USOO6607477B1 (12) United States Patent (10) Patent No.: US 6,607,477 B1 LOngton et al. (45) Date of Patent: Aug. 19, 2003

(54) GRADUATED INTRALUMINAL CATHETER 5,378,230 A 1/1995 Sakharam AND METHODS OF USE THEREOF 5,383,866 A 1/1995 Chang 5,882.290 A 3/1999 Kume 5,968,068 A * 10/1999 Dehdashtian et al...... 606/192 (76) Inventors: Wallace A. Longton, 7 Derbyshire Dr., 5.997.462 A 12/1999 Löffler Carlisle, PA (US) 17013; Curtis 6,123,083. A * 9/2000 McGrath et al. Miyamoto, 32 Parkdale Pl, Marlton, 6.210,312 B1 * 4/2001 Nagy NJ (US) 08053; Daniel B. Rukstalis, 808 Westview St., Philadelphia, PA OTHER PUBLICATIONS (US) 19119 Badlani, et al., 1995, Adult 45(5): 846–856. (*) Notice: Subject to any disclaimer, the term of this Baskin, et al., 1993, Urol. 150:642–647. patent is extended or adjusted under 35 Bosniakovic, et al., 1994, Cardiovasc. Intervent. Radiol. 17:280-284. U.S.C. 154(b) by 206 days. Gibbons, et al., 1979, Urol. 121:310-312. Harada, et al., 1993, Rad. Oncol. 11(4): 139-145. (21) Appl. No.: 09/639,510 Koukourakis, et al., 1994, Med. Dosimetry 19:67-72. Filed: Aug. 16, 2000 Mundy, 1989, Br. J. Urol. 64:626–628. (22) Quartey, 1993, Ann. Urol. 27:228-232. Related U.S. Application Data Raju, 1993, Rad. Oncol. Biol. Phys. 27(3):677-680. Singh, et al., 1979, Urol. 121:268-270. (63) Continuation of application No. PCT/US99/03203, filed on Skarlatos, et al., 1994, Urol. Int. 53:209–213. Feb. 16, 1999. Smith, et al., 1979, Urol. 121-133. (60) Provisional application No. 60/074,801, filed on Feb. 16, Stormont, et al., 1993, Urol. 150:1725–1728. 1998. (51) Int. Cl...... A61N 5/00 * cited by examiner (52) U.S. Cl...... 600/3 Primary Examiner Mark Bockelman (58) Field of Search ...... 600/1–3, 6-8; (74) Attorney, Agent, or Firm Akin Gump Strauss Hauer 604/101.01, 101.04, 43 & Feld, L.L.P. (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Graduated catheters including, but not limited to, graduated urethral and ureteric catheters are provided, the catheters 4,037,599 A 7/1977 Raulerson each comprising a catheter tube, an expandable portion, and 4,072,146 A 2/1978 Howes at least one indicator. The position of at least one indicator 4,406,656 A 9/1983 Hattler may be determined by an extracorporeal imaging method. A 4,423,725 A 1/1984 Baran et al. 4,790.810 A * 12/1988 Pugh, Jr. et al. kit comprising a matched pair of graduated catheters is also 4.945,895 A * 8/1990 Takai et al...... 600/104 provided, wherein the position within a bodily lumen of a 5,002,558 A 3/1991 Klein et al. Subject of at least one indicator of a graduated locator 5,078.684 A 1/1992 Yasuda catheter of the kit has a known relationship to the position 5,167,623. A 12/1992 Cianci within the bodily lumen of at least one indicator of a 5,167,662 A 12/1992 Hayes graduated delivery catheter of the kit. Brachytherapy meth 5,180,367 A * 1/1993 Kontos et al. ods are also provided, including methods of treating urethral 5,207,648 A 5/1993 Gross and ureteric Strictures, , and benign prostatic 5,221,255 A 6/1993 Sakharam hypertrophy. 5,221,256 A 6/1993 Mahurkar 5,308,323 A 5/1994 Sogawa 5,314,443 A * 5/1994 Rudnick ...... 606/192 27 Claims, 7 Drawing Sheets

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ZI?!!! US 6,607,477 B1 1 2 GRADUATED INTRALUMINAL CATHETER ficity. Radiation or drug delivered near a relevant tissue may AND METHODS OF USE THEREOF induce death of cells in both the relevant tissue and other tissueS which are located in close proximity to the relevant CROSS-REFERENCE TO RELATED tissue. Because of the inaccuracy of prior art intracavitary APPLICATIONS brachytherapy methods for directing treatment only to rel evant tissue, as described above, prior art methods have This application is a continuation of international patent required the use of excess amounts of cytotoxic agents. So application PCT/US99/03203 file date Feb. 16, 1999 that death of relevant tissue cells will be effected even if the (publication number WO 99/42149;), and is entitled to agent is not accurately placed. Use of excess cytotoxic priority pursuant to 35 U.S.C. S119(e) to U.S. provisional agent, however, induces damage in non-relevant tissue. patent application No. 60/074,801, which was filed on Feb. Collateral damage to non-relevant tissues could be avoided 16, 1998 (abandoned). if the cytotoxic agents could be delivered more accurately to relevant tissues. Accordingly, there is a great need for FIELD OF THE INVENTION devices, kits, and methods for accurately delivering cyto The field of the invention is a catheter which is insertable 15 toxic agents to relevant tissueS while minimizing delivery of into or through a Subject's , or into or through another the agents to Surrounding tissues. pre-existing or artificial bodily lumen of an animal, for a The prostate is a Solid which Surrounds the urethra diagnostic or therapeutic purpose. of the male between the base of the bladder and the urogenital diaphragm. Benign prostatic hypertrophy (BPH) BACKGROUND OF THE INVENTION is a common condition among male aged 45 or The use of catheters, including multi-lumen catheters, is older. ProState cancer is a leading cause of death among known for many therapeutic and diagnostic medical pur males, and can frequently be diagnosed with the aid of a poses. For example, the use of urethral catheters, including Simple blood antigen-detecting test. Radiation therapy and multi-lumen urethral catheters, is known in the art of urol prostatectomy are the primary treatments available for proS ogy. Such urethral catheters are useful for delivering 25 tate cancer and prostatectomy is currently the primary compositions, including radioactive compositions, to the treatment for BPH. Prostatectomy has numerous drawbacks, urethra of a subject (e.g. Harada et al., 1993, Rad. Oncol. which have been widely described in the art. External beam 11:139-145; Skarlatos et al., 1994, Urol. Int. 53:209–213). irradiation of the prostate for the treatment of localized However, the use of prior art urethral catheters is limited by prostate cancer is associated with Small bowel injury, radia the ability of the practitioner to accurately identify the tion proctitis, and urethral stricture (Gibbons et al., 1979, J. position of a tissue in need of radiation treatment with Urol. 121:310-312). At least two groups have employed respect to the position of the catheter and the ability of the transurethral radiation therapy as a Supplement to external practitioner to accurately position a radiation Source within beam irradiation of localized prostate cancer tissue (Harada a urethral catheter to deliver radiation to the tissue. et al., 1993, Rad. Oncol. 11:139-145; Skarlatos et al., 1994, Furthermore, prior art urethral catheters do not permit use of 35 Urol. Int. 53:209-213). In addition, another group has a first catheter to determine the position of a tissue of the employed transurethral radiation therapy as a Sole treatment Subject, removal of the first catheter, and use of a Second for recalcitrant BPH-related urine retention (Koukourakis et catheter to accurately provide a composition to the position al., 1994, Med. Dosimetry 19:67–72). Each of these groups of the tissue without determining the position of the tissue a employed ultraSonography, computerized tomography, or Second time. 40 fluoroscopy imaging methods to identify the tissue to be treated or to confirm the position of the radiation Source Intracavitary Brachytherapy relative to the tissue to be treated. Identification of the location of tissue in need of treatment and placement of a Various apparatus and techniques are known in the art of radiation Source using one of these imaging methods is brachytherapy for exposing an animal tissue to a radioactive 45 dependent upon the deformability of the tissues being material using a conduit placed in a cavity of the animal. By imaged, the body posture of the Subject during the identi way of example, bronchial, esophageal, rectal, vaginal, and fication or placement, the position of the imaging device, arterial conduits have been described (e.g. Raju et al., 1993, and other factors which may not be easily replicated. Int. J. Radiation Oncology Biol. Phys. 27:677-680). Failure to precisely control the amount and location of A Serious limitation of prior art intracavitary brachy 50 transurethrally-delivered radiation can result in damage to therapy methods has been the inability of Such methods to the urethra itself or to other organs located in close proX enable accurate and reproducible placement of radiation imity thereto, including the bladder and the prostate. It is Sources in close proximity to a tissue in need of Such thus critical to identify the position of a tissue in need of treatment. Significant Shortcomings of prior art intracavitary treatment and the location of radiation Source as accurately brachytherapy catheters include the tendency of the catheter 55 as possible. to move within the bodily lumen and the inability of practitioners to accurately determine both the location of a Urethral and Ureteric Stricture relevant tissue relative to the catheter and the location of a Urethral Stricture is a common complication of urological radiation Source or pharmaceutical composition within or procedures, particularly following urethral intervention by a along the catheter. Typical prior art methods have involved 60 urologist (Baskin et al., 1993, J. Urology 150:642–647; attempting to identify the position of a relevant tissue, Stormont et al., 1993, J. Urology 150: 1725–1728). Forma thereafter attempting to position a catheter near the relevant tion of a urethral Stricture is thought to involve disruption of tissue, and thereafter attempting to position a radiation the urothelium, followed by hypertrophy of urothelial or Source or pharmaceutical composition within or along the other tissues, resulting in . A urethral Stricture may catheter near the relevant tissue. 65 also be formed by hypertrophy of a tissue located in close A limitation on the use of radiation and other potentially proximity to the urothelium, Such as prostate tissue or corpus cytotoxic medical treatments is the lack of cytotoxic Speci Spongiosum penis tissue in male humans or muscle tissue or US 6,607,477 B1 3 4 Spongiose erectile tissue in humans. Non-limiting (c) an indicator associated with the tubular body for examples of urological interventions known to be associated indicating a reference position within the bodily lumen. with urethral stricture include transurethral resection of the In one embodiment, the tubular body has a proximal prostate, radical prostatectomy, external beam irradiation of portion and a lumen extending longitudinally therein prostate tissue, and other urological interventions which from the proximal portion. The expandable member disturb the urethra. Non-limiting examples of diseases or may, for example, be a balloon wherein at least one disorders known to be associated with urethral Stricture lumen extends from the proximal portion of the tubular include BPH, prostate cancer, and urethral cancer. Further body to the interior of the balloon. The balloon may, for details of tissues which comprise the urethra or which are example, be disposed about the distal portion of the located in close proximity thereto in the human are found in, catheter tube. for example, Williams et al., eds. (1980, Gray's , The graduated catheter of the invention may further 36th ed., W.B. Saunders Co., Philadelphia, pp. 1408–1409). comprise a movable element having an indicator associated Known treatments for urethral Strictures include Surgical therewith. The position of the movable element with respect modification of the urethra, laser-assisted modification of to the tubular body may be determined by comparing the the urethra, urethroplasty, and urethral Stent implantation position of the indicator associated with the movable ele (Bosnjakovic et al., 1994, Cardiovasc. Intervent. Radiol. 