heart chambers, such as the left ventricle.

Myocardial contraction and relaxation are regulated by intracellular calcium handling proteins that regulate calcium release and uptake inside myocardial cells. Severe remodeling of these proteins results in abnormal calcium release and uptake, leading to poorly developed contraction and relaxation.

System 10 makes use of one or more light-activated compounds to dynamically release and/or buffer intracellular calcium, which, in turn, controls myocardial contraction and/or relaxation. In operation, one or more light-activated compounds are administered to a patient through any of a number of means for administering. The means of administering may be, for example, an injection device, an orally administered composition, a patch or topically administered composition, a suppository, etc. As shown in FIG. 1, the means for administering may also be drug delivery pump 12. Drug delivery pump 12 is typically refillable and implantable. A suitable pump is the SynchroMedEL™ Drug Delivery Pump from Medtronic Inc.

Delivery lead 14 is shown placed within the coronary sinus to allow delivery of light-activated compounds directly into the heart. In alternative embodiments, delivery lead 14 may be positioned within other chambers or even outside of the heart. For example, U.S. Patent Application Serial No. 11/124,984 describes a device for delivering therapeutic agents to the pericardial sac. With the light-activated compounds delivered locally in and/or around the heart, the dosage of light-activated compounds is minimized as compared to administering the compounds orally, where they circulate systemically. This also minimizes side effects that could result from the compounds.

Optical lead 18 is positioned at a location dependent on where the compounds are delivered and/or where treatment is needed. Light delivery device 16 includes a flash lamp or light emitting diode that discharges high intensity, short duration light pulses at one or more wavelengths (depending on the number of photo-reactive compounds that are administered). The pulses are carried by optical lead 18, which is typically a fiber optic lead, to the treatment site. In this embodiment, the treatment site is the right ventricle. The light is dispersed into the chamber by light dispersion lens 22, such as a spherical lens that directs light in all directions simultaneously. In another embodiment, a light emitting diode may be located at the distal end of optical lead 18 and be energized by electrical pulses from light delivery device 16 to produce the light pulses.

Anchoring tip 24 is attached at or near the tip of optical lead 18. Anchoring tip 24 is shown in FIG. 1 as a helical fixation element that anchors optical lead 18 in place by being screwed into tissue. Any of a number of types of anchoring mechanisms that are known in the art may be used with optical lead 18, such as spring loaded arms that extend radially outward once deployed into tissue.

Light delivery device 16 may incorporate sensing lead 20 to sense physiological parameters or markers. For example, sensing lead 20 may include sensing electrodes to sense electrogram (EGM) signals from which atrial and ventricular sensed events may be derived. In other embodiments, sensing lead 20 may include a pressure sensor to sense hemodynamic parameters such as ventricular pressure, an accelerometer to sense mechanical activity of the heart, a bioimpedence sensor, or a chemical sensor to sense concentrations of ions, proteins, or other molecules related to cardiac function. In still other embodiments, sensing lead 20 can comprise electrodes mounted on the can or housing of light delivery device 16, without a lead body. Light delivery device 16 controls flash photolysis such that the timing of the light pulses from light delivery device 16 is coordinated with or is a function of the physiological markers and parameters sensed. The delivery of light pulses may be required with every heart beat, or may be required less frequently based upon the physiological parameters and markers sensed.

The operation of drug pump 12 may also be controlled as a function of one or more of the sensed physiological parameters or markers. For example, timing of delivery by drug pump 12 of a bolus of the light-activated compound(s) to the heart may vary based on patient activity. Similarly, pump 12 may not operate while the patient is asleep, physiologically stable or is in no need for flash photolysis therapy.

System 10 may be used as therapy for myocardial function regulation. Mechanistically, myocardial contraction and relaxation are regulated by intracellular calcium handling. In non-diseased hearts, intracellular homeostasis is maintained by calcium handling proteins that regulate calcium release and re-uptake inside the cell. In heart failure, severe remodeling of these proteins leads to poorly developed contraction and slow relaxation. Specifically, with impaired contraction, the sarcoplasmic reticulum (SR) exhibits a reduced calcium release upon electrical activation due to a reduction in calcium re-uptake back into the SR. In instances of impaired cardiac relaxation, defective calcium regulatory proteins cause abnormal elevations in intracellular calcium levels. In order to regulate both the myocardial contraction and relaxation, two photo- reactive compounds activated at different wavelengths are used to dynamically release and buffer intracellular calcium. These photo-reactive compounds supplement the abnormally functioning calcium handling proteins, which forces the heart to better contract and relax without increasing metabolic demand or energy requirements.

