METHOD FOR STABILIZING A DETRUSOR MUSCLE WHILE INCREASING DETRUSOR MUSCLE STRENGTH

Abstract: A method for inhibiting unplanned or premature detrusor muscle contractions while at the same time increas­ ing the force of contraction of the detrusor muscle is pro­ vided. The method comprises administering to the patient a di-N-substituted aminoethyl ester of diphenylthioacetic acid having the formula: in which R represents a disubstituted amino radical of the group consisting of the diethylamino group, the morpholino group or the piperidino group.

Description: Background of the Invention Field of the Invention This invention relates to a novel method of inhibiting detrusor muscle spasticity and increasing the force of detrusor muscle contraction. Such an invention has many novel applications including but not limited to the treatment of patients suffering from unstable bladder conditions. Description of the Prior Art The human bladder is composed of four coats; serous, muscular, submucous and mucous. The muscular coat consist; of three layers of unstriped muscular fiber: an external layer, composed of fibers having for the most part a longitudinal arrangement; a middle layer in which the fibers are arranged, more or less, in a circular manner; and an internal layer, in which the fibers have a general longitudinal arrangement. In the external longitudinal layer at the sides of the bladder, the muscle fibers are arranged obliquely and intersect one another. This layer is called the detrusor muscle. Thiphenamil hydrochloride is a class of compounds comprising a di-N-substituted aminoethyl ester of diphenylthioacetic acid having the formula: EMI1.1 in which R represents a disubstituted amino radical of either the diethylamino group, the morpholino group or the piperidino group. G4i22SS3 485G58 3 201 150.00 CK O4/2?/ 4S505o' 204 50.00 CK The prior uses for thiphenamil hydrochloride center around its use as an anti-spasmotic agent in the upper and lower gasto-intestinal tract for pylorospasn, spasm associated with the gallbladder and coson bile duct, as well as diarrhea and the irritable bowel syndrome. Prior art uses also include treatment of ureterospasm and bladder irritation. There have been further reports that thiphenamil hydrochloride has been successfully used for the treatment of bronchospasm. Thiphenamil hydrochloride is a well-known compound and is described in detail in U.S. Patent No. 2,390,555 to Richardson, incorporated herein by reference. Additional methods of making thiphenamil hydrochloride are described in U.S. Patent No. 2,510,773 to Clinton. The term 'Idetrusor instability" generally refers to the condition wherein the bladder spontaneously contracts and empties before the patient is ready. Generally, the following compounds have been used for the pharmacological treatment of detrusor instability: "URISPAS" (flavoxate hydrochloride) which is a smooth muscle relaxant; tDITROPANS (oxybutynin chloride) an anti-cholinergic used for the relief of neurogenic bladder symptoms; and "BANTHINEt (methantheline bromide) an anti-cholinergic and anti-spasmodic drug. For the most part, the above listed and other derivatives of atropine are unpredictable in their effect on bladder instability. In addition to their rather poor successful treatment record, anti-cholinergic compounds produce undesirable side effects such as dryness of the mouth, dilation of the pupils and slowed heartbeat. In the uses of thiphenamil hydrochloride as a smooth muscle relaxant It: has generally been assumed that the drug relaxes and inhibits the ability of smooth muscles to contract. This phenomenon has been shown in a number of studies: 1. STUDIES ON THE PHARMACOLOGY OF BETA-LIETHYLAMINOETHYL- DIPNENYLTHIOACETATE, A SYNTHETIC ANTISPASMODIC, Kamsey & Richardson, J. Pharm. & Exp. Th., Feb. 1947, pp. 131 142. 2. CLINICAL EVALUATION OF TROCINATE, AN hl{TlSPAShODIC, MacDonald, J. Missouri Medical Association, Sept. 1951, pp. 685-6. 3. USE OF ANTISPASMODICS IN TREATMENT OF SPASTIC URETERITIS, Thackston et. al., J. Urology, March 1955, pp. 487-493. 4. EFFECT OF A LOCAL SMOOTH MUSCLE ANTAGONIST ON WOUND CONTRACTION, Morton et.al., Surg. Forum, Vol. 23, 1972. 