BACKGROUND OF THE INVENTION
This invention relates generally to the medical field and, more particularly, to the use of photodynamic therapy to treat prostate tissues, and to the use of transurethral photodynamic therapy to treat malignant transformation of the prostate tissue, such as obstructive carcinoma of the prostate and inflammatory conditions of the prostate. The present invention involves treatment of a patient with prostatic disorders using a photosensitive composition which accumulates in the prostate tissue.
Various types of prostatic tissue become hypertrophied or increased in size, which increase does not necessarily involve malignant transformation. While the causes of such hypertrophy of the tissue are numerous, until the present invention, the treatments of such hypertrophied tissue have various limitations. In particular, benign prostate hypertrophy (BPH) causes enlargement of the prostate gland and/or constriction of the urethra. Benign prostatic hypertrophy is a relatively common disorder in older males. Another type of prostate disorder is cancer of the prostate, such as obstructive carcinoma of the prostate. Still another type of prostate disorder is prostatitis. Prostatitis is an inflammatory condition due to an infective pathogen, such as a bacterium or other microbe. Often prostatitis does not respond well to antibiotic treatment. In chronic or severe cases of prostatitis, abscesses can form and destroy prostatic tissue. Some manifestations of these prostate disorders cause a constriction of the urethra within the prostate and results in various symptoms including stanguria, nocturia, frequency of urination and sometimes retention of urine.
Currently there are various methods for treating prostatic disorders including surgical treatment, drug therapy, hypothermia and hyperthermia treatment, implantation of prostatic stents and enlargement of the urethra using dilation balloons.
The surgical treatment of these disorders involves exposing the prostate and removing the affected prostatic tissue under direct vision by the surgeon. Another surgical method involves transurethral resection wherein an instrument is placed in the external opening of the urethra and sections of the prostate gland are removed from within the prostatic urethra. Despite the significant advances in patient treatment using transurethral resection, there is a need for less invasive treatment to relieve the patient of the symptoms of such prostate disorders. It is widely known that complications including bleeding, infection, residual urethral obstruction or stricture, retrograde ejaculation, incontinence or impotence may result from these surgical methods.
One partially effective method in achieving urinary outflow involves the placement of a tube or catheter through the external urethra into the bladder in order to allow urine to flow from the bladder. The urinary catheter may have a balloon at the distal tip which, when inflated within the bladder, prevents the removal of the catheter from the body. This method generally is not a suitable long term treatment since problems from infection and maintenance of the catheter may arise.
Other attempts to treat prostatic disorders involve dilation of the urethra in an area adjacent the prostate gland. Various methods of dilation have been proposed in order to enlarge the urethra to allow for normal urination. One continuing concern is that the prostate gland returns to its original dimensions after dilation. Thus, the dilation provides only a temporary solution to the urethral constriction. The fibrous prostate gland is resilient and causes constriction of the urethra to recur shortly after treatment. This is of particular concern since prostatic disorders involve the fibrous and enlarged tissue of the prostate gland itself. Enlargement by dilation of the urethra wall typically has no lasting effect on relieving the constriction on the urethra since the prostate gland returns to its previous shape shortly after dilation.
Therefore, it is important that a method for treating prostatic disorders include a way to keep the urethra from being constricted by the prostate gland after such treatment. Without such treatment, the patient may be required to undergo repeated treatments in order to maintain the integrity of the urethra lumen.
In photodynamic therapy photosensitive compositions are used to selectively destroy pathologic tissue. For example, various photosensitive compounds localize in tumorous tissue where the compositions absorb light at certain wavelengths when irradiated. The photosensitive compositions are useful due to their ability to localize in the cancerous or tumorous tissue and not in the surrounding non-cancerous or normal tissues.
Photosensitive compositions have been proposed as useful compounds for topical application for diagnosis and treatment of skin diseases. In addition, photosensitive compositions have been proposed for use to sterilize biological samples containing infectious agents such as bacteria and viruses. The bactericidal effects are induced by irradiation of tissues treated with photosensitive compositions against gram-positive and gram-negative microorganisms (Martinetto et al. Drugs Exp. Clin. Res. XII (4) 335-342, 1986). The photosensitive compositions have also been used to decontaminate blood and blood components. In addition, photosensitive compositions have been used in the treatment of blood vessel occlusions such as atherosclerotic plaques, thrombi, and the like.
Photodynamic therapy in combination with hyperthermia has also been proposed as a useful method in treating many of these applications. Photosensitive compositions have also been proposed as useful in the diagnosis of disease. These photosensitive compositions have fluorescent properties and since the photosensitive compositions sequester in diseased tissue, fluorescent measurement can be used to diagnose and localize the disease, or direct therapy.
Until the present invention there has been no suggestion of using photodynamic therapy, either alone or in combination with hyperthermic therapy, in the diagnosis and treatment of non-cancerous, prostatic disorders, such as benign prostatic hypertrophy and prostatitis.
Further, until the present invention, there has been no suggestion of using photodynamic therapy in the in vivo treatment of an infectious prostatitis.