Drug pump 12 delivers a controlled dose of two photo-reactive compounds over time into the coronary perfusion bed. One photo-reactive compound forces myocardial contraction, while the other photo-reactive compound forces myocardial relaxation. These compounds are large polar molecules that do not normally cross cellular membranes. Therefore, they are administered in a membrane-permeable acetoxymethyl ester (AM) form that neutralizes the charge. Once inside the myocardial cells, an enzymatic reaction occurs between the AM -bound inert compounds and intrinsic non-selective esterases that dissociate the AM portion of the inert photo-reactive compounds, converting them to polar compounds capable of responding to a light stimulus.

In one embodiment, drug pump 12 and light delivery device 16 communicate via a wireless link to coordinate their operation. For example, drug pump 12 may provide light delivery device 16 with a signal indicating whether drug pump 12 is on or off. As a result, light delivery device does not continue to produce light flashes (and thus waste energy) when drug pump 12 is empty or otherwise not operating. In another embodiment, drug pump 12 and light delivery device 16 may be contained in a common housing. This allows devices 12 and 16 to share sensor signals and to communicate directly without telemetry.

FIG. 2 shows a block diagram of system 10 shown in FIG. 1. Drug pump 12 includes reservoir 30, pump 32, controller 34, and telemetry circuitry 36. The photo- reactive compounds are stored in reservoir 30 and are delivered under pressure through delivery lead 14 by pump 32. Controller 34 controls the operation of pump 32, and communicates with light delivery device 16 through telemetry circuitry 36. The communication can include messages from controller 34 indicating when drug pump 12 is in an operating state, and when it is not operating (e.g. when reservoir 30 is empty or when there is no need for the drug in response to the physiological marker or signal). Leads 14,

18 or 20 can include dose sensors built in to sense drug concentrations, so that drug pump 12 can monitor drug concentrations and control delivery accordingly. If reservoir 30 is empty, an alarm can also be activated by drug pump 12, controller 34 or an external device linked to the system by telemetry. Light delivery device 16 includes light pulse generator 40, signal processing circuit

42, controller 44, and telemetry circuit 46. Light pulse generator 40 produces high intensity light pulses at one or more wavelengths at timing determined by controller 44. Signal processing circuit 42 processes the physiological signals sent by sensing lead 20 and provides signals to controller 44 representing sensed parameters or markers. Controller 44 controls the light pulses produced by light pulse generator 40 and delivered through optical lead 18 as a function of the sensed physiological parameters or markers, as well as information provided from drug pump 12 to telemetry circuit 46. Controller 44 may also provide sensed parameter or marker information by telemetry to drug pump 12, so that controller 34 can control operation of pump 32 based upon those parameters or markers.

FIG. 3 is a representation of a timing protocol for delivering light pulses and photo-reactive compounds. FIG. 3 includes ECG signal 50, relaxation light pulse waveform 52, contraction light pulse waveform 54 and drug infusion waveform 56. In order to force relaxation, a photo-reactive compound such as NP-EGTA, which has a low affinity for Ca²⁺ in its inert state, is delivered at a time and rate that provides a therapeutic concentration to the heart. During diastole, which can be determined from ECG signal 50, a short light pulse of about 260 nm is delivered to the ventricular chamber as indicated by waveform 52. When activated by the light, NP-EGTA develops a high affinity for Ca²⁺, which buffers and lowers the intracellular calcium concentration in the myocardial cells and forces myocardial relaxation. Once NP-EGTA binds to calcium, it becomes inert again and is actively transported out of myocardial cells by anionic transporters on the sarcolemmal membrane.

To force contraction, another photo-reactive compound such as DMNP-EDTA, which has a high affinity for calcium in its inert state, is delivered at a therapeutic concentration, preloaded with calcium. During systole, which can be determined from ECG signal 50, a short pulse of light at about 355 nm is delivered to the ventricular chamber. When activated, the DMNP-EDTA loses its high affinity for calcium, which releases it and increases the intracellular calcium concentration to force myocardial contraction. Once the DMNP-EDTA releases its calcium store, it is actively transported out of the cells as previously described.

Depending on the symptoms being experienced, an individual may require forced relaxation, forced contraction or both. Individuals with abnormal intracellular calcium handling have typically been treated pharmacologically with drugs that regulate calcium handling in the cell (catecholamines, channel blockers, β-blockers, etc.). Such therapy has a dramatic systemic effect. Implanted cardiac devices using electrical stimulation, although effective at stimulating contraction, do not increase contractility or elicit relaxation. In addition to heart failure, system 10 may also be effective in treating hypertension, pulmonary edema, diastolic dysfunction, renal dysfunction and many other serious conditions.

