Method for dilating the smooth muscles of the upper urinary tract

Dilation of smooth muscles of the upper urinary tract with a di-N-substituted aminoethyl ester of diphenylthioacetic acid.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a novel method of dilating the smooth muscles of 
the upper urinary tract. Such an invention has many novel applications 
including but not limited to the treatment of patients passing kidney 
stones through the upper urinary tract. 
2. Description of the Prior Art 
To date, no clinically effective upper urinary tract dilator is in use. 
Currently used urinary tract dilators are generally anti-cholinergic drugs 
or direct smooth muscle relaxants such as papavarin, a narcotic 
derivative. These drugs have either been ineffective as dilators or have 
undesirable side effects such as dryness of the mouth, blurred vision, and 
slowed heart beat. 
Thiphenamil hydrochloride is a class of compounds comprising a 
di-N-substituted aminoethyl ester of diphenylthioacetic acid having the 
formula: 
##STR1## 
in which R represents a disubstituted amino radical of either the 
diethylamino group, the morpholino group or the piperidino group. 
The prior uses for thiphenamil hydrochloride center around its use as an 
anti-spasmotic agent in the upper and lower gastro-intestinal tract for 
pylorospasm, spasm associated with the gallbladder and common 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. Pat. No. 2,390,555 to Richardson, incorporated herein by 
reference. Additional methods of making thiphenamil hydrochloride are 
described in U.S. Pat. No. 2,510,773 to Clinton. 
Thus, it is an important object of the present invention to provide a 
method for dilating and relaxing the smooth muscles of the upper urinary 
tract 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 heart beat. 
It is a further important object of the present invention to provide such a 
method which is safe for use on human patients and which is also safe for 
particularly sensitive patients such as glaucoma patients. 
It is yet another object of the present invention to provide a method for 
treating patients passing kidney stones without subjecting the patient to 
surgery. 
It is another important object of the present invention to provide such a 
method of dilating and relaxing the smooth muscles of the upper urinary 
tract without leaving or accumulating any foreign substances in the human 
body tissues. 
SUMMARY OF THE INVENTION 
These and other objects are met in the novel method for dilating the smooth 
muscles of the upper urinary tract comprising the administration of a 
di-N-substituted aminoethyl ester of diphenylthioacetic acid having the 
formula: 
##STR2## 
in which R represents a disubstituted amino radical of the group 
consisting of the diethylamino group, the morpholino group and the 
piperidino group. 
A more specific method for treating a patient passing a kidney stone 
comprises administering to the patient a di-N-substituted aminoethyl ester 
of diphenylthioacetic acid of the formula: 
##STR3## 
in which R represents a disubstituted amino radical of the group 
consisting of the diethylamino group, the morpholino group and the 
piperidino group. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
It is now been surprisingly discovered that thiphenamil hydrochloride can 
be used for dilating the smooth muscles of the upper urinary tract and 
specifically to dilate and relax the smooth muscles of the upper urinary 
tract in order to treat a patient passing a kidney stone through the upper 
urinary tract. 
It is evident from the experimental results which follow that thiphenamil 
hydrochloride increases the compliance of the renal pelvis. Under 
conditions of increased compliance, the capacity of the renal pelvis is 
significantly increased. Additionally, the renal pelvic pressure is 
concomitantly reduced with the contractile rate. Under these 
circumstances, the upper urinary tract dilates and peristaltic 
contractions are greatly diminished in both amplitude and frequency. 
Further, thiphenamil hydrochloride acts as an effective upper urinary tract 
dilator and would be effective in treating patients passing kidney stones 
through the upper urinary tract. 
The experimental results reveal that thiphenamil hydrochloride acts as an 
effective upper urinary tract dialator in a dosage range of from about 0.7 
to about 11.4 mg per kiligram of body weight. A preferred dosage is in the 
range of from about 1.4 to about 5.7 mg per kiligram of body weight. A 
still more preferred dosage range is from about 2.8 to about 5.7 mg per 
kiligram of body weight. 
Thiphenamil hydrochloride can be administered orally, typically in tablets 
of 100-400 mg, or by intravenous injection. 
Because thiphenamil hydrochloride slowly hydrolyzes 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 administration 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 1-9 
Nine pigs, five male and four female, were implanted with a telemetry 
package to record the amplitude and frequency of the filling and emptying 
phase of the renal pelvis. The pigs were lightly anesthetized with 2% 
halothane and 98%, oxygen. A dose of 1 milligram of a thiphenamil 
hydrochloride (in which R is a disubstituted amino radical of the 
diethylamino group) per kiligram of body weight (mg/kg) was given to each 
pig intravenously through an ear vein following a 20 minute control 
period. 