15 ment with the position associated with the indicator of the 17:280–284; Badlani et al., 1995, Urology 45:846-856; graduated catheter. The graduated catheter may also com Mundy, 1989, Brit. J. Urology 64:626–628; Quartey, 1993, prise a plurality of the indicators longitudinally Spaced along Ann. Urol. 27:228-232). the catheter tube. Ureteric Stricture is another known complication of uro In an important embodiment, the graduated catheter of the logical procedures and of disease and disorder States. Ure invention, the catheter tube includes a Second lumen extend teric Strictures may involve hyperplasia or hypertrophy of ing longitudinally into the catheter tube from the proximal any of the tissue layers of a , namely the fibrous layer, portion. The catheter may further comprising a radiation the , or the mucous layer, or may involve Source, a radiation Source positioner, or both disposed within hyperplasia or hypertrophy of a tissue or organ located in 25 the Second lumen. The radiation Source may, for example be close proximity to a ureter. Further details of tissues which a radioisotope Selected from the group consisting of a comprise a ureter or which are located in close proximity beta-emitter, a gamma-emitter, and an X-ray emitter. For thereto in the human are found in, for example, Williams et example, if the radioisotope is a beta-emitter, it may be al., eds. (1980, Gray's Anatomy, 36th ed., W.B. Saunders selected from the group consisting of 'Y, Re, P, Re, Co., Philadelphia, pp. 1402–1404). Surgical treatments are 'Rh, and 'Sr; if the radioisotope is a gamma-emitter, it known for treatment of ureteric Stricture. may be selected from the group consisting of 'Co, '7Cs, A Significant unmet need remains for a device and method and 'Ir; or if the radioisotope is an X-ray emitter, it may which can be used within the urinary tract to identify the be selected from the group consisting of 'Pd, 'Cd, position of a tissue in need of treatment in a Subject in a 145Sm, 149Pm, 169Yb, and 125I. manner which is not dependent upon the deformability of 35 In other embodiments of the graduated catheter of the the Surrounding tissues, the position of the Subject, the invention, the catheter tube further includes position of the imaging device, or other factors which are not (a) an inlet orifice positioned along the catheter tube for easily replicated. AS used herein, the “urinary tract' includes withdrawing a composition from the bodily lumen and the urethra, the bladder, the , and the kidneys of a a third lumen extending longitudinally within the cath Subject, and tissues located in close proximity thereto. 40 eter tube from the proximal portion and communicating There also remains a Significant unmet need for an with the inlet orifice, efficacious method for treating urethral or ureteric Stricture (b) an outlet orifice positioned along the catheter tube for which does not exhibit the Side effects and shortcomings providing a composition to the bodily lumen and a asSociated with prior art methods of treating these Strictures. fourth lumen extending longitudinally within the cath Numerous other catheters are known in the art for place 45 eter tube from the proximal portion and communicating ment within a naturally-occurring bodily lumen or an arti with the outlet orifice, or ficial (i.e. Surgically or traumatically formed) bodily lumen. (c) both. Many of the known catheters share a common disadvantage, The graduated catheter of the invention may further namely that the catheter cannot practically be Secured within comprise a sleeve Surrounding at least a portion of the the bodily lumen in such a way that a point on or within the 50 catheter tube. The tubular body of the graduated catheter catheter may be reproducibly situated at the same location may have a diameter Sufficiently Small to fit within a human within the bodily lumen upon removal and re-emplacement urethra, and may have a Sufficient length that the distal end of the catheter. Such reproducibility is critical if the same thereof may be inserted into a ureter of the Subject. catheter is to repeatedly used to deliver agents (e.g. The invention also relates to a matched pair of graduated radionuclides) for which the tolerance for misplacement is 55 catheters. The matched pair comprises a first and a Second low. This reproducibility is also critical if matched pairs or graduated catheter of the invention. The position of the Sets of catheters are to be used cooperatively. indicator of the first catheter along the longitudinal axis of The catheters, kits, and methods of using them described the bodily lumen when the first catheter is seated therein has herein overcome these shortcomings. a known relationship to the position of the indicator of the 60 Second catheter along the longitudinal axis of the bodily SUMMARY OF THE INVENTION lumen when the Second catheter is Seated therein. The invention relates to a graduated catheter for repro In one aspect, the invention relates to a graduated urethral ducibly seating within a bodily lumen of an animal. The catheter for use within the urethra of a subject. This catheter catheter comprises comprises (a) a tubular body having a distal portion, 65 (a) a catheter tube having a proximal portion including a (b) an expandable member on the distal portion of the proximal end and a distal portion including a distal end, tubular body, and the distal portion having a balloon inflation orifice, the US 6,607,477 B1 S 6 catheter tube including a first lumen extending longi (b) thereafter inflating the balloon of the graduated locator tudinally into the catheter tube from the proximal catheter; portion and communicating with the balloon inflation (c) thereafter seating the balloon of the graduated locator orifice; catheter against an internal orifice of the bodily lumen; (b) a balloon affixed to the distal portion, wherein the interior of the balloon communicates with the balloon (d) thereafter identifying, with respect to the indicator of inflation orifice; and the graduated locator catheter, a position within the (c) at least one indicator associated with the catheter tube bodily lumen which is in close proximity to the tissue; for indicating a reference position within the urethra. (e) inserting into the bodily lumen of the Subject a The invention also relates to a urethral catheter kit. This 1O graduated delivery catheter of the invention; kit comprises a graduated locator catheter and a graduated (f) thereafter inflating the balloon of the graduated deliv delivery catheter, each of which is a graduated catheter of ery catheter; the invention. The graduated locator catheter comprises (g) thereafter Seating the balloon of the graduated delivery (a) a locator catheter tube having a proximal portion catheter against the internal orifice of the bodily lumen; including a proximal end and a distal portion, the distal 15 and portion including a balloon inflation orifice, the locator (h) positioning, with respect to at least one the indicator catheter tube including a lumen extending longitudi of the graduated delivery catheter, a radiation Source nally within the locator catheter tube from the proximal within the Second lumen of the graduated delivery portion and communicating with the balloon inflation catheter. orifice; The radiation source is thereby located at the position within (b) a balloon affixed to the distal portion, wherein the the bodily lumen which is in close proximity to the tissue. interior of the balloon communicates with the balloon The bodily lumen may, for example, be the urethra, in which inflation orifice; and instance the tissue may, for example, be Selected from the (c) at least one indicator associated with the locator group consisting of a urethral tissue, a strictured urethral catheter tube for indicating a locator position within a 25 tissue, a urethral tissue at risk for Stricture formation, a Subject's urethra when the balloon of the graduated ureteric tissue, a strictured ureteric tissue, a ureteric tissue at locator catheter is Seated against the internal urethral risk for Stricture formation, prostate tissue, cancerous proS orifice of the Subject’s bladder. tate tissue, and benign hypertrophic prostate tissue. The graduated delivery catheter comprises The invention still further relates to a method of providing (i) a delivery catheter tube having a proximal portion radiation to a tissue located in close proximity to the urethra including a proximal end and a distal portion including of a Subject. This method comprises a distal end, the distal portion including a balloon (a) inserting into the urethra a graduated delivery catheter inflation orifice, the delivery catheter tube including a of the invention; first lumen extending longitudinally within the delivery (b) thereafter inflating the balloon within the subject's catheter tube from the proximal portion and commu 35 bladder; nicating with the balloon inflation orifice, the delivery catheter tube also including a Second lumen extending (c) thereafter Seating the balloon against the internal longitudinally into the delivery catheter tube from the urethral orifice of the bladder; and proximal portion; (d) positioning a radiation Source within the Second lumen 40 of the graduated delivery catheter. (ii) a balloon affixed to the distal portion, wherein the Radiation is thereby provided to the tissue located in close interior of the balloon communicates with the balloon proximity to the urethra. inflation orifice; and The invention also relates to a method of providing (iii) at least one indicator associated with the delivery radiation to a tissue located in close proximity to the urethra catheter tube for indicating a reference position within of a Subject. This method comprises the urethra of the subject when the balloon of the 45 graduated delivery catheter is Seated against the inter (a) inserting into the urethra a graduated locator catheter nal urethral orifice of the Subject’s bladder; of the invention; The locator position has a known relationship to the refer (b) thereafter inflating the balloon of the graduated locator ence position. catheter in the subject's bladder; The invention also relates to a method of providing 50 (c) thereafter seating the balloon of the graduated locator radiation to a tissue located in close proximity to a bodily catheter against the internal urethral orifice of the lumen of a Subject. This method comprises bladder; (a) inserting into the bodily lumen a graduated delivery (d) thereafter identifying, with respect to an indicator of the graduated locator catheter, a position within the catheter of the invention; 55 (b) thereafter inflating the balloon; urethra which is in close proximity to the tissue; (c) thereafter Seating the balloon against an internal orifice (e) inserting into the urethra of the Subject a graduated of the bodily lumen; and delivery catheter of the invention (d) positioning a radiation Source within the Second lumen (f) thereafter inflating the balloon of the graduated deliv of the graduated delivery catheter. 60 ery catheter within the subject's bladder; Radiation is thereby provided to the tissue located in close (g) thereafter Seating the balloon of the graduated delivery proximity to the bodily lumen. catheter against the internal urethral orifice of the The invention further relates to a method of providing bladder; and radiation to a tissue located in close proximity to a bodily (h) positioning, with respect to at least one the indicator lumen of a Subject. This method comprises 65 of the graduated delivery catheter, a radiation Source (a) inserting into the bodily lumen a graduated locator within the Second lumen of the graduated delivery catheter of the invention; catheter. US 6,607,477 B1 7 8 Because the indicators on the graduated locator catheter and the radiation dose. This relationship is illustrated for several the graduated delivery catheter have a known positional radioisotopes, including I, 7Cs, Pd, 'Ir, and Co. relationship, the radiation Source is located at the position within the urethra which is in close proximity to the tissue. DETAILED DESCRIPTION OF THE In another aspect, the invention relates to a graduated INVENTION ureteric catheter for use within a ureter of a subject. The The invention relates to graduated catheters which are graduated ureteric catheter comprises a catheter tube and at insertable within a naturally-occurring or artificial bodily least one indicator associated with the catheter tube for lumen of an animal and which are reproducibly Seatable indicating a reference position within the ureter. within the bodily lumen optionally, but preferably, by means In Still another aspect, the invention relates to graduated of an expandable member on the distal portion of the catheter for indicating a position within a bodily lumen of an catheter. The graduated catheters may be seated within the animal. This catheter comprises a tubular body having a bodily lumen, for example, by expanding the expandable distal portion for inserting into the bodily lumen and an member within a space which communicates with the bodily indicator associated with the distal portion for indicating a lumen and then urging the catheter proximally to Seat the position within the bodily lumen. 