In an alternative embodiment shown in FIG. 4, system 10a includes implantable cardioverter defibrillator (ICD) 60 (or an implantable pulse generator), electrical lead(s) 62 and physiological sensor 70 are combined with the components of system 10 (shown in

FIGS. 1 and 2). In FIG. 4, ICD 60 with electrical lead(s) 62 is connected to light delivery device 16. Electrical lead(s) 62 may deliver pacing pulses or cardioversion/defibrillation shocks to the heart. Although shown as separate components, ICD 60 may reside within the same housing as light delivery device 16, and sensing lead 20 may be combined with electrical lead(s) 62.

ICD 60 may be adapted or programmed to serve several purposes. For example, ICD 60 may act as a backup to the operation of pump 12 and light delivery device 16. In the event that an element of the optical components fails, malfunctions or a slowing in the pacing is sensed or drug pump 12 is empty and not refilled, ICD 60 may be activated to provide electrical therapy until the problem is resolved. Further, ICD 60 may supplement flash photolysis therapy if electrical stimulation is needed in addition. FIG. 4 also shows physiological sensor 70, which is separate from drug pump 12 and light delivery device 16. Sensor 70, which is typically an implantable device, senses one or more physiological parameters or markers and provides information regarding those parameters or markers to one or more of drug pump 12, light delivery device 16 and ICD 60 via telemetry. In yet another alternative embodiment shown in FIGS. 5 and 6, system 10b includes scanning optical lead 80. Optical lead 80 includes cladding 82, rotating light guide 84, prism 86 with exit window 88, and anchor tip 90.

Rotating light guide 84 is typically comprised of a fiber optic, UV-grade material such as fused silica or a liquid light guide. Cladding 82 is opaque to insure total internal reflection. Prism 86 is a fully enclosed, 90° prism that delivers light in a radial direction through exit window 88.

Rotating guide 84 is connected to prism 86 and can rotate in order to scan the light pulses in a circular fashion. Stepper motor 92 (shown in FIG. 6) within light delivery device 16 will rotate guide 84 based on the therapeutic requirements of the patient. For instance, light delivery device 16 can be programmed to deliver light to a specific area by keeping prism 86 fixed in one orientation. If needed, the orientation can be adjusted using rotating guide 84. By rotating prism 86 with rotating guide 84, light pulses may travel or scan across the tissue, which can force contraction and/or relaxation in a manner that mimics the natural conduction across the heart. By rotating prism 86 very quickly, a near- simultaneous exposure can be elicited that exposes the entire surrounding area.

System 10b, as shown in FIG. 6, is generally similar to system 10 of FIG. 2, except for stepper motor 92 and optical lead 80. Similar elements are designated with the same reference numerals. Alternatively, system 10b can include additional elements such as ICD 60, electric lead(s) 62 and physiological sensor 70 shown in FIG. 4.

FIG. 7 shows flash photolysis system 10c, which is generally similar to system 10 (FIG 1) and system 10a (FIG. 5). System 10c includes optical lead 90, which has multiple optical windows 92 along its length from which activating light is emitted. Windows 92 may include lenses similar to light dispersion lens 22 of FIG. 1. Alternatively, windows 92 may include scanning elements similar to FIG. 5, and may feature separate rotation speeds or directions. Multi-window optical lead 90 may also be advantageous for therapy in other parts of the body such as the kidneys or the neurological system. The flash photolysis system may be used to treat other conditions, such as kidney stones. A majority of kidney stones are caused by excess calcium in urine and some individuals are predisposed to forming kidney stones.

In this embodiment, a sensing lead is positioned in or around the urinary tract to monitor calcium levels in the urine. A delivery lead is positioned within or around the kidney to deliver a photo-reactive compound such as diazo-2 that, upon activation, will buffer calcium levels in the urine. Alternatively, the photo-reactive compound may be administered orally or by injection when high calcium levels are detected and any of a number of types of alerts are provided by the light delivery device. An optical lead is positioned within or around the kidney such that a light pulse is able to access the urine. When high calcium levels are detected, diazo-2 is administered to the individual by any of the means described previously. The light delivery device delivers light pulses that activate the diazo-2 causing it to develop a high affinity for calcium. The result is lower urine calcium levels and a reduced likelihood of kidney stone formation.