DISCLOSURE OF THE INVENTION
The present invention provides a method of diagnosing and treating prostatic disorders and the related symptoms of urinary retention or urinary frequency. The method of the present invention requires little or no hospitalization and avoids the possible complications which accompany other methods of treating prostatic tissues. In one embodiment, the present invention provides a method for relieving the constriction of the urethral opening or lumen. The present invention further provides a method for treating prostatic disorders which method comprises destruction of photosensitized prostate tissue using photodynamic therapy either alone or in combination with hyperthermic therapy.
It is contemplated that various photosensitive compositions are useful in the present invention. There are various classes of useful photosensitive compositions, including, for example, porphyrins, chlorins (such as benzochlorins, benzochlorin metal complexes, bacteriochlorins and the like), purpurins, verdins, phthalocyanines and iminium salts of these compositions and other compositions. It is to be understood that the present invention envisions the use of these and other classes of photosensitive compositions, and the present invention is not limited to particular photosensitive compositions.
Examples of various known photosensitive compositions include those compounds disclosed in Selman et al., Photochem and Photobiol., 57:681-685 (1993), Morgan et al., J. Org. Chem. 51:1347-1350 (1986), Skalkos, et al., Med. Chem. Res. 2:276-281 (1992), the U.S. patent application Ser. No. 07/901,597 and Morgan, et al., U.S. Pat. Nos. 4,877,872, 4,988,808, 5,051,415 and 5,216,012 references, which are expressly incorporated herein. (All references disclosed herein form a part of the disclosure and are expressly incorporated by reference.) These compositions are physiologically acceptable for subcutaneous or intravenous administration as solutions, emulsions or suspensions or for topical, rectal or oral preparations.
The photosensitive composition is administered in an effective amount such that a sufficient amount of the photosensitive composition accumulates in the prostatic tissue. In certain embodiments of the present invention, a predetermined period of time is allowed to pass in order to optimize the accumulation of the photosensitive composition in the affected tissue. It is contemplated that various protocols of treatment using the method of the present invention may involve illuminating the photosensitive compositions for time periods ranging from a relatively short time of approximately one hour or less to a longer time of three to four days after administration of the composition to the patient. However, it should be understood that the optimum time lapse (if any) between drug administration and illumination depends on the type and amount of photosensitive composition administered, the patient's history and the judgment of the practitioner.
After the photosensitive composition accumulates in the tissue, the tissue is irradiated with light of a predetermined wavelength at which the composition shows absorbance peaks optimum for fluorescence excitation or, using another wavelength, for tissue destruction. This absorption of light energy by the photosensitive composition causes a reaction which destroys the tissue in which the composition has accumulated and the light is delivered. It is to be understood that the particular wavelength and intensity of light energy delivered to the tissue is dependent, in part, upon the type of photosensitive composition being used. In certain embodiments, photosensitive compositions which have absorbance peaks at longer wavelengths and show greater absorbencies may be used. In various embodiments, the longer wavelength peaks are advantageous because the light of the longer wavelengths is capable of greater penetration of tissue, while the greater absorbencies are desirable because less light energy is required to cause a given degree of reaction.
In addition to the required photosensitive composition, certain additional components may be chemically attached to or physically combined with the photosensitive composition for administration to the patient. These additional components may include labeling compositions including, for example, cytotoxins, monoclonal antibodies and receptor ligands, which may enhance the photosensitive composition's selectivity for the prostate.
The photosensitive compositions and any additional components are formulated into a final pharmaceutical formulation for administration to the patient using techniques generally known in the art. The pharmaceutical formulation can be administered systemically, in particular by intravenous injection and can be used singly or as components of mixtures as solutions, emulsions or suspensions. The pharmaceutical formulation may be delivered orally, topically, intravenously, subcutaneously, rectally, or by direct injection into the tissue. For example, in one embodiment of the invention, the photosensitive composition is delivered by direct injection into the prostate via a transurethral, transrectal or transperineal approach. It is to be understood that the injectable materials can be prepared in conventional forms either as liquid suspensions or solutions, solid forms suitable for solution or suspension and liquid prior to injection or as emulsions. The formulation may include suitable excipients such as saline, dextrose, glycerol, water and the like. The injectable formulation may also contain additional components such as pH buffering agents, wetting or emulsifying agents and the like. Various modes of administration are well known in the art and the systemic administration can be implemented in a manner which is most suitable for delivery of the photosensitive composition. This administration can include a slower sustained release system or, if properly formulated, an oral administration. The quantity of the formulation being administered is dependent upon the choice of the active photosensitive composition, the condition to be treated, the mode of administration, the individual patient and the expertise and judgment of the practitioner. As such, smaller or larger doses may be needed depending upon the specificity of the formulation. It is contemplated that in formulations having such additional components such as highly specific monoclonal antibody preparations and specific receptor ligands, the dosages may be less than formulations which are less specific to the target tissue. It is contemplated that ranges in about 0.05-10 mg/kg are suitable. It is to be understood that these ranges are merely suggestive and many variables must be taken into consideration in the treatment of individual patients and variations from these recommended values are expected.