15 expandable member against the internal orifice of the bodily lumen (i.e. the location at which the bodily lumen opens into BRIEF DESCRIPTION OF THE DRAWINGS the Space). By way of example, a graduated catheter of the For the purpose of illustrating the invention, there are invention may be urged distally into the urethra of an animal, depicted in the drawings certain embodiments of the inven the expandable member may be expanded in the animals tion. However, the invention is not limited to the precise bladder, and the catheter may be seated by urging the arrangements and instrumentalities of the embodiments catheter proximally to Seat the member against the internal depicted in the drawings. urethral orifice of the animal's bladder. Further by way of FIG. 1 depicts a side elevation view of a first embodiment example, a graduated catheter of the invention may be urged of a graduated urethral catheter, as described herein. distally into a Surgically-created puncture in the chest wall FIG. 2 depicts a transverse cross sectional view of the 25 of a human, the expandable member may be expanded graduated urethral catheter depicted in FIG. 1 taken gener within the cage, and the catheter may be Seated by urging ally along line 2-2 of FIG. 1. the catheter proximally to Seat the member against the rib FIG.3 depicts a detailed side elevation view of the distal Cage. portion of the first embodiment of a graduated urethral The graduated catheters of the invention are useful, for catheter depicted in FIG. 1, partially broken away to reveal example, for insertion into orifices which, at the exterior the presence of the balloon inflation orifice and a balloon body surface, are surrounded by pliable or deformable retaining receSS. tissues unsuitable for Seating the catheter in a fixed position FIG. 4 depicts a side elevation view of the distal portion relative to the lumen of the orifice. In humans, for example, of a Second embodiment of a graduated urethral catheter. a catheter which is inserted through the may be FIG. 5 depicts a transverse cross sectional view of the 35 fixedly Seated in place within the by means of an distal portion of the catheter depicted in FIG. 4, taken adapter which is connected to the catheter and with Seatable generally along line 5-5 of FIG. 4. engages the teeth. However, the human and the human FIG. 6 depicts a longitudinal cross sectional view of the urethra are Surrounded by tissues which are pliable and distal portion of the graduated urethral catheter depicted in deformable. An adapter adapted to the external anatomy of FIGS. 4 and 5, taken generally along line 6-6 of FIG. 5. 40 either of these orifices will not maintain the catheter in a FIG. 7 depicts a side elevation view of the distal portion fixed position within the lumen of the colon and the urethra, of a third embodiment of a graduated urethral catheter. respectively, and will allow movement of the catheter along FIG. 8 depicts a transverse cross sectional view of the the long axis of the bodily lumen when the external tissue graduated urethral catheter depicted in FIG. 7, taken gener deforms. 45 In certain situations, Such as when radiation or a phar ally along line 8–8 of FIG. 7. maceutical composition is to be delivered to a particular FIG. 9 depicts a longitudinal cross sectional view of an lumenal location, displacement of an emplaced catheter embodiment of a graduated urethral catheter having an along the long axis of the bodily lumen complicates accurate inflated balloon Seated against the internal urethral orifice of delivery. The invention overcomes the Shortcomings of prior the bladder of a human subject. 50 art intraluminal catheters by providing a graduated catheter FIG. 10a depicts a longitudinal cross sectional view of an which has an expandable member at a distal portion of the embodiment of a graduated locator catheter having an catheter and an indicator associated with the catheter for inflated balloon Seated against the internal urethral orifice of indicating a position within the bodily lumen into which the the bladder of a human Subject and a urethroScope within the catheter is inserted. The expandable member is expanded urethra of the human Subject. 55 within a void with which the lumen communicates in the FIG. 10b depicts a longitudinal cross sectional view of an body of the animal, thereby reproducibly Seating the gradu embodiment of a graduated delivery catheter which is ated catheter in the bodily lumen. For example, the expand matched with the graduated locator catheter depicted in FIG. able member may be an inflatable balloon which is circum 10a. The graduated delivery catheter has an inflated balloon ferentially affixed to the exterior portion of the tubular body Seated against the internal urethral orifice of the bladder of 60 of the catheter or affixed to the distal end of the tubular body, the human subject depicted in FIG. 10a. and which can be inflated within the bladder of a human FIG. 11 is a graph which illustrates the relationship patient, thereby reproducibly Seating the graduated catheter between distance from a 'I radiation source and the total in the patient's urethra. Each time the same graduated radiation dose delivered. Doses are shown corresponding to catheter is reproducibly Seated in the bodily lumen, the exposure times of 10, 20, 40, and 60 minutes. 65 indicator is located at the same position along the long axis FIG. 12 is a graph which illustrates the relationship of the bodily lumen. Thus, a catheter of the invention which between distance from a radiation Source and the intensity of is reproducibly Seated in the urethra of a human patient has US 6,607,477 B1 9 10 an indicator which is located at a certain position (e.g. at the to identify the position of a relevant tissue (e.g. a neoplastic center of the prostate or, alternatively, a fixed distance from portion of a tissue) only a single time and to thereafter be the center of the prostate) within the patient's urethra. After able to reproducibly deliver radiation or a pharmaceutical the catheter of the invention is emplaced within the bodily composition to that position without once again locating the lumen, it may be used, for example, to determine the relevant tissue. Using one or more matched catheters of the position of an abnormal tissue relative to the indicator or to invention, this may be achieved. Because the positions position a radiation Source within a lumen of the catheter at within the bodily lumen of indicators on matched catheters a Selected position relative to the indicator. have a known relationship, and because the catheters of the The catheter of the invention comprises invention may be reproducibly Seated in the bodily lumen, (i) a tubular body, optionally having one or more lumens one or more catheters of a matched group may be used to extending longitudinally therein, deliver the Source or composition to the same position after (ii) an expandable member on a distal portion of the determining the position of the relevant tissue only once. catheter, and In one embodiment, the catheter of the invention does not (iii) one or more indicators on the tubular body or comprise a expandable member (i.e. it comprises a tubular expandable member. Each of the lumens may extend 15 body having an indicator on the distal portion thereof). In from an orifice at the proximal end of the catheter or this embodiment, the catheter is useful for indicating a from an orifice located on a proximal portion of the position within a bodily lumen by reference to an anatomical catheter other than the proximal end. Each lumen may landmark (e.g. the external urethral orifice). extend to the distal end of the catheter, to an orifice on The catheter of the invention may have one or more a distal portion of the catheter, or Simply within the movable elements associated there with. Such elements may, catheter (i.e. having an opening only on the distal for example, be tissue imaging or other diagnostic devices. portion of the catheter). One or more of the catheters (e.g. a urethroscope), an indicator fixed to a movable ele may communicate with the interior of a balloon on the ment (e.g. an indicator fixed to a sheath Surrounding the distal portion of the catheter. catheter or fixed to a shaft disposed within a lumen in the An important advantage of the catheter of the invention is 25 catheter), a drug delivery device (e.g. the outlet of a capillary that it may be manufactured in pairs, in trios, or in larger or a unit dosage form of a pharmaceutical composition), or groups, of matched catheterS Such that each catheter of the the like. The movable element may be disposed within a group is reproducibly Seatable within a bodily lumen of an lumen in the catheter, Slidably or threadedly engaged with animal and Such that each catheter of the group has an the exterior of the catheter, or the like. indicator which, when the catheter is seated within the The catheter of the invention is used by inserting the bodily lumen, is located at the same position along the catheter into the external orifice of a naturally-occurring longitudinal axis of the bodily lumen as an indicator on each bodily lumen (e.g. into the anus or the external opening of of the other catheters of the group when seated. the urethra) or into an external opening of an artificial bodily Alternatively, the matched catheters may be constructed lumen (e.g. into a trephination) and urging the catheter Such that the positions of the indicators on the catheters of 35 distally along the axis of the bodily lumen until the expand the group, when each catheter is Seated, have a known able member on the distal portion of the catheter is within a mathematical relationship with one another. void within which the member may be expanded such that An example of an advantage of Such groups of matched it has a diameter greater than the diameter of the bodily catheters is as follows. A first catheter (e.g. a catheter lumen. Urging the catheter proximally Seats the expandable adapted for identifying the position of a tissue along the axis 40 member against the opening of the lumen into the Void. of the bodily lumen) may be seated within the bodily lumen When matched catheters are used, it is important the geom and used to determine the position of a relevant tissue etry of the expandable member be Substantially identical, So relative to an indicator on the first catheter. The first catheter that the matched catheters will Seat at the opening in may be removed and replaced with a Second matched Substantially the same way. After Seating a catheter of the catheter (e.g. a catheter adapted for positioning a radiation 45 invention, the position of an indicator on the catheter is source within the bodily lumen). The second catheter also determined. The position of an anatomical feature Such as a has an indicator, and the position of this indicator within the tissue of interest may then be determined relative to the bodily lumen has a known relationship to the position of the indicator. Alternatively, the position of a radiation Source indicator of the first catheter. Thus, once the position of the may be Selected relative to the indicator. relevant tissue is determined using the first catheter, a 50 While the invention is susceptible to numerous modifi radiation Source may be positioned at that position using the cations and alternative forms, Specific embodiments thereof second catheter. When the diameter of the bodily lumen is have been illustrated by way of example in the drawings and sufficiently small that the lumen will not accommodate both are described herein in detail. One skilled in the art would a tissue-locating device and a radiation Source positioning appreciate that the invention is not limited to the particular device, matched catheters of the invention permit Sequential 55 forms illustrated and described herein, but rather, includes use of these two devices without Sacrificing the accuracy of all modifications, equivalents, and alternatives falling within the radiation Source positioning. Furthermore, these two the Spirit and Scope of the invention as defined by the devices may be used with a Single graduated catheter of the appendant claims. For the purpose of illustrating the invention, if the catheter is adapted for use with either invention, descriptions of graduated urethral and ureteric device. 