The use of a flash photolysis system for kidney stone therapy may reduce or eliminate chronic usage of systemic medications. In addition, flash photolysis therapy begins treatment prior to formation of kidney stones.

Flash photolysis therapy may also be used to treat other diseases including neurological disorders, γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter found in multiple projection and local systems in the brain. GABA concentrations are decreased in the basal ganglia of Huntington's disease patients and may contribute to the dementia, mood disorders, and psychoses related to this condition. In addition, postmortem studies of Alzheimer's patients have shown GABA deficits. In this embodiment, a photo-reactive compound such as CNB can be used to cage GABA. An optical lead placed strategically within the brain is used to release GABA in specific regions to alleviate symptoms of these or other neurological disorders.

Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.

Claims

1. A therapeutic flash photolysis system comprising: means for administering a photo-reactive compound to a patient, the photo-reactive compound being inert until activated by light to form an active compound that regulates a physiological function of the patient; and means for emitting light at a wavelength that activates the photo-reactive compound.

2. A system according to claim 1 and further comprising: means for sensing a physiological condition of the patient, the means for sensing being in communication with one or more of the means for administering and the means for emitting.

3. A system according to claim 1 wherein the photo-reactive compound undergoes a chemical reaction prior to activation.

4. A system according to claim 1, wherein the photo-reactive compound is administered in a membrane-permeant form.

5. A method according to claim 4, wherein the photo-reactive compound is administered in an acetoxymethyl ester form.

6. A system according to claim 5, wherein photo-reactive compound is convertible to an active form capable of responding to the light through an enzymatic reaction within the cells.

7. A system according to claim 4, wherein the photo-reactive compound is transportable out of the cells following activation by light.

8. A system according to claim 1, wherein the photo-reactive compound comprises a calcium sensitive compound.

9. A system according to claim 8, wherein the photo-reactive compound is capable of manipulating intracellular calcium concentration when activated by light.

10. A system according to claim 9, wherein the photo-reactive compound has an affinity for calcium that increases in response to being activated.

11. A system according to claim 9, wherein the photo-reactive compound has an affinity for calcium that decreases in response to being activated.

12. A system according to claim 1, wherein administering the photo-reactive compound comprises one of orally administering, injecting, topically administering, administering in a suppository, and pumping.

13. A system according to claim 1 and further comprising: means for sensing a physiologic parameter; and means for controlling, the means for emitting light as a function of the physiologic parameter sensed.

14. A system according to claim 1, wherein the means for emitting light delivers the light to cells within a region of an organ.

15. A system according to claim 14, wherein the means for emitting light delivers the light in a scanning pattern to the cells.

16. A system according to claim 14, wherein the cells comprise myocardial cells.

17. A system according to claim 14, wherein the photo-reactive compound forces myocardial contraction when activated.

18. A system according to claim 17, wherein the means for emitting light delivers a light pulse during systole.

19. A system according to claim 14, wherein the photo-reactive compound forces myocardial relaxation when activated.

20. A system according to claim 19, wherein the means for emitting light delivers a light pulse during diastole.

21. A method of treatment to affect a physiological function, the method comprising: administering a photo-reactive compound to cells of a patient, the photo-reactive compound being capable of affecting intracellular activity when activated; and delivering a light stimulus to the cells to activate the photo-reactive compound.

22. A method according to claim 21, wherein the photo-reactive compound is administered in a membrane-permeant form.

23. A method according to claim 22, wherein the photo-reactive compound is administered in an acetoxymethyl ester form.

24. A method according to claim 23, wherein photo-reactive compound is convertible to an active form capable of responding to the light stimulus through an enzymatic reaction within the cells.

25. A method according to claim 22, wherein the photo-reactive compound is transportable out of the cells following activation by the light stimulus.

26. A method according to claim 21, wherein the photo-reactive compound comprises a calcium sensitive compound.

27. A method according to claim 26, wherein the photo-reactive compound is capable of manipulating intracellular calcium concentration when activated by the light stimulus.

28. A method according to claim 27, wherein the photo-reactive compound has an affinity for calcium that increases in response to being activated.

29. A method according to claim 27, wherein the photo-reactive compound has an affinity for calcium that decreases in response to being activated.

30. A method according to claim 21, wherein administering the photo-reactive compound comprises one of orally administering, injecting, topically administering, administering in a suppository, and pumping.

31. A method according to claim 21 and further comprising:

sensing a physiologic parameter; and controlling delivery of the light stimulus as a function of the physiologic parameter sensed.