5. MUSCLE DRUG SLOWS WOUND COIITKCT10N, Medical World News, March 1974, p. 74A. 6. CONTRACTION OF EXPERIMENTAL WOUNDS I. INHIBITING WOUND CONTRACTION BY USING A TOPICAL SMOOTH MUSCLE ANTAGONIST, Madden et.al., Surgery, July 1974, pp. 8 15. As a result of these and other studies, persons skilled in the art generally expect the force of the smooth muscle contractions to be greatly diminished after administering thiphenamil hydrochloride. There has been a need in the pharmaceutical art for a drug which inhibits involuntary detrusor contractions while at the same tine increasing the strength of voluntary detrusor contractions. Thus, it is an important object of the present invention to provide a method for inhibiting unplanned or premature muscle contraction of the detrusor muscle while at the same time increasing the force of voluntary contraction of the detrusor muscle. it is yet another, important object of the present invention to provide such a method which is safe for use on human patients, particularly sensitive patients such as glaucoma patients without subjecting the patient to the undesirable side effects of anti-cholinergic drugs,-for example dryness of the mouth, dilation of the pupils and slowed heartbeat. It is another important object of the present invention to provide such a method of inhibiting unplanned or prenature muscle contraction while at the same time increasing the force of the detrusor muscle contraction without leaving or accummulatinp, any foreign substances in the human body tissues. Summary of the Invention These and other Objects are met in the novel method for inhibiting unplanned or premature detrusor muscle contractions while at the same time increasing the force of contraction of the detrusor muscle comprising the administration of a di-N-substituted aminoethyl ester of diphenylthioacetic acid having the formula: EMI4.1 in which R represents a disubstituted amino radical of the group consisting of the diethylanino group, the morpholino group or the piperidino group. Brief Description of the Drawings Figure 1 is a graph showing data taken from a subject with a normal detrusor under control conditions. Figure 2 is a graph showing data taken from the same subject used in Figure 1, after taking a dose of 400 mg of thiphenamil hydrochloride. Figure 3 is a graph showing data taken from a subject having an unstable detrusor. Figure 4 is a graph showing delta taken frox the same subject used in Figure 3, after having taken a 400 mg dose of thiphenamil hydrochloride 30 minutes prior to recording. Description of the Preferred Embodiments It is evident from the experimental results which follow that thiphenamil hydrochloride inhibits involuntary detrusor muscle contraction while at the same time increasing the force of voluntary detrusor muscle contractions. Apparently, the combined action of inhibiting detrusor spasticity while increasing the force of detrusor contraction is a unique property of thiphenamil hydrochloride and is an unknown action of any other compound. The advantage of this effect of thiphenamil hydrochloride .s that involuntary detrusor muscle contraction is inhibited thereby giving the patient effective bladder control. Furthermore, because the strength of the detrusor muscle contraction is increased, there is a more complete emptying of the bladder, even in cases where there is a partial obstruction such as in a prostatic obstruction generally encountered in older patients suffering from prostatic hypertrophy. The experimental results reveal that thiphenamil hydrochloride acts as an effective detrusor spasticity inhibitor and detrusor force of contraction increaser in a dosage range of from about 0.7 to about 11.4 mglkg of body weight. A preferred dosage is in the range of from about 1.4 to about 5.7 mg/kg of body weight. A still more preferred dosage range is from about 2.8 to about 5.7 mg/kg of body weight. Thiphenamil hydrochloride can be administered orally, typically in tablets of 100-400 mg or by intravenous injection necause thiphenamil hydrochloride slowly hydrolizes in water, it is generally not used as a serum or suspension. It is possible however to encapsulate microspheres of thiphenamil hydrochloride in the form of a liquid suspension for adminis- tration to patients. The invention is further disclosed by. means of the following examples which are intended only as illustrations and which in no way limit the invention. Examples Urodynamic studies were performed on 20 women having a mean age of 28 + 7 years. Those studies incorporated water cystometrogram, UPP, and isometric tests. Control urodynamic testing without use of thiphenamil hydrochloride was undertaken in all subjects. The effects of a single dose of 400 mg and a single dose of 800 ng of thiphenamil hydrochloride given orally were compared with the control value for each subject. Specifically, the measurements taken included bladder capacity, residual volume, maximum detrusor voiding pressure, and isometric contractility during bladder filling and at bladder capacity. The results of these experiments are shown in Tables I IV. The experimental results show no significant increase in bladder capacity and a decrease in the detrusor muscle contractility of from 41.3 + 15.3 cm H20 to 37.2 + 16.0 cm H20- The test results further demonstrate