60 catheters, kits comprising Such catheters, and methods of Another example of an advantage of using matched using the catheters are included below. It is understood that catheters is as follows. Identifying the position of a relevant analogous catheters may be made and used wherein the tissue along the axis of a bodily lumen may be difficult, may expandable member of the catheter of the invention is require the use of hazardous or expensive reagents, and expanded within substantially any bodily void which is in (especially when the relevant tissue is one which is to be 65 fluid communication with a naturally-occurring bodily Selectively killed) may become increasingly difficult as the lumen. Analogous catheters may be made and used wherein tissue disappears over time. Therefore, it may be preferable the expandable member of the catheter of the invention is US 6,607,477 B1 11 12 expanded within a bodily void which can be accessed by methacrylate, polyurethane, poly Vinylpyrrollidone, creating (e.g. Surgically) an artificial bodily lumen through 2-pyrrollidone, polyacrylonitrile butadiene, polycarbonate, which the distal portion of the catheter of the invention may polyamide, a fluoropolymer Such as a homopolymer or be urged. Thus, by way of example, and not limitation, it is copolymer of polytetrafluoroethylene and polyvinyl understood that the expandable member of the catheter of fluoride, polystyrene, a homopolymer or copolymer of Sty the invention may be expanded in an animal in a bladder, rene acrylonitrile, cellulose acetate, a homopolymer or , , , gall bladder, bile duct branch, copolymer of acrylo nitrile butadiene Styrene, chamber (after halting myocardial contraction), arterial polymethylpentene, polysulfone, polyester, polyimide, or venous branch, Sinus, cerebral Ventricle, , polyisobutylene, polymethylstyrene, and other Similar com capsule, marrow, bronchial branch, nasal cavity, oral pounds known to those skilled in the art. It should be cavity, or tympanic cavity of an animal, preferably a human. understood that these possible biocompatible polymers are By expanding the expandable member in one of these included above for exemplary purposes and should not be locations, the catheter of the invention may be used to construed as limiting. The preferred biocompatible polymer provide radiation or a pharmaceutical agent to one or more is polytetrafluoroethylene. Suitable biocompatible elas of the following exemplary tissues located in close proxim 15 tomers include, for example, Silicone rubber, polyvinyl ity thereto: urethra, prostate, ureter, bladder, restenotic chloride elastomer, polyolefin homopolymeric or copoly tissue, , uterus, Stomach, colon, intestine, , meric elastomer, urethane-based elastomer, latex, or Syn head, neck, brain, muscle, melanoma, bone, connective, thetic rubber. The preferred biocompatible elastomer is colon, intestine, , pancreas, kidney, gall bladder, , medical grade latex. cardiac, arterial, Venous, , , esophageal, The catheter tube 10 may comprise a unitary piece of a skin, or a cancerous tissue. biocompatible polymer or elastomer, or it may be con Referring now to the drawings, wherein like numerals Structed of numerous pieces of biocompatible polymer or indicate like elements throughout the Several views, a first elastomer. By way of example, the catheter tube 10 may embodiment of the graduated urethral catheter described comprise a hollow cylinder and an internal tube having a herein is depicted in FIGS. 1, 2, and 3. The graduated 25 bore, wherein the internal tube extends within the hollow urethral catheter comprises a catheter tube 10 having a cylinder from the proximal end 20 of the catheter tube 10 to proximal portion 12 including a proximal end 20 and a distal the balloon inflation port 16, and wherein the first lumen 18 portion 14 including a distal end 28. A balloon 22 is affixed is the bore of the hollow bore tube. Also, by way of example, to the distal portion 14 of the catheter tube 10; A plurality of the catheter tube 10 may comprise a plurality of tubes, each indicators 24 are embedded in the catheter tube 10 and having a lumen, as depicted, for example in FIGS. 3 and 4 Spaced longitudinally along the catheter tube 10. A first of U.S. Pat. No. 4,072,146 to Howes. One skilled in the art lumen 18 extends longitudinally within the catheter tube 10 would recognize that numerous multi-lumen catheters are from the proximal end 20 thereof and communicates with a known in the art and, in view of the present disclosure, can balloon inflation orifice 16. be adapted for use as the catheter tube 10 of the graduated In this first embodiment of the graduated urethral catheter 35 urethral catheter of this invention. By way of further of the invention, the catheter tube 10 and the balloon 22, example, the catheter tube 10 may be a multi-lumen catheter when deflated, are preferably sized So as to be Susceptible of tube, Such as that disclosed in U.S. Pat. No. 5,221,256 to insertion into the urethra of a subject. The size of the urethra Mahurkar, in of U.S. Pat. No. 5,378,230 to Mahurkar, in of the Subject is dependent upon the Species and, in Some U.S. Pat. No. 5,308,323 to Sogawa et al., in U.S. Pat. No. Species, the gender of the Subject. The sizes of the 40 5,167,623 to Cianci et al., in U.S. Pat. No. 4,037,599 to of numerous species are known in the art. Methods of Raulerson, in U.S. Pat. No. 4,072,146 to Howes, in U.S. Pat. determining the size of the urethra of a Subject not described No. 4406,656 to Hattler et al., in U.S. Pat. No. 5,167,662 to in the art would be apparent to one skilled in the art without Muto, in U.S. Pat. No. 5,221,255 to Mahurkar et al., in U.S. undue experimentation. Following insertion of the graduated Pat. No. 5,207,648 to Gross, and the like. urethral catheter of the invention, the balloon 22 may be 45 The shape of the catheter tube 10, as viewed in a cross inflated within the bladder of the subject by inserting the Section taken perpendicular to the longitudinal axis of the graduated urethral catheter into the urethra of the Subject and catheter tube 10, is not critical. A Substantially circular croSS urging the graduated urethral catheter in a direction from the Section, as depicted herein in FIG. 2, is preferred. The proximal end 20 thereof toward the distal end 28 thereof transverse cross section of the catheter tube 10 may be until the balloon 22 is located at the site where inflation 50 circular, oval, ellipsoid, kidney-bean shaped, a composite of thereof is desired. An indicator 24 may be associated with a Substantially circular, Oval, or ellipsoid forms, or irregularly portion of the balloon 22 to assist the practitioner to position shaped. The catheter may have for Supporting the the balloon 22 at the site where inflation thereof is desired. catheter or for inhibiting kinking of the catheter. The cath Where the catheter is inserted through the urethra into a eter tube is preferably Sufficiently rigid that it may be urged ureter, it is not necessary that the catheter comprise a 55 distally into the urethra of a human patient without kinking, balloon. but sufficiently pliable that, when urged distally, the catheter Preferred Subjects include animals, more particularly Ver will follow the curvature of the patient's urethra. It is tebrates. Mammalian vertebrates are preferred Subjects, and preferred that the catheter tube 10 is smooth along its human Subjects are most preferred. exterior Surface. The catheter tube 10 preferably comprises a biocompat 60 The length of the catheter tube 10, as measured from the ible plastic or elastomer. Suitable biocompatible plastics proximal end 20 to the distal end 28 thereof, is similarly not include materials. Such as polyethylene, a homopolymer or critical. It is preferred that the length of the catheter tube be copolymer of vinyl acetate Such as ethylene Vinyl acetate greater than about 20 centimeters, which represents the copolymer, polyvinylchloride, a homopolymer or copoly approximate length of the urethra of a human male. It is mer of acrylate Such as polymethylmethacrylate, 65 more preferred that the distance from the proximal end 20 of polyethylmethacrylate, polymethacrylate, ethylene glycol the catheter tube 10 to the portion of the balloon 22 nearest dimethacrylate, ethylene dimethacrylate and hydroxymethyl the proximal end 20 be greater than about 20 centimeters, so US 6,607,477 B1 13 14 that the graduated urethral catheter is of Sufficient length 18, 26, 32, and 36 of the catheter tube 10, and all Such Such that at least part of the proximal portion of the modifications are within the Scope of the graduated urethral graduated urethral catheter extends from the external ure catheter described herein. The choice of adapting means is thral orifice of a male human Subject after the graduated not critical. urethral catheter has been inserted into the urethra of the The balloon 22 preferably comprises a biocompatible subject, the balloon 22 thereof has been inflated within the elastomer. Suitable biocompatible elastomers include sili bladder of the Subject, and the balloon 22 thereof has been cone rubber, polyvinyl chloride elastomer, polyolefin Seated against the internal urethral orifice of the Subject's homopolymeric or copolymeric elastomer, urethane-based bladder. elastomer, latex, or Synthetic rubber. The preferred biocom The internal urethral orifice of a subject's bladder is the patible elastomer is medical grade lateX. portion of the subject's bladder where the tissue of the In one embodiment of the graduated.urethral catheter of bladder and the tissue of the Subject's urethra merge as the invention, the balloon 22 is situated in a receSS23 located depicted and described, for example, in FIG. 8.162 and on the distal portion 14 of the catheter tube 10, such that supporting text of Williams et al., eds. (1980, Gray's when the balloon 22 is deflated, substantially no portion of Anatomy, 36th ed., W.B. Saunders Co., Philadelphia, 15 the balloon 22 extends further from the longitudinal axis of p. 1402–1408). A graduated urethral catheter is seated the catheter tube 10 than the of the exterior Surface of against the internal urethral orifice of the bladder of a Subject the catheter tube. when the balloon of the graduated urethral catheter has been In another embodiment of the graduated urethral catheter inflated within the bladder of the Subject and the graduated of the invention, best depicted in FIG. 8, the balloon 22 is urethral catheter has Subsequently been urged in the direc located within an elastomeric sleeve 38 which Surrounds at tion from the distal end thereof to the proximal end thereof, least a portion of the catheter tube 10, such that the sleeve Such that the balloon is flush against a tissue lining the 38 is sufficiently resilient that when the balloon 22 is inflated bladder of the Subject, including, but not necessarily, the the sleeve expands with the balloon 22 and when the balloon tissue lining the internal urethral orifice in the bladder of the is deflated, the sleeve 38 resiliently urges the balloon 22 Subject. 25 against the catheter tube 10. A graduated urethral catheter having a length shorter than The catheter includes at least one indicator 24 associated about 20 centimeters can be used according to the methods with the catheter tube 10 for indicating a reference position described herein. The balloon of a graduated urethral cath for the indicator, and therefore, for the catheter, with respect eter having a length less than 20 centimeters may be Seated to the subject's urethra or other body tissue with which the against the internal urethral orifice of the bladder of a female catheter is used. human Subject and will extend externally beyond the exter Each indicator 24 comprises any material, capable of nal urethral orifice of the female human subject. By way of indicating its position within the urethra of a Subject, as example, the proximal portion 12 of the graduated urethral determined by any extracorporeal method. Preferably, the catheter may be about five centimeters in length when the position of the indicator 24 is determined using tomography, graduated urethral catheter is to be used within the urethra 35 ultraSonography, positron emission tomography, X-ray of a human female. AS described herein, a graduated urethral tomography, or 2-dimensional X-ray visualization. The use catheter to be used as a graduated ureteric catheter will have of 2-dimensional X-ray visualization including, but not a length sufficient to traverse the urethra and the bladder of limited to, fluoroscopy is more preferred. One skilled in the a Subject and to extend into a ureter of the Subject. Thus, the art would recognize that this description of position distal portion 14 of the catheter tube 10 may be shorter than, 40 determining indicators and methods is not limiting, and that approximately the same length as, or Significantly longer other position-determining indicators and methods may be than the proximal portion 12 thereof. By way of example, employed without departing from the invention. the graduated ureteric catheter may have a length Sufficient It is critical that each indicator 24 has at least one to traverse the urethra, the bladder, and a ureter of a Subject visualization property which differs from the visualization and to extend into a kidney of the Subject. 