The wavelength of irradiating light is chosen to match the maximum absorbance of the photosensitive composition. The suitable wavelengths for the photosensitive compositions are readily determined by the composition's absorption spectrum. For example, the photosensitive composition tin (II) chloride etiopurpurin is illuminated with light that includes the absorption peak at 660 nm. The irradiation dosages are readily determined and dependent upon the method of delivery of the photosensitive composition (i.e. intravenous; topical administration, direct injection and the like) and the type and amount of photosensitive composition being administered. Thus, the intensities of light illumination will typically be in the range of less than about 15 to more than about 500 joules of light.
Other ingredients which can be included in the formulation include antimicrobial agents and/or preservatives as necessary. Many variations of the above, along with other suitable vehicles will suggest themselves to those skilled in the art in light of the description herein.
Irradiation of the tissue containing the photosensitive composition in accordance with the instant invention can be achieved by delivering light energy from conventional light source, or a laser, or by sending an electromagnetic signal from an appropriate transmitting device. The particular method of irradiation of the tissue depends upon the location in the patient of the affected prostate tissue.
The light energy can be delivered through a light delivery means via a transurethral, transrectal or transperineal approach. It is also contemplated that the light can be delivered by direct insertion of a light delivery means into the prostatic tissue. For example, in one embodiment, the light energy is delivered through an optical fiber which can optionally have a light diffusing means operatively attached thereto. Another embodiment of the present invention also provides for delivery of light to the prostate via a transurethral approach.
In one particular embodiment, the light energy is delivered to a patient's prostate by placing the light delivery means in a urethral catheter. The light delivery means is properly located within the urethra and positioned adjacent to the target prostate tissue. A portion of the catheter is sufficiently transparent or translucent to allow the light energy to adequately irradiate the adjacent prostate tissue. In various embodiments of the present invention, a balloon may be affixed to the distal end of the catheter for fixation of the balloon within the bladder and adjacent the bladder sphincter muscle in various embodiments of the present invention, it is also possible to affix a second balloon coaxially around the catheter. The distal end of the second balloon adjacent the distal end of the catheter may be coated with an opaque or reflective shield type material such that light does not penetrate the adjacent sphincter muscle or bladder tissues. It is also contemplated that an opaque and/or reflective stop means can be positioned adjacent the distal end of the catheter to prevent the light delivery means from entering the sphincter or bladder. The stop means also aids in confirming proper localization of the catheter.
It is also contemplated that the catheter can be provided with an apparatus to cool or heat the affected tissue area. It is also contemplated that the catheter can be provided with various means for guiding the catheter through a lumen, and means for measuring light intensity, temperature and drug fluorescence or illumination. It is also contemplated that the catheter can be provided with an irrigation apparatus to provide a source of irrigation to the area as desired and to keep the area being irradiated relatively clear.
Accurate positioning of the light delivery means assures that there is limited penetration of light into the tissue and that only the desired tissue is irradiated. Such accurate positioning can be aided by using an ultrasound probe. It is also contemplated that other methods of accurately positioning the light delivery means can be used. For example, the catheter and/or light delivery means can have graduated marks thereon so that the actual position of the light delivery means can be accurately located.
The light delivery means can be in the form of a light guide, such as a fiber optic bundle, which in preferred embodiments, comprises at least one optical fiber having an appropriate provision for lighting thereof, The light delivery means and catheter each have a sufficiently small cross section so that the light delivery means and catheter may be fabricated within the appropriate dimensions to comfortably fit within the patient's body or desired orifice. The catheter may be of a rigid type material or may be made of sufficiently flexible material for positioning the light delivery means and catheter throughout a tortuous path.
If desired, the light energy may be delivered interstitially into the prostatic tissue by first inserting a needle into the prostatic tissue via a transurethral, transrectal or transperineal approach. The light delivery means is coaxially inserted through the needle and the needle is thereafter removed, leaving the light delivery means directly in contact with the affected prostatic tissue.
After proper localization of the light delivery means is achieved, the light source is operatively engaged and light energy irradiates the adjacent tissue. The preferred length of time of irradiation and wavelength of light are determined by the type and amount of photosensitive composition being used and other factors as described above. The irradiation of the photosensitive composition causes the photosensitive composition to absorb light generally or induces a photochemical reaction of the photosensitive composition, thereby inducing destruction of the affected tissue. The photosensitive composition may cause a hemorrhagic necrosis of the affected tissue. Further, with the passage of time there is subsequent diminishment or cessation of the cellular and/or tissue functions and subsequent atrophy of the prostatic tissue. It is surprisingly found that when using a transurethral approach, the urethra itself and the urethra mucosa are either spared any damage or regenerate while the tissue of the prostate gland remains in the destroyed or atrophied state.
Further objects, features and advantages of the present invention will become apparent from the detailed description of the preferred embodiments which follows, when considered together with the attached Figures.