that the isometric detrusor pressure during the filling phase of the bladder significantly increases from 36.1 + 26.9 cm H20 to 63.0 + 27.1 cm 1120. Referring to figure 1, data is shown taken from a subject having normal detrusor activity. The parameters measured include isometric detrusor pressure during bladder filling and while voiding under control conditions, EG and urine flow rate. Typical segments of a polygraph recording were obtained at a bladder volume of 100 ml (segment A), 200 ml (segment B) and-the voiding at 30C ml (segment C). The parameters shown are detrusor pressure in cm H20, E!'16 (electromyogram) recording showing muscle electrical activity and urine flow rate. This subject exhibited no detrusor instability during the measurements. The same subject was then monitored after a 400 mg dose of thiphenamii hydrochloride and the measurments were plotted in Figure 2. Three segments of a polygraph recording are shown at the bladder capacity and conditions described in Figure 1. As can be seen, the detrusor pressures in segments A and B in Figure 2 are considerably higher than the corresponding values shown in Figure 1. Figure 3 illustrates the voiding phase of the cystometrogram for a subject havin an unstable detrusor muscle. Spontaneous detrusor contractions are shown to precipitate voiding at a bladder urine volume of about 210 ml. The onset of-voiding is associated with involuntary contractions (series of detrusor pressure peaks between 0 and 50 seconds) that are suppressed by increased EMG activity. The voiding was voluntary and complete with no residual urine volume. The same subject used in Figure 2 was monitored, and the results traced, in Figure 4 after being given a 400 ml dose of thiphenamil hydrochloride 30 minutes prior to recording. The polygraph shows that the pattern oi detrusor instability (i.e., the series of increasing peaks in the detrusor pressure during the time leading up to voiding) observed under the control conditions illustrated in Figure 3 has shifted significantly to the right as well as a general decrease in the height of those peaks. Hence, there is really only a significant detrusor pressure peak immediately before the onset of voiding. As can be seen from the EMG tracing in Figure 4, the range of fluctuations is greatly decreased indicating that the detrusor instability is nearly eliminated, In Figure 4, voiding was voluntary and complete. TABLE I Stable Detrusor: Urodynamic parameters of the tilling and voiding phase of the bladder under control conditions and also with 400 mg and 800 mg thiphenamil hydrochloride. Thiphenamil Hydrochloride Control (400mg) (800mg) Compliance 0.003+0.001 0.002+0.001 0.0025+0.003 V (lst sense) 281+126 314+99 298+67.6 (21) (19) (11) V (Urge) 525+200 551+195 381+61 (21) (19) (11) V (max) 552+168 581+155 436+165 (21) (19) (11) P (opening) 29.9+14.0 25.4+13.3 39.1+12.2 (21) (19) (7) P (max flow) 36.7+15.8 37.9+9.1 49.5+14.8 (21) (19) (11) P (voiding) 41.3+15.5 37.2+16 65.1+19.1 (21) (20) (11) Q (max) 16.9+4.6 16.7+4.4 27.7+9.0 (21) (21) (8) R.U. 69.3+83.1 132.3+121.4 95.0+72.2 (18) (18) (9) Wherein: 1. Compline is the compliance of the detrusor muscle in liters/cm 1120. 2. V (lst sense) is the bladder urine plume in ml's at the patient's first sensation to urinate. 3. V (Urge) is the bladder urine volume in ml's at the patients urge to urinate. TABLE I (con't) 4. V (max) is the maximum bladder urine volume in ml's. 5. P (opening) is the bladder pressure at the patient's initiating urination in cm 1120. 6. P (max flow) is the bladder pressure at maximum urine flow rate in cm H2O. 7. P (voiding) is the bladder voiding pressure in cm H2O. 8. Q (max) is the maximum urine flow rate in mllsec. 9. R.U. is tile residual or left over bladder urine volume in ml's. 10. (n) is the number of measurements taken, i.e. sample size. TABLE 11 Stable Detrusor: Maximum isometric pressure as a function of bladder volune under control conditions and also with 400 mg and 800 mg of thiphenamil hydrochloride. Thiphenamil Hydrochloride Control (400mg) (8OOmg) 1 (100) 36.1+26.9 63.0+27.1 74+34.6 (10) (13) (6) 1 (200) 37.9+23.4 4 51.9+26.0 65.0+37.8 (12) (14) (7) 1 (300) 35.9+12.9 50.3+25.8 63.4+26.2 (8) (12) - (7) I (400) 37.2+17.9 46.6+19.5 50.0+27.5 (il) (10) (6) 1 (500) 36.8+23.7 30.1+15.6 34.0+14.4 (9) (8) (2) V (lst sense) 316+147 358+106 253.3+56.9 (18) (18) (6) V (Urge) 503+138 467+94 385+74.6 (18) (18) 7) V (Max) 515+162 544+151 425+82 (13) (11) (10) Wherein: 1. I (100 etc.) is the maximum bladder isometric pressure at a bladder urine volume of 1C3. 200 etc. ml's in cm H20. 2. V (lst sense) is the bladder urine volume in ml's at the patient's first sensation to urinate. 3. V (Urge) is the bladder urine volume in nl's at the patient's urge to urinate. 