45 property of the catheter tube 10. As used herein, “visualiza The shape of the distal end 28 of the catheter tube 10 of tion property” includes the ability to detect the position of the graduated urethral catheter is not critical. Preferably, the the indicator with respect to body tissue, using any method distal end 28 is rounded. The distal end 28 may be blunt as for Seeing, detecting or otherwise identifying the indicator's depicted in FIG. 1, rounded, frustoconical as depicted in position, even if the indicator cannot be directly observed. FIGS. 4 and 6, conical as depicted in FIG. 10a, or shaped 50 Preferably, the Visualization property is a property which can otherwise. be detected by tomography, ultraSonography, positron emis The proximal end 20 of the catheter tube 10 is preferably Sion tomography, or X-ray visualization. Hence, the Visual adapted So that the practitioner may provide to one or more ization property may be, but is not limited to, the density of of the lumens 18, 26, 32, and 36 of the catheter tube 10 a the indicator 24, the radiation emission of the indicator 24, composition, including a liquid, a gas, a Solid, a radiation 55 and the radiopacity of the indicator 24. Preferably, the Source, a powder, an aerosol, or the like. Methods and Visualization property is the radiopacity of the indicator 24. Structures for adapting a composition delivery means and a Preferably, the visualization property of each indicator 24 lumen of a catheter are well known in the art and are also differs from the Visualization property of any tissue of described, for example, in U.S. Pat. No. 5,221,256 and the subject which is between the indicator 24 and the means 5,378,230 to Mahurkar, in U.S. Pat. No. 5,167,623 to Cianci 60 of Visualizing the position of the indicator 24. et al., in U.S. Pat. No. 4,037,599 to Raulerson, in U.S. Pat. Each indicator 24 may be associated with the catheter No. 4,072,146 to Howes, in U.S. Pat. No. 4406,656 to tube 10 in any manner in which the position of the indicator Hattler et al., in U.S. Pat. No. 5,167,622 to Muto, in U.S. Pat. 24 along the longitudinal axis of the catheter tube 10 is fixed. No. 5,207,648 to Gross, and in U.S. Pat. No. 5,221,255 to Thus, by way of example, the indicator 24 may be embedded Mahurkar et al. Numerous modifications to the proximal end 65 in, fused with, affixed to, adhered to, painted onto, pressed 20 of the catheter tube 10 are possible to facilitate adapting into, electroplated onto, wrapped around the catheter tube composition delivery means to one or more of the lumens 10, or joined or otherwise provided to the interior wall of the US 6,607,477 B1 15 16 bore of the catheter tube 10. A graduated urethral catheter balloon 22 and the balloon 22 is Seated against the internal having only a Single indicator 24 may be used. It is preferred urethral orifice of the bladder of a Subject, a composition, that the catheter tube 10 comprises a plurality of radiopaque Such as a treatment Solution, for example, may be provided indicators 24 Spaced at regular intervals along the longitu to the bladder of the subject by way of the third lumen and dinal axis thereof. The indicators may be located on any the inlet orifice. Similarly, when the outlet orifice is located portion of the catheter tube 10, including the proximal end nearer the distal end 28 of the catheter tube 10 than the 20, the proximal portion 12, the distal portion 14, and the balloon 22 and the balloon 22 is Seated against the internal distal end 28 thereof. Indicators 24 may also be located on urethral orifice of the bladder of a Subject, a composition, the balloon 22, on the radiation source positioner 40, on the including but not limited to urine, may be removed from the sleeve 38, or within any of the lumens 18, 26, 32, and 36 bladder of the subject by way of the fourth lumen and the associated with the catheter tube 10. outlet orifice. The catheter tube 10 may have any number of The indicators 24 are dimensioned such that they may be lumens which may extend longitudinally through the cath Visualized by a practitioner. If the indicators are positioned eter tube 10 from the proximal end 20 to the distal end 28 on a portion of the catheter which extends proximally thereof, which may extend from either the proximal end 20 beyond the urethra of the patient when the catheter is Seated; 15 or the distal end 28 of the catheter tube 10 and communicate the indicators need only be Sufficiently large that they may with an orifice located in the wall of the catheter tube 10, or be visually observed by a practitioner (e.g. 0.1 to 1 milli which may extend into the catheter tube 10 from either the meter in breadth by 0.1 to 1 millimeter in width). If the proximal end 20 or the distal end 28 thereof. Examples of indicators are positioned on a portion of the catheter which embodiments of graduated catheters with more than one is situated within the urethra of the patient when the catheter lumen are depicted in FIGS. 4-10b. is Seated, then the indicators must be dimensioned Such that The distal portion of a Second embodiment of the gradu they may be visualizable using an extracorporeal Visualiza ated urethral catheter described herein is depicted in FIGS. tion device (e.g. a fluoroscope or MRI machine) or using an 4, 5, and 6. The second embodiment of the graduated intra-urethral device (e.g. a urethroscope). The precise urethral catheter comprises a catheter tube 10 which, at its dimensions which may be visualized depend on the Visual 25 distal end 28, has a frustoconical shape. A balloon 22 is ization method. Once the visualization method is Selected, affixed to the catheter tube 10. An indicator 24 is embedded the necessary minimum dimensions of the indicators 24 will in the catheter tube 10. A first lumen 18 extends longitudi be apparent to one skilled in the art. The indicators 24 are nally within the catheter tube 10 from the proximal end preferably Small, relative to the intra-urethral distances to be thereof and communicates with a balloon inflation orifice measured, in order to permit measurement of Such distances 16. The balloon inflation orifice 16 communicates with the as accurately as possible. For example, when intra-urethral interior of the balloon 22. A second lumen 26 extends distances on the order of a few millimeters are to be longitudinally into the catheter tube 10 from the proximal measured, it is preferred that the width of the indicators in end thereof and is Substantially coaxially therewith. "Sub the direction along the axis of the bodily lumen in which the Stantially coaxial,” as used herein, means that the longitu catheter is Seated is not greater than about 1 millimeter. 35 dinal axis of the catheter tube 10 and the longitudinal axis of The catheter tube 10 may comprise any number of lumens the Second lumen 26 are separated by a distance less than extending from the proximal end of catheter tube 10. Some one-half the radius of the catheter tube 10. Preferably, the or all of the lumens may extend distally through the catheter longitudinal axis of the catheter tube 10 and the longitudinal tube 10 to one or more ports located at the surface of the axis of the Second lumen 26 are separated by a distance leSS catheter tube 10. The sizes and relative locations of these 40 than one-quarter the radius of the catheter tube 10, and more lumens and ports are not critical, although it is preferred that preferably by a distance less than one-tenth the radius of the the lumens extend generally parallel to the axis of the catheter tube 10. Most preferably, the catheter tube 10 and catheter tube 10. Ports may be located distally or proximally the Second lumen 26 have the same longitudinal axis. on the surface of the catheter tube 10 with respect to the FIGS. 7 and 8 depict a third embodiment of the graduated balloon 22, or may communicate with the interior of the 45 urethral catheter described herein. The catheter tube 10 of balloon 22. this third embodiment comprises a first lumen 18 extending The number of indicators associated with the catheter tube longitudinally within the catheter tube 10 from the proximal 10 of the graduated urethral catheter is not critical, beyond end thereof to a balloon inflation orifice positioned on the the presence of at least one indicator 24 associated there distal end 28 of the catheter tube 10. The balloon inflation with. Preferably, a plurality of indicators 24 are associated 50 orifice communicates with the interior of a balloon 22 with the catheter tube 10 and are spaced longitudinally along affixed to the distal end 28 of the catheter tube 10. A second the catheter tube 10. Also preferably, at least a portion of the lumen 26 extends longitudinally through the catheter tube 10 catheter tube 10 comprises a plurality of indicators 24 from the proximal end to the distal end 28 thereof. The longitudinally spaced thereon a Specific distance apart, Such catheter tube 10 of this third embodiment further comprises as one centimeter apart, but other spacing distances, e.g., one 55 a third lumen 32, which extends longitudinally within the millimeter, may also be used, as desired. catheter tube 10 from the proximal end thereof and com The catheter tube 10 of the first embodiment of the municates with an inlet orifice 30, and a fourth lumen 36, graduated urethral catheter depicted in FIGS. 1, 2, and 3 may which extends longitudinally within the catheter tube 10 further comprise a Second lumen extending longitudinally from the proximal end thereof and communicates with an into the catheter tube 10 from the proximal end 20 thereof, 60 outlet orifice 34. A sleeve 38 surrounds a portion of the a third lumen extending longitudinally within the catheter catheter tube 10, and indicators 24 are affixed to the exterior tube 10 from the proximal end 20 thereof and communicat of the sleeve 38. The sleeve may be, but need not be, made ing with an inlet orifice, a fourth lumen extending longitu of the same type of material as the catheter tube 10. The dinally within the catheter tube 10 from the proximal end 20 preferred sleeve material is polytetrafluoroethylene. thereof communicating with an outlet orifice, or a combi 65 FIG. 9 depicts an embodiment of a graduated urethral nation of Such lumens. When the inlet orifice is located catheter as it is employed in the performance of an embodi nearer the distal end 28 of the catheter tube 10 than the ment of the urethral brachytherapy method described herein. US 6,607,477 B1 17 18 The graduated urethral catheter of this embodiment com formation. Any radiation Source may be used to deliver the prises a catheter tube 10 having a balloon 22 affixed to the doses described herein including, but not limited to, an distal portion thereof. A first lumen 18 extends longitudi electromagnetic radiation emitter (e.g. radio-frequency nally within the catheter tube 10 from the proximal end emitter), a light emitter (e.g. a laser Source for ablating a thereof and communicates with a balloon inflation orifice tissue or a visible, UV, or IR light for photodynamic 16, which communicates with the interior of the balloon 22. therapy), a thermal energy emitter (e.g. a high intensity IR The catheter tube 10 includes a second lumen 26 which Source), or a radioactive isotope (e.g. a beta-emitter, a extends longitudinally into the catheter tube 10 from the gamma-emitter, or an X-ray emitter). When the isotope is a proximal end thereof. A radiation Source positioner 40 is beta-emitter, it preferably emits particles having an energy in slidably mounted within the second lumen 26. An indicator the range 800 to 4000 MeV; when it is a gamma-emitter, the 24 is embedded in the catheter tube 10. In one embodiment particles preferably have energy from 100 to 3000 keV; of the transurethral brachytherapy method of the invention, when it is an X-ray emitter, the particles preferably have the distal portion of the catheter tube 10 is inserted into the energy from 10 to 100 keV. Exemplary isotopes which may urethra U of a Subject, for example, a human patient. The be used include, but are not limited to, beta-emitterS Such as catheter tube 10 is urged within the urethra U of the patient, 15 'Y, Re, P, Re, Rh, and Sr., gamma-emitters such in the direction from the proximal end of the catheter tube as 'Co, '7Cs, and 'Ir, and X-ray-emitting radionuclides 10 to the distal end of the catheter tube 10, until the balloon such as Pd, O'Cd, 'Sm, ''Pm, Yb, and 'I, 22 is located within the tissue lining the bladder B of the The radioisotope may, for example, be delivered in a Solid patient. The balloon 22 is inflated within the bladder B of the form, in an encapsulated Solid or liquid form, or in the form patient by providing a fluid, Such as compressed air or of a liquid Solution or Suspension of the isotope. Of course, isotonic saline, to the interior of the balloon 22 through the radiation may be administered to a relevant tissue both by first lumen 18 and the balloon inflation orifice 16. The providing a radiation Source in close proximity to the catheter tube 10 is urged longitudinally in the direction from relevant tissue using a catheter of the invention and by the distal end thereof to the proximal end thereof until the administering external beam radiation using any of the balloon 22 is Seated against the internal urethral orifice of the 25 variety of known prior art devices (e.g. an X-ray generator). bladder B of the subject. A radiation source R is provided to Because Systemic and non-focal local delivery of radio the Second lumen 26. The radiation Source R is positioned isotopes are undesirable, it is preferred that the isotope within the second lumen 26 at a distance d from the indicator remains contained within the catheter of the invention. By 24 using the radiation Source positioner 40. Upon position way of example, the isotope may be provided in the form of ing of the radiation Source R. radiation is provided to the pellets or “seeds” of a solid form of the isotope clad with an tissue lining the urethra U located in close proximity to the inert physiologically compatible material Such as titanium or radiation Source R and to other tissues located in close Stainless Steel. Such pellets or Seeds may be provided to the proximity to the radiation Source R. relevant tissue by providing loose pellets or Seeds to a lumen Any radiation Source positioner 40 may be employed in of the catheter of the, invention such that they rest at the site the graduated urethral catheter and the urethral brachy 35 of the relevant tissue (e.g. they are held by gravity against therapy methods described herein. Preferably, the radiation the end of the lumen at the site). Preferably, however, such Source positioner 40 is a flexible