32. A method according to claim 21, wherein delivering the light stimulus comprises delivering the light stimulus to cells within a region of an organ.

33. A method according to claim 21, wherein delivering a light stimulus comprises directing light in a scanning pattern to the cells.

34. A method according to claim 21, wherein the cells of the patient comprise myocardial cells.

35. A method according to claim 34, wherein the photo-reactive compound forces myocardial contraction when activated.

36. A method according to claim 35, wherein the light stimulus comprises a light pulse delivered during systole.

37. A method according to claim 34, wherein the photo-reactive compound forces myocardial relaxation when activated.

38. A method according to claim 37, wherein the light stimulus comprises a light pulse delivered during diastole.

39. A system for providing therapy, the system comprising: a drug delivery device for administering a photo-reactive compound to cells; and a light delivery device for delivering a light stimulus to the photo-reactive compound to cause the photo-reactive compound to affect a cellular function.

40. A system according to claim 39, wherein the drug delivery device comprises a drug pump.

41. A system according to claim 40, wherein the drug delivery device comprises an implantable, refϊllable drug pump.

42. A system according to claim 41, wherein the drug delivery device further comprises a delivery conduit having a proximal end connected to the drug pump and a distal end positionable proximate the cells.

43. A system according to claim 39, wherein the light delivery device comprises: a light source; and a light guide for directing light from the light source to the cells.

44. A system according to claim 43, wherein the light delivery device further comprises: a light distribution element at a distal end of the light guide.

45. A system according to claim 44, wherein the light distribution element is movable to scan light from the light guide onto the cells.

46. A system according to claim 45, wherein the light distribution element is rotatable.

47. A system according to claim 39 and further comprising: a sensor for sensing a physiologic parameter; and a controller for controlling light delivery device as a function of the physiologic parameter sensed.

48. A system according to claim 47, wherein the cells comprise myocardial cells and the physiologic parameter comprises one of myocardial electrical, chemical and mechanical activity.

49. A system according to claim 39, wherein the photo-reactive compound is administered in a membrane permeant form.

50. A system according to claim 49, wherein the photo-reactive compound is administered in an acetoxymethyl ester form.

51. A system according to claim 50, wherein photo-reactive compound is convertible to an active form capable of responding to the light stimulus through an enzymatic reaction within the cells.

52. A system according to claim 51 , wherein the photo-reactive compound is transportable out of the cells following activation by the light stimulus.

53. A system according to claim 39, wherein the photo-reactive compound comprises a calcium sensitive compound.

54. A system according to claim 53, wherein the photo-reactive compound is capable of manipulating intracellular calcium concentration when activated by the light stimulus.

55. A system according to claim 54, wherein the photo-reactive compound has an affinity for calcium that increases in response to being activated.

56. A system according to claim 54, wherein the photo-reactive compound has an affinity for calcium that decreases in response to being activated.

57. A system according to claim 39, wherein the light delivery device delivers the light stimulus in a scanning pattern to the cells.

58. A system according to claim 39, wherein the cells of the patient comprise myocardial cells.

59. A system according to claim 58, wherein the photo-reactive compound forces myocardial contraction when activated.

60. A system according to claim 59, wherein the light stimulus comprises a light pulse delivered during systole.

61. A system according to claim 58, wherein the photo-reactive compound forces myocardial relaxation when activated.

62. A system according to claim 61, wherein the light stimulus comprises a light pulse delivered during diastole.

63. A method of enhancing myocardial function, the method comprising: delivering a photo-reactive calcium sensitive compound in membrane-permeant form to myocardial cells; and activating the photo-reactive calcium sensitive compound with a light stimulus to cause a change in calcium concentration in the cells.

64. A method according to claim 63, wherein the photo-reactive calcium sensitive compound increases in calcium affinity when activated.

65. A method according to claim 63, wherein the photo-reactive calcium sensitive compound decreases in calcium affinity when activated.

66. A method according to claim 63 and further comprising: timing the activating of the photo-reactive calcium sensitive compound to a cardiac rhythm.

67. A method of delivering cardiac therapy, the method comprising: delivering to myocardial cells at least one photo-reactive compound that manipulates intracellular calcium concentration when activated; and directing a light stimulus to the myocardial cells to activate the photo-reactive compound.

68. A method according to claim 67, wherein the photo-reactive compound is delivered in a membrane-permeant form.

69. A method according to claim 68, wherein the photo-reactive compound is administered in an acetoxymethyl ester form.

70. A method according to claim 69, wherein photo-reactive compound is convertible to an active form capable of responding to the light stimulus through an enzymatic reaction within the cells.