4. V (max) is the maximum bladder urine volume in ml's. 5. (n) is the number of measurements taken, i.e. sample size. TABLE III Unstable Detrusor: Urodynamic parameters of the filling and voiding phase of the bladder under control conditions and also with 400 mg and 800 mg of thiphenamil hydrochloride. Thiphenamil Hydrochloride Control 400 mg 800 mg Compliance 0.003+0.001 0.002+0.001 0.0027+0.0004 V (lst sense) 217+202 270+99 275+35 (4) (3) (3) V (Urge) 345+209 345+191 325+35 (2) V (max) 398+171 440+57 499+177 (3) (-2) (3) P (opening) 38+17 30+12 44+11.3 (4) (2) P (maxflow) 44.3+3.1 44.0+4.4 55.3+7.0 (3) (3) (3) P (voiding) 53-18 47+7 52.7+6.4 (4) (4) (3) Q (max) 18.2+1.2 15+1.9 18.0+1.8 (3) R.U. 18+22 140+85 27.5+3.5 (3) (2) (3) Wherein: 1. Compliance is the compliance of the detrusor muscle in liters/cm H20. 2. V (lst sense) is the bladder urine volume in ml's at tne patient's first sensation to urinate. 3. V (Urge) is the bladder urine volume in ml's at the patient's urge to urinate. TABLE III (con't) 4. V (max) is the maximum bladder urine volume in ml's. 5. P (opening) is the bladder pressure at the patient's initiating urination in cm H20. 6. P (max flow) is the bladder pressure at maximum urine flow rate in c H20. 7. P (voiding) is the bladder voiding pressure in cm H20. 8. Q (max) is the maximun urine flow rate in ml/sec. 9. R.U. is the residual or left over bladder urine volume in ml's. 10. (n) is the nunber of measurements taken, i.e. sample size. TABLE IV Unstable detrusor: Maximun isometric pressure as a function of bladder volune under control conditions and also with 400 mg and 800 mg of thiphenamil hydrochloride. Thiphenamil Hydrochloride Control (400mg) (800mg) 1 (100) 32+13 73+39 78+53 - (3) (14) 1 (200) 42+35 44114 62+57 (4) (3) 1 (300) 35+13 75+5 96 (2) (1) V (lst sense) 217+143 270+99 (4) (4) V (urge) 320+170 355+53 423+27.5 (4) (4) Wherein: 1. Compliance is the compliance of the detrusor muscle in liters/cm H2O. 2. V (lst sense) is the bladder urine volume in ml's at the patient's first sensation to urinate. 3. V (Urge) is the bladder urine volume in ml's at the patient's urge to urinate. 4. (max) is the maximum bladder urine volume in ml's. 5. @ (opening) is the bladder pressure at the patient's initiating urination in cm 1120. 6. P (max flow) is the bladder pressure at maximum urine flow rate in cm 1120. 7. P (voiding) is the bladder voiding pressure in cm hZ0. TABLE 1V (con't) 8. Q (max) is the maximum urine flow rate in ml/sec. 9. R.U. is the residual or left over bladder urine volume in ml's. 10. (n) is the. number of measurements taken, i.e.-sample size.

Claims: Ue claim: 1. A method for inhibiting detrusor muscle spacticity comprising administering to a patient a di-N-substituted aminoethyl ester of diphenylthioacetic acid having the formula: EMI16.1 in which R represents a disubstituted amino radical of the group consisting of the diethylamino group, the morpholino group and the piperidino group. 2. A method for increasing the force O1 contraction of the detrusor muscle comprising administering to a patient a di-N-substituted aninoethyl ester of diphenlthioacetle acid having the formula: EMI16.2 in which R represents a disubstituted amino radical of the group consisting of the diethylamino group, the morpholino group and the piperidino group. 3. A method for simultaneously inhibiting detrusor muscle spasticity and increasing the force of contraction ot the detrusor muscle comprising administering to a patient a di-N-substituted aninoethyl ester of diphenylthioacetic acid having the formula: EMI16.3 in which R represents a disubstituted amino radical of the group consisting of the diethylamino group, the morpholino group al.J the piperidino group. 4. The method as described in claim 1, 2 or 3, wherein the di-N-substituted amineethyl ester of diphenylthioacetic acid is administered in a dosage of from about 0.7 to about 11.4 mg per kilogran of body weight. 5. The method as described in claim 1, 2 or 3, wherein the di-N-substituted aminoethyl ester of diphenylthioacetic acid is adninistered in a preferred dosage of from about 1.4 to about 5.7 mg per kilogram of body weight. 6. The method as described in claim 1, 2 or 3, wherein the di-N-substituted aminoethyl ester of diphenylthicacetic acid is administered in a sore preferred dosage of froia about 2.8 to about 5.7 mg per kilogram of body weight. 7. The method as described in claim 1, 2, or 3, wherein the di-N-substituted aninc thyl ester of diphenylthioacetic acid is combined with a pharmaceutically accepted carrier.

Inventors: DAVIS, WILLIAM M. M.D.
Applicants: UNITED PHARMACEUTICALS, INC.
Application year: 1984
Main classification: A61K31
IPC codes: A61K31, C07D295, A61P13, A61P15, A61P25