filament or a flexible Seeds or pellets are fixed to a Solid member, Such as a catheter which is attached to a radiation Source R and which filament or ribbon which may be passed through a lumen of has a size suitable for insertion within and which is slidably the catheter, or to the catheter itself (e.g. by embedding the mounted within the Second lumen 26 of the graduated 40 pellets within the catheter or attaching them to the exterior urethral catheter described herein. The radiation Source of the catheter body, optionally beneath a sheath covering positioner 40 may, for example, be operably linked with a the body). Optionally, the isotope may be provided to the remote after-loading device, whereby the after-loader may interior of a balloon on the catheter, Such as the balloon on be directed from a remote location to position the radiation the distal end of the catheter which is used for Seating the Source R within the second lumen 26 of the graduated 45 catheter. If R is a liquid, the Second lumen may be a closed urethral catheter. The health and safety of the practitioner are cavity, optionally communicating with a radiation-shielded thereby protected. In addition, because the practitioner may reservoir at the proximal end of the catheter. A preferred be isolated from the radiation dose, it is feasible to use a method of delivering the doses described herein is by using higher radiation dose rate than might otherwise be possible. a graduated urethral catheter of the invention to position the Any other device or technique capable of positioning a 50 radiation Source in close proximity to Strictured urethral or radiation Source R within the second lumen 26 of the ureteric tissue. graduated urethral catheter may be used, including, but not The dose of radiation to be delivered will depend on the limited to, application to the Second lumen 26 of compressed nature of the relevant tissue, the Size of the relevant tissue air, flow through the Second lumen 26 of a fluid, pushing the mass, the age, family history, and general health of the radiation Source R with a filament or catheter to which the 55 subject to which the radiation is to be delivered. Methods of radiation Source R is not attached, fixing the radiation Source determining Suitable radiation doses are well known in the R within the graduated urethral catheter and longitudinally art and may be used to determine an appropriate dose for use positioning the graduated urethral catheter, and magnetically with the catheters, kits, and methods described herein. Of positioning the radiation Source R within the Second lumen course, in View of the improved accuracy with which 26 using a magnetic Source. 60 catheters of the present invention can deliver a radiation It is believed that urethral and ureteric strictures may be dose to a relevant tissue, it will be understood that the treated by providing radiation to the affected tissue. A radiation dose may accordingly be Smaller than doses used therapeutic radiation dose of about 800 cGy to about 3000 with prior art methods. cGy may be delivered to the strictured tissue. Furthermore, Using a catheter of the invention, or a matched pair of delivery of a prophylactic radiation dose of about 800 cGy 65 catheters of the invention, it is possible to position a radia to about 2000 cGy immediately before or immediately tion Source, a pharmaceutical composition, or an outlet of a following a urological intervention can prevent Stricture delivery lumen in close proximity to a relevant tissue. An US 6,607,477 B1 19 20 important aspect of the catheter of the invention is the The first radioisotope has a desirable half-life (e.g. 0.5 to presence on or in the catheter of an indicator which can be 3000 days) but does not necessarily emit the most desired detected after the distal portion of the catheter has been type of radiation. The Second radioisotope emits the desired Seated in an animal. Because an indicator of the catheter is type of radiation (e.g. beta-particles), but does not neces located at a fixed distance from the Seated distal portion of sarily have a half-life which makes delivery of a sufficient the catheter, the indicator will be located at the same position amount of the isotope from a Supplier to a medical practi along the axis of the bodily lumen whenever the catheter is tioner feasible. An example of Such a composition is one Seated within the lumen. Similarly, each of a matched pair of which comprises W and Re. catheters has an indicator which is located at the same Because Smaller doses of radiation may be used with the position along the axis of the bodily lumen whenever the catheters, kits, and methods of the invention, and because catheter is Seated within the lumen. Alternatively, the this radiation is more focally delivered than with prior art matched pair of catheters may each have an indicator, methods, the present invention enables treatment of both wherein the indicators are not located at the same position benign and imminently life-threatening lesions located in when each catheter is Seated, but instead have a known close proximity to a bodily lumen (e.g. both benign and relationship with each other (e.g. in a thatched pair, the 15 malignant cancerous lesions). Some medical practitioners indicator of the first matched catheter is located 1.0 centi prefer nonradioactive therapeutic methods over methods meter nearer the external orifice of the bodily lumen when involving administration of radionuclides because of per the first matched catheter is Seated in the lumen than is the ceived difficulties relating to radiation shielding and indicator of the Second matched catheter when it is Seated in repeated exposure of the practitioner to radiation. Because the lumen). the catheters, kits, and methods of the invention enable use Methods of Visualizing an indicator include, but are not of reduced doses of radioactivity and less energetic radiation limited to fluoroscopy, ultrasound imaging, computerized Sources, perception of these Supposed difficulties should be tomographic (CT) scanning, magnetic resonance (MR) reduced. The invention also allows use of radiation Sources imaging, Videographic imaging, detection of ferromag which are more nearly tailored to treating a particular netism of an indicator, detection of radiation emitted by an 25 localized tissue of the patient. The invention thus enables indicator, and the like. Using prior art catheters, radiation more widespread use of effective radiation therapies both by Sources and the like could be placed with an accuracy of no reducing the reluctance of practitioners to employ the thera less than it. Several millimeters or even it a few centimeters. pies and by increasing the effectiveness of the therapies. In contrast, the graduated catheter of the invention allows It is understood that the dose of radiation delivered to a radiation Sources and the like to be placed on or within the tissue located in close proximity to a radiation Source catheter with an accuracy of, for example t3-5 millimeters depends on the period of time for which the Source is when Visualized using fluoroscopy or 1-2 millimeters when maintained in proximity to the tissue. Furthermore, as visualized using ultrasound or MR imaging or CT Scanning. described above, the dose of radiation delivered to a tissue Other factors which are relevant in the selection of a also depends upon the distance between the Source and the radiation Source and dose include the availability and cost of 35 tissue and the identity of the material(s) interposed between the radiation Source, the radiation density of a radiation the Source and the tissue. For example, the relationships Source, the type of radiation emitted by the Source, and the between dose per unit emission and distance from the quality of the radiation produced by the source. When emitting source are illustrated in FIG. 12 for several radio radioisotopes are used, the half-life of the isotope is pref isotopes. In general, the dose decreases more Sharply with erably in the range of about 0.5 to 3000 days, the total 40 increasing distance for beta-emitters than for X-ray emitters, radioactivity of the isotope used is generally in the range of and likewise for X-ray emitters than for gamma-emitters. In about 10 megabequerels to about 1 terabequerel, and the general, it is preferable that therapeutic radiation be limited, Specific radioactivity of the isotope is preferably in the range to the extent possible, to the site of treatment. This may be of about 10 megabequerels per gram to about 30 terabe done by Selecting a radiation Source having appropriate querels per gram. X-ray-emitting radioisotopes are 45 emission properties. Thus, when the distance from the preferred, Since these radioisotopes may be more conve radiation Source delivered using a catheter of the invention niently contained by Shielding than gamma-emitters, thereby and the furthest extent of the relevant tissue to which the reducing radiation exposure of tissues other than the target radiation is to be delivered is from 0 to about 5 millimeters, tissue in the Subject and also reducing radiation exposure of the Source is preferably a beta-emitter because beta-radiation the attending Staff. 50 field Strength drops markedly beyond this range, as illus The “quality” of a radiation field refers to the intensity of trated in FIG. 12. When the distance is from 0 to about 15 radiation which penetrates the field, expressed (for example) millimeters, the source is preferably an X-ray emitter. When in the units Gray per hour, at particular positions in the the distance is greater than about 15 millimeters, the Source Subjects anatomy. Such radiation fields are usually is preferably a gamma-emitter. Thus, as illustrated in FIG. described in terms of dosimetry calculations Such as that 55 12 for example, the total dose of radiation delivered using an described in Koukourakis et al. (1994, Med. Dosimetry 'I is a function of both distance from the source and the 19:67–72). These calculations take into account the pre total time of exposure. Scriptive dose level, expressed (for example) in the units It is understood that a desired total radiation dose may be Grays, the anatomy of the patient, including the radiation achieved either by exposing the tissue to the radiation Source absorbing properties of tissues Surrounding the Site of radia 60 for a single continuous period or for by dividing the period tion administration, the design of the radiation Source, and of exposure into two or more periods during which the tissue the type of particles emitted from the radiation Source. is exposed to the Source and between which periods the It is understood that radioisotopes which exhibit a tissue is not exposed to the Source. The exposure periods "parent-daughter decay Scheme are useful in the catheters, may be separated by Seconds, minutes, hours, days, weeks, kits, and methods of the invention. A "parent-daughter 65 or more. The goal of exposing tissue of the Subject to the decay Scheme refers to radioactive decay of a composition radiation Source is to deliver a fatal dose of radiation to comprising a first radioisotope and a Second radioisotope. non-desirable cells (e.g. cancerous cells or cells in a stric US 6,607,477 B1 21 22 tured tissue) while delivering a Sub-fatal dose of radiation close proximity to the Strictured region A of the urethra U of (and preferably a dose that is also non-carcinogenic) to the Subject using the radiation Source positioner 40. An healthy tissue which is located in close proximity to the X-ray image is optionally made by transmitting X-rays in non-desirable cells. In certain instances (e.g. prostate the direction indicated in FIG. 10b, whereby the relative cancer), the non-desirable cells divide more rapidly than distance date between the radiation Source R and a cells in healthy tissue and are therefore more Sensitive to radiopaque indicator 24 which is embedded within the radiation than the healthy tissue cells. catheter tube 10 of the graduated delivery catheter is deter The graduated urethral catheters and the brachytherapy mined. The position of the indicator 24 embedded within the methods described herein may be used to provide radiation catheter tube 10 of the graduated delivery catheter depicted to any tissue located in close proximity to the urethra of a in FIG. 10b corresponds to the position of the radiopaque Subject, preferably a human patient. Such tissue includes, indicator 24 embedded within the catheter tube 10 of the but is not limited to, urothelium, Strictured urethral tissue, graduated locator catheter depicted in FIG. 10a. The posi urethral tissue at risk for Stricture formation, cancerous tion of the radiation Source R is adjusted using the radiation urethral tissue, other urethral tissue, cancerous prostate Source positioner 40 such that data is at least tissue, benign hypertrophic prostate tissue, other prostate 15 approximately, and preferably exactly, equal in magnitude tissue, tissue lining the internal urethral orifice of the and direction to d, whereby the radiation Source is bladder, bladder