71. A method according to claim 68, wherein the photo-reactive compound is transportable out of the cells following activation by the light stimulus.

72. A method according to claim 67, wherein the photo-reactive compound has an affinity for calcium that increases in response to being activated.

73. A method according to claim 67, wherein the photo-reactive compound has an affinity for calcium that decreases in response to being activated.

74. A method according to claim 67 and further comprising: sensing a physiologic parameter; and controlling delivery of the light stimulus as a function of the physiologic parameter sensed.

75. A method according to claim 67, wherein delivering the light stimulus comprises delivering the light stimulus to cells within a region of an organ.

76. A method according to claim 67, wherein delivering the light stimulus comprises directing light in a scanning pattern to the cells.

77. A method according to claim 67, wherein the cells of the patient comprise myocardial cells.

78. A method according to claim 77, wherein the photo-reactive compound forces myocardial contraction when activated.

79. A method according to claim 78, wherein the light stimulus comprises a light pulse delivered during systole.

80. A method according to claim 77, wherein the photo-reactive compound forces myocardial relaxation when activated.

81. A method according to claim 80, wherein the light stimulus comprises a light pulse delivered during diastole.

82. A method of enhancing myocardial function, the method comprising: delivering a photo-reactive compound in membrane-permeant form to myocardial cells; and activating the photo-reactive compound with a light stimulus to change intracellular calcium concentration in the myocardial cells.

83. A method according to claim 82, wherein the photo-reactive compound is administered in a membrane-permeant form.

84. A method according to claim 82, wherein the photo-reactive compound is administered in an acetoxymethyl ester form.

85. A method according to claim 84, wherein photo-reactive compound is convertible to an active form capable of responding to the light stimulus through an enzymatic reaction within the cells.

86. A method according to claim 83, wherein the photo-reactive compound is transportable out of the cells following activation by the light stimulus.

87. A method according to claim 82, wherein the photo-reactive compound comprises a calcium sensitive compound.

88. A method according to claim 87, wherein the photo-reactive compound is capable of manipulating intracellular calcium concentration when activated by the light stimulus.

89. A method according to claim 82 and further comprising: sensing a physiologic parameter; and controlling delivery of the light stimulus as a function of the physiologic parameter sensed.

90. A method according to claim 82, wherein the photo-reactive compound forces myocardial contraction when activated.

91. A method according to claim 90, wherein the light stimulus comprises a light pulse delivered during systole.

92. A method according to claim 82, wherein the photo-reactive compound forces myocardial relaxation when activated.

93. A method according to claim 92, wherein the light stimulus comprises a light pulse delivered during diastole.

94. A system for controlling cardiac filling, the system comprising: a drug delivery device for administering a photo-reactive compound to myocardial cells; and a light activation device for applying a light stimulus to the photo -reactive compound to cause at least one of forced myocardial relaxation and forced myocardial contraction.

95. A system according to claim 94, wherein the drug delivery device comprises an implantable, refϊllable drug pump.

96. A system according to claim 95, wherein the drug delivery device further comprises a delivery conduit having a proximal end connected to the drug pump and a distal end positionable proximate the cells.

97. A system according to claim 94, wherein the light activation device comprises: a light source; and a light guide for directing light from the light source to the cells.

98. A system according to claim 97, wherein the light activation device further comprises: a light distribution element at a distal end of the light guide.

99. A system according to claim 98, wherein the light distribution element is movable to scan light from the light guide onto the cells.

100. A system according to claim 99, wherein the light distribution element is rotatable.

101. A system according to claim 94 and further comprising: a sensor for sensing a physiologic parameter; and a controller for controlling light activation device as a function of the physiologic parameter sensed.

102. A system according to claim 101, wherein physiologic parameter comprises one of myocardial electrical, chemical and mechanical activity.

103. A system according to claim 94, wherein the photo-reactive compound is administered in a membrane permeant form.

104. A system according to claim 103, wherein the photo-reactive compound is administered in an acetoxymethyl ester form.

105. A system according to claim 104, wherein photo-reactive compound is convertible to an active form capable of responding to the light stimulus through an enzymatic reaction within the cells.

106. A system according to claim 103, wherein the photo-reactive compound is transportable out of the cells following activation by the light stimulus.

107. A system according to claim 94, wherein the photo-reactive compound comprises a calcium sensitive compound.