EXAMPLES 10-18 
The same procedures as followed in examples 1-9 were repeated using a dose 
of 1 milligram of a thiphenamil hydrochloride (in which R is a 
disubstituted amino radical of the morpholino group) per kiligram of body 
weight (mg/kg). 
EXAMPLES 19-27 
The same procedures as followed in examples 1-18 were repeated using a dose 
of 1 milligram of a thiphenamil hydrochloride (in which R is a 
disubstituted amino radical of the piperidino group) per kiligram of body 
weight (mg/kg). 
Examples 1-27 demonstrate that at a dose of 1 mg/kg thiphenamil 
hydrochloride (all types) the rate of contraction in the renal pelvis 
increases from 1.84.+-.0.15 to 2.03.+-.0.35 contractions per minute. 
EXAMPLES 28-54 
The same procedure as utilized in examples 1-27 was used on the nine pigs 
which were given a dose of 2 milligrams of: first, a thiphenamil 
hydrochloride (in which R is a disubstituted amino radical of the 
diethylamino group) per kiligram of body weight; second, a 2 milligram 
dose of a thiphenamil hydrochloride (in which R is a disubstituted amino 
radical of the morpholino group) per kiligram of body weight (mg/kg); and 
third, a 2 milligram dose of a thiphenamil hydrochloride (in which R is a 
disubstituted amino radical of the piperidino group) per kiligram of body 
weight (mg/kg). 
EXAMPLES 55-81 
The same procedure as utilized in examples 1-54 was used on the nine pigs 
which were given a dose of 5 milligrams of: first, a thiphenamil 
hydrochloride (in which R is a disubstituted amino radical of the diethyl 
amino group) per kiligram of body weight (mg/kg); second, a 5 milligram 
dose of a thiphenamil hydrochloride (in which R is a disubstituted amino 
radical of the morpholino group) per kiligram of body weight (mg/kg); and 
third, a 5 milligram dose of a thiphenamil hydrochloride (in which R is a 
disubstituted amino radical of the piperidino group) per kiligram of body 
weight (mg/kg). 
EXAMPLES 82-108 
The same procedure as utilized in examples 1-80 was used on the nine pigs 
which were given a dose of 10 milligrams of: first, a thiphenamil 
hydrochloride (in which R is a disubstituted amino radical of the 
diethylamino group) per kiligram of body weight (mg/kg); second, a 10 
milligram dose of a thiphenamil hydrochloride (in which R is a 
disubstituted amino radical of the morpholino group) per kiligram of body 
weight (mg/kg); and third, a 10 milligram dose of a thiphenamil 
hydrochloride (in which R is a disubstituted amino radical of the 
piperidino group) per kiligram of body weight (mg/kg). 
The in vivo data show that the effect of thiphenamil hydrochloride on renal 
pelvic frequency is bimodal. Thus, while at a dose of 1 mg/kg of 
thiphenamil hydrochloride (all types) the renal pelvis contraction 
frequency increases, at doses greater than 1 mg/kg of thiphenamil 
hydrochloride (all types) the frequency of pelvic contractions decreases 
significantly. The data follows a roughly linear equation computed from 
the dose response curves: 
EQU .DELTA.F=-11.5-3.3X 
where .DELTA.F is the percent change in frequency and X is the dose of 
thiphenamil hydrochloride in miligrams per kiligram of body weight. 
In the test animals, renal pelvic pressure decreased significantly from a 
mean of 6.6.+-.0.66 cm H.sub.2 O to 2.3.+-.0.16 cm H.sub.2 O. 
In five of the experimental animals, measurements were taken with the 
abdomen open and the ureter obstructed. Under these circumstances renal 
pelvic pressure was effectively raised to a mean value of 18.4.+-.6.3 cm 
of H.sub.2 O. Intravenous thiphenamil hydrochloride at 2.5 mg/kg 
significantly reduced the resting renal pelvic pressure to 5.9.+-.3.1 cm 
H.sub.2 O in four of the five test animals. 
The data also demonstrate a linear decrease in the frequency of spontaneous 
renal pelvic contractions. A linear equation computed from the dose 
response curves is given by: 
EQU .DELTA.F=-5.2-5.6X 
where .DELTA.F is the percent change in frequency and X is the dose of 
thiphenamil hydrochloride in 10-3 M. Furthermore, the amplitude of the 
spontaneous contractions decreased according to the relationship: 
EQU .DELTA.T=1.2+0.4X 
where .DELTA.T is the percentage decrease in amplitude of contraction and X 
is the dose of thiphenamil hydrochloride at 10-3 M. 
Experiments 1-108 show that at doses above 1 mg/kg, thiphenamil 
hydrochloride will act as an effective agent to dilate and relax the upper 
urinary tract smooth muscles and further suggest that thiphenamil 
hydrochloride (all types) will be effective in treating patients passing 
kidney stones.