tissue, tissue lining a ureteral orifice of the positioned in close proximity to the Strictured region A of the bladder, Strictured ureteric tissue, ureteric tissue at risk for urethra U of the Subject. A composition may be delivered to Stricture formation, other ureteric tissue, and kidney tissue. or removed from the bladder B of the subject before, during, The catheters and methods may therefore be used to treat or or after positioning of the radiation Source R by passing the prevent conditions Such as Stenoses, Stricture formation, composition through the inlet orifice 30 and the third lumen prostate cancer, benign prostatic hypertrophy, and the like. 32 of the graduated delivery catheter. After the radiopaque In one aspect of the method of using the graduated radiation Source R has been left in place for a desired time, urethral catheter of the invention to treat a urethral Stricture, the graduated delivery catheter is removed from the urethra which aspect is depicted in FIGS. 10a and 10b, a matched 25 U of the subject. pair of graduated urethral catheters is used, the matched pair An alternate method of positioning the radiation Source R comprising a graduated locator catheter and a graduated in close proximity to the Strictured region A of the urethra U delivery catheter, respectively. In this aspect of using a of the Subject relies upon knowledge of the distance from the matched pair of graduated urethral catheters, the graduated proximal end of the catheter tube of the graduated delivery locator catheter is inserted into the urethra U of the human catheter to the indicator 24. In this method, the radiation patient or other Subject and the catheter's balloon 22 is Source R is provided to the Second lumen 26, and is inflated. The catheter tube 10 of the graduated locator positioned, using the radiation Source positioner 40, a dis catheter is urged longitudinally in the direction from the tance equal to the Sum of the distance from the proximal end distal end thereof to the proximal end thereof until the of the catheter tube of the graduated delivery catheter and balloon 22 is Seated against the internal urethral orifice of the 35 d locator bladder B of the subject, as depicted in FIG. 10a. A It is important that the relationship between the position urethroscope or other tissue examining means S is also along the longitudinal axis of the urethra of a Subject of at inserted into the urethra U of the subject. The urethroscope least one indicator of the graduated locator catheter and the or other tissue imaging means S may be associated with the position along the longitudinal axis of the urethra of the graduated locator catheter, integral with the graduated loca 40 Subject of at least one indicator of the graduated delivery tor catheter, contained within a lumen of the graduated catheter is known. Preferably, as depicted in FIGS. 10a and locator catheter, or not associated with the graduated locator 10b, the position (i.e. as depicted in FIG. 10a) along the catheter. Using the urethroScope S, the practitioner views the longitudinal axis of the urethra U of the subject of at least tissue lining the urethra U of the Subject through the viewing one indicator 24 of the graduated locator catheter following window W of the urethroscope S and identifies a strictured 45 insertion of the graduated locator catheter into the urethra U, region A of the urethra U of the subject. The practitioner inflation of the balloon 22 thereof in the bladder B of the positions a marker M of the urethroscope S, which marker Subject, and Seating of the balloon 22 thereof against the M is preferably radiopaque and is preferably associated with internal urethral orifice of the bladder B is substantially the viewing window W of the urethroscope S, near the identical to the position (i.e. as depicted in FIG. 10a) along strictured region A of the urethra U of the Subject. An X-ray 50 the longitudinal axis of the urethra U of at least one indicator image is then made by transmitting X-rays in the direction 24 of the graduated delivery catheter following insertion of indicated in FIG. 10a, whereby the relative distance de the graduated delivery catheter into the urethra U, inflation between the marker M and a radiopaque indicator 24 embed of the balloon 22 thereof in the bladder B, and seating of the ded within the catheter tube 10 of the graduated locator balloon 22 thereof against the internal urethral orifice of the catheter can be assessed. The graduated locator catheter and 55 bladder B. urethroscope S are removed from the urethra U of the The relationship between the position along the longitu Subject. dinal axis of the urethra U of the Subject of an indicator 24 After removing the graduated locator catheter, the gradu of the seated graduated locator catheter (e.g. as depicted in ated delivery catheter is inserted into the urethra U of the FIG. 10a) and the position along the longitudinal axis of the subject and the catheter's balloon 22 is inflated. The catheter 60 urethra U of the subject of an indicator 24 of the seated tube 10 is urged longitudinally in the direction from the matched graduated delivery catheter (e.g., as depicted in distal end thereof to the proximal end thereof until the FIG. 10b) may be a relationship of substantial identity, an balloon 22 is Seated against the internal urethral orifice of the offset relationship, or any other predictable relationship. A bladder B of the subject, as depicted in FIG. 10b. A radiation relationship of Substantial identity means that the position Source R having a visualization property as discussed above 65 along the longitudinal axis of the urethra of a particular with reference to the Visualization property of the indicator Subject of an indicator of a Seated locator catheter varies by 24 is provided to the Second lumen 26 and is positioned in less than one centimeter, more preferably by less than one US 6,607,477 B1 23 24 millimeter, and more preferably by less than one or the right ureter thereof, within the bladder such that the micrometer, from the position along the longitudinal axis of inflated balloon may be seated against the internal urethral the urethra of the particular Subject of an indicator of a orifice thereof, or within the urethra. Preferably, the balloon matched Seated delivery catheter. An offset relationship is located on the catheter tube of the graduated ureteric catheter Such that the balloon may be seated against the means that the position along the longitudinal axis of the 5 internal urethral orifice of the bladder. urethra of a particular Subject of an indicator of a Seated AS used herein, a “disease' is a State of health of an locator catheter varies by a known quantity and in a known animal wherein the animal cannot maintain homeostasis, direction from the position along the longitudinal axis of the and wherein if the disease is not ameliorated then the urethra of the particular Subject of an indicator of a matched animal's health continues to deteriorate. In contrast, a "dis Seated delivery catheter. order” in an animal is a State of health in which the animal In order to maximize the predictability of the relationship is able to maintain homeostasis, but in which the animals between the position along the longitudinal axis of the state of health is less favorable than it would be in the urethra of a particular Subject of an indicator of a Seated absence of the disorder. Left untreated, a disorder does not graduated locator catheter and the position along the longi necessarily cause a further decrease in the animal's State of health. tudinal axis of the urethra of the particular Subject of an 15 indicator of a Seated matched graduated delivery catheter, it The disclosures of each and every patent, patent applica is preferable that the section of the distal portion of the tion and publication cited herein are hereby incorporated Seated graduated locator catheter which contacts the internal herein by reference in their entirety. urethral orifice of a Subject geometrically resembles the While this invention has been disclosed with reference to Section of the distal portion of the Seated matched graduated Specific embodiments, it is apparent that other embodiments delivery catheter which contacts the internal urethral orifice and variations of this invention may be devised by others of the subject. More preferably, these two sections are skilled in the art without departing from the true Spirit and geometrically identical, as depicted in FIGS. 10a and 10b. Scope of the invention. The appended claims are intended to “Geometrically identical,” as used herein, means that the be construed to include all Such embodiments and equivalent dimensions of the Section of the distal portion of the gradu variations. ated locator catheter which contacts the internal urethral 25 What is claimed is: orifice of a particular Subject when the graduated locator 1. A matched group of graduated catheters the matched catheter is Seated against the internal urethral orifice of the group comprising a first graduated catheter and a Second particular subject vary by less than 10%, and preferably by graduated catheter, the first catheter being reproducibly less than 1% from the dimensions of the section of the distal Seatable within a bodily lumen of a Subject and comprising portion of the matched graduated delivery catheter which 1) a first tubular body having a distal portion, a proximal contacts the internal urethral orifice of the particular Subject portion, and a first lumen extending longitudinally when the matched graduated delivery catheter is Seated therein from the proximal portion, against the internal urethral orifice of the particular Subject. 2) a first expandable member on the distal portion of the Another type of graduated urethral catheter which is first tubular body. Specifically contemplated herein is a graduated ureteric 35 3) a first indicator associated with the first tubular body catheter. A graduated ureteric catheter is a graduated urethral for indicating a first reference position within the catheter which has a Sufficient length from its proximal end bodily lumen; and to its distal end and which is shaped Such that insertion of the graduated ureteric catheter into the urethra of a Subject and 4) a radiation Source positioner disposed within the first urging of the graduated ureteric catheter in the direction lumen, from the proximal end thereof to the distal end thereof 40 the Second catheter being reproducibly Seatable within the permits the practitioner to insert the graduated ureteric bodily lumen and comprising catheter into one of the two ureters of the subject. Preferably, 1) a second tubular body having a distal portion, and a the graduated ureteric catheter includes at least one indicator proximal portion configured differently from Said on the distal portion thereof, whereby the indicator is located proximal portion of Said first tubular body, wherein Said within the ureter of the Subject when the graduated ureteric 45 different configuration accommodates the use of a catheter is ureterically Seated. Also preferably, the graduated locater member, ureteric catheter includes an indicator at or very near the 2) a second expandable member on the distal portion of distal end thereof, whereby the practitioner is more easily the Second tubular body, and able to position the distal end of the graduated ureteric 3) a second indicator associated with the Second tubular catheter within the ureteric orifice of the bladder of either the 50 left or the right ureter during insertion of the graduated body for indicating a Second reference position within ureteric catheter into the Subject. "At or very near,” as used the bodily lumen herein, means within one inch, preferably within one wherein the first reference position when the first catheter is centimeter, and more preferably within one millimeter. In Seated in the bodily lumen has a known relationship to the one embodiment, the graduated ureteric catheter comprises Second reference position when the Second catheter is Seated a plurality of radiopaque indicatorS Spaced longitudinally on 55 in the bodily lumen. the graduated ureteric catheter. 2. The matched group of claim 1, wherein the first The length and shape of the graduated ureteric catheter of reference position when the first catheter is Seated in the the invention are not critical, and may be Similar to any of bodily lumen is Substantially the same as the Second refer the ureteric catheters known in the art. For example, ureteric ence position when the Second catheter is Seated in the catheters are described in U.S. Pat. No. 5,383,866 to Chang 60 bodily lumen. and in U.S. Pat. No. 5,078,684 to Yasuda. The balloon of the 3. The matched group of claim 1, comprising at least one graduated ureteric catheter of the invention may be located additional graduated catheter, wherein each additional cath on the catheter tube thereof such that the balloon may be eter is reproducibly seatable within the bodily lumen and inflated within the of one of the kidneys of the subject, comprises within one of the major or minor calices of the kidney, 65 1) an additional tubular body having a distal portion, within one of the ureters, within the bladder Such that the 2) an additional expandable member on the distal portion inflated balloon may be seated against the orifice of the left of the additional tubular body, and US 6,607,477 B1 25 26 3) an additional indicator associated with the additional if the radioisotope is an X-ray emitter, then the radioiso tubular body for indicating an additional reference Re is selected from the group ale consisting of "Pd, position within the bodily lumen O Cd, 'Sm, 19Pm s 1. Yb, and 125. wherein the additional reference position when the addi 20. A urethral catheter kit comprising a graduated locator tional catheter is Seated in the bodily lumen has a known 5 catheter and a graduated delivery catheter, relationship to the reference position of another catheter of wherein the graduated locator catheter is reproducibly Seat the matched group when the other catheter is Seated in the able within the bodily lumen and comprises bodily lumen. (a) a locator catheter tube having a proximal portion 4.The matched group of claim 1, wherein each expand including a proximal end and a distal portion, the distal able member is a balloon and wherein at least one balloon portion including a balloon inflation orifice, the locator inflation lumen extends from the proximal portion of each catheter tube including a lumen extending longitudi tubular body to the interior of the corresponding balloon. nally within the locator catheter tube from the proximal 5. The matched group of claim 4, wherein each balloon is portion and communicating with the balloon inflation on the distal end of the corresponding tubular body. orifice, 6. The matched group of claim 4, wherein each balloon is (b) a balloon affixed to the distal portion, wherein the disposed about the distal portion of the corresponding tubu 15 interior of the balloon communicates with the balloon lar body. inflation orifice; and (c) at least one indicator associated with the locator 7. The matched group of claim 1, wherein at least one of catheter tube for indicating a locator position within a the first and Second catheters further comprises a movable Subject's urethra when the balloon of the graduated element having an indicator associated there with, whereby locator catheter is Seated against the internal urethral the position of the movable element with respect to the orifice of the Subject’s bladder; catheter may be determined by comparing the position of the wherein the graduated delivery catheter is reproducibly indicator associated with the movable element with the Seatable within the bodily lumen and comprises position of the indicator associated with the tubular body. (i) a delivery catheter tube having a proximal portion 8. The matched group of claim 7, wherein the movable including a proximal end and a distal portion including element is the radiation Source positioner. 25 a distal end, the distal portion including a balloon 9. The matched group of claim 7, wherein the movable inflation orifice, the delivery catheter tube including a element is associated with the Second graduated catheter. first lumen extending longitudinally within the delivery 10. The matched group of claim 1, wherein at least one of catheter tube from the proximal portion and commu the first and Second catheters comprises a plurality of nicating with the balloon inflation orifice, the delivery indicators longitudinally spaced along its tubular body. catheter tube also including a Second lumen extending 11. The matched group of claim 1, wherein the first longitudinally into the delivery catheter tube from the tubular body further includes proximal portion; an inlet orifice positioned along the first tubular body for (ii) a balloon affixed to the distal portion, wherein the withdrawing a composition from the bodily lumen and interior of the balloon communicates with the balloon a third lumen extending longitudinally within the first inflation orifice; and tubular body from the proximal portion and commu 35 (iii) at least one indicator associated with the delivery nicating with the inlet orifice. catheter tube for indicating a reference position within 12. The matched group of claim 1, wherein the first the urethra of the subject when the balloon of the tubular body further includes graduated delivery catheter is Seated against the inter an outlet orifice positioned along the first tubular body for nal urethral orifice of the Subject’s bladder; providing a composition to the bodily lumen and 40 and wherein the locator position has a known relationship to a fourth lumen extending longitudinally within the first the reference position and Said locater catheter tube has a tubular body from the proximal portion and commu proximal portion configuration that is different from the nicating with the outlet orifice. proximal portion of the delivery tube wherein said different 13. The matched group of claim 1, wherein at least one of configuration accommodates the use of a locater member. the first and Second catheters further comprises a sleeve 45 21. The graduated urethral catheter kit of claim 20, Surrounding at least a portion of its tubular body. wherein the graduated delivery catheter further comprises 14. The matched group of claim 1, wherein each tubular (iv) a radiation Source disposed within the Second lumen. body has a diameter sufficiently small to fit within a human 22. A method of providing radiation to a tissue located in urethra. close proximity to a bodily lumen of a Subject, the method 15. The matched group of claim 1, wherein each tubular 50 comprising body has a sufficient length that the distal end thereof may be inserted into a ureter of the Subject. (a) inserting into the bodily lumen a graduated locator 16. The matched group of claim 1, wherein the geometry catheter comprising of the first and Second expandable members is Substantially (i) a locator catheter tube identical. having a proximal portion including a proximal end 17. The matched group of claim 1, wherein the first 55 and a distal portion including a distal end, the catheter further comprises a radiation Source disposed within distal portion having a balloon inflation orifice, the first lumen. and 18. The matched group of claim 17, wherein the radiation also having a lumen extending longitudinally within Source is a radioisotope Selected from the group consisting the locator catheter tube from the proximal portion of a beta-emitter, a gamma-emitter, and an X-ray emitter. 60 and communicating with the balloon inflation ori 19. The matched group of claim 18, wherein fice; if the radioisotope is a beta-emitter, then the radioisotope (ii) a balloon affixed to the distal portion, wherein the is selected from the group consisting of 'Y, Re, P. interior of the balloon communicates with the bal 18.Re, ORh, and 89Sr; loon inflation orifice; and if the radioisotope is a gamma-emitter, then the radioiso 65 (iii) an indicator associated with the locator catheter tope is selected from the group consisting of 'Co, tube for indicating a locator position within the '7Cs, and 'Ir; and bodily lumen; US 6,607,477 B1 27 28 (b) thereafter inflating the balloon of the graduated locator (b) thereafter inflating the balloon of the graduated locator catheter; catheter in the subject's bladder; (c) thereafter seating the balloon of the graduated locator (c) thereafter seating the balloon of the graduated locator catheter against an internal orifice of the bodily lumen; catheter against the internal urethral orifice of the (d) thereafter identifying, with respect to the indicator of 5 bladder; and the graduated locator catheter, a position within the bodily lumen which is in close proximity to the tissue; (d) thereafter identifying, with respect to the indicator of (e) inserting into the bodily lumen of the Subject a the graduated locator catheter, a position within the graduated delivery catheter comprising urethra which is in close proximity to the tissue; (i) a delivery catheter tube (e) inserting into the urethra of the Subject a graduated having a proximal portion including a proximal end delivery catheter comprising and a distal portion including a distal end, the (i) a delivery catheter tube distal portion having a balloon inflation orifice having a proximal portion including a proximal end located on the distal portion, and a distal portion including a distal end, the having a first lumen extending longitudinally within 15 distal portion having a balloon inflation orifice the delivery catheter tube from the proximal por located on the distal portion, tion and communicating with the balloon inflation having a first lumen extending longitudinally within orifice, and the delivery catheter tube from the proximal por also having a Second lumen extending longitudinally tion and communicating with the balloon inflation into the delivery catheter tube from the proximal orifice, and portion; also having a Second lumen extending longitudinally (ii) a balloon affixed to the distal portion, wherein the into the delivery catheter tube from the proximal interior of the balloon communicates with the bal portion, loon inflation orifice, and wherein the Second lumen and the catheter tube are (iii) at least one indicator associated with the delivery 25 Substantially coaxial; catheter tube for indicating a reference position within the bodily lumen, the reference position hav (ii) a balloon affixed to the distal portion, wherein the ing a known relationship with the locator position; interior of the balloon communicates with the bal (f) thereafter inflating the balloon of the graduated deliv loon inflation orifice; and ery catheter; (iii) at least one indicator associated with the catheter (g) thereafter Seating the balloon of the graduated delivery tube for indicating a reference position within the catheter against the internal orifice of the bodily lumen; urethra, the reference position having a known rela and tionship with the locator position; (h) positioning, with respect to at least one indicator of the (f) thereafter inflating the balloon of the graduated deliv graduated delivery catheter, a radiation Source within 35 ery catheter within the subject's bladder; the Second lumen of the graduated delivery catheter, (g) thereafter Seating the balloon of the graduated delivery whereby the radiation Source is located at the position within the bodily lumen which is in close proximity to catheter against the internal urethral orifice of the the tissue. bladder; and 23. The method of claim 22, wherein the bodily lumen is (h) positioning, with respect to at least one the indicator the urethra. 40 of the graduated delivery catheter, a radiation Source 24. The method of claim 23, wherein the tissue is selected within the Second lumen of the graduated delivery from the group consisting of a urethral tissue, a strictured catheter, whereby the radiation Source is located at the urethral tissue, a urethral tissue at risk for Stricture position within the urethra which is in close proximity formation, a ureteric tissue, a Strictured ureteric tissue, a to the tissue. ureteric tissue at risk for Stricture formation, prostate tissue, 45 26. A graduated ureteric catheter for use within a ureter of cancerous prostate tissue, and benign hypertrophic prostate a Subject via a transurethral placement, the catheter com tissue. prising 25. A method of providing radiation to a tissue located in (a) a catheter tube having a proximal portion, a distal close proximity to the urethra of a Subject, the method portion, and a lumen extending longitudinally therein comprising 50 from the proximal portion and having a closed distal (a) inserting into the urethra a graduated locator catheter end; comprising(i) (b) at least one indicator associated with the catheter tube a locator catheter tube for indicating a reference position within the ureter; having a proximal portion including a proximal end (c) a radiation Source positioner disposed within the and a distal portion including a distal end, the 55 lumen; and distal portion having a balloon inflation orifice, (d) an expandable member positioned on the distal portion and of the catheter tube such that the expandable member also having a lumen extending longitudinally within can be expanded in one of the bladder, a calix of a the locator catheter tube from the proximal portion kidney, and the pelvis of a kidney of the Subject. and communicating with the balloon inflation ori 60 27. The graduated ureteric catheter of claim 26, wherein fice; the expandable member is a balloon and wherein the indi (ii) a balloon affixed to the distal portion, wherein the cator and the balloon are positioned on the catheter tube Such interior of the balloon communicates with the bal that the indicator is positioned within a ureter of the Subject loon inflation orifice, and when the balloon is inflated and Seated against the corre (iii) an indicator associated with the locator catheter 65 sponding internal ureteric orifice of the Subject's bladder. tube for indicating a locator position within the urethra; k k k k k