Method for treatment of male impotence

Trazodone and its pharmaceutically acceptable salts are useful in the treatment of male sexual impotence.

FIELD OF THE INVENTION 
This invention is concerned with a drug bio-affecting body-treating process 
which employs the triazolopyridine compound 
2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridi 
n-3(2H)-one or a pharmaceutically acceptable acid addition salt thereof. 
BACKGROUND OF THE INVENTION 
This invention concerns a novel therapeutic treatment for male sexual 
impotence by the administration of "trazodone" which is the USAN-approved 
generic name for 
2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo 
[4,3-a]pyridin-3(2H)-one. Trazodone and related compounds are described in 
U.S. Pat. No. 3,381,009 as having tranquilizing and hypotensive activity. 
Trazodone has also been described as having utility in the treatment of 
individuals suffering from the acute phases of stroke (U.S. Pat. No. 
4,154,832) and for use in the treatment of Parkinsonism (U.S. Pat. No. 
4,162,318) and in combination with L-DOPA in treating Parkinsonism (U.S. 
Pat. No. 4,131,675). However, trazodone is best known as a potent and safe 
antidepressant agent and has been accepted internationally for use in the 
clinical treatment of depression. 
Male impotence is a sexual dysfunction which relates to difficulty in 
achieving and maintaining penile erection. Currently, male impotence is a 
broad-ranging problem of social, psychologic, and medical significance. 
There exists today a diversity of possible causes of impotence as well as 
suggested methods of treatment. These have been described in a number of 
available literature reviews on male impotence and on male sexual 
dysfunctioning in general. While impotence can result from psychogenic or 
physical causes, a review by L. M. Martin in Geriatrics, (December 1980), 
pages 79-83; emphasizes that organic causes of impotence are more common 
than has been currently believed. Any condition that impairs the 
endocrine, vascular, neurologic, or anatomic systems can produce 
impotence. Among various causes of impotence that are specifically 
implicated are: diabetes, surgery, vascular disease, hypertension and 
hardening of arteries, side-effects from drugs, and hormonal imbalance. 
Concerning the treatment of impotence, H. G. Kudish in Postgraduate 
Medicine, Vol. 74/4 (October 1983), pages 233-240; lists therapies for 
impotence as being in two categories: surgical and non-surgical. The 
surgical category comprises implantation of a penile prosthetic device; 
revascularization of the penis; and incision or excision of Peyronie's 
plaques. The non-surgical category comprises sex therapy, endocrine 
therapy, pharmacologic therapy, and electrostimulation. Non-surgical 
therapies, when effective, are the treatments of choice. Of these, the 
favored treatment in most instances would be pharmacologic therapy if it 
was effective. Unfortunately, the use of pharmacologic agents in treatment 
of impotence has achieved little success. This is evidenced by the absence 
of any recognized accepted pharmacologic treatment for use in male 
impotence, although anecdotal reports of the use of various agents, 
compositions, and formulations abound. Currently, yohimbine, a drug 
occasionally prescribed for hypertension, is being studied for possible 
use in the treatment of impotence. Improvement in erectile function after 
administration of the .alpha.-adrenergic blocking agent phenoxybenzamine 
has also been reported anecdotally. 
While reports of beneficial drug effects on sexual functioning in the male 
are mainly anecdotal, a considerable literature deals with sexual 
dysfunction associated with drug treatment. In general, these effects are 
considered to be undesirable side effects from any of many medications 
including inter alia, antihypertensives and antidepressants. While most 
types of sexual dysfunction associated with drug administration appear to 
be medically benign and reversible with drug discontinuation, an important 
exception is priapism, which necessitates prompt urologic consultation and 
which in many cases may require surgical intervention. While not well 
understood, priapism, a prolonged painful and abnormal erection of the 
penis, can have numerous possible etiologies in addition to administration 
of pharmacologic agents. It is felt that priapism may involve a different 
physiologic mechanism than that for normal penile erection. In the state 
of priapism the viscosity of the blood engorging the penile tissue 
increases abnormally (of: The Merck Manual, 14th Edition (1982) page 
1602). Although the onset of priapism can in some instances be initiated 
by sexual stimuli, the prolonged painful abnormal erection persists long 
after the sexual excitement is gone. One reason for the poor understanding 
of the underlying causes and mechanisms of development of priapism is the 
low frequency of occurrence of priapism. Since priapism frequently 
requires surgical intervention, impotence is a possible consequence. 
Although several drugs have been reported in the literature as being 
associated with priapism (see for example: J. E. Mitchell and M. K. 
Popkin, "Antipsychotic Drug Therapy and Sexual Dysfunction in Man" in Am. 
J. Psychiatry, 139:5 (May 1982) pages 633-637); none of these drugs is 
employed in treating penile erectile dysfunction. In fact, the potential 
permanent impotence which can result from priapism causes any 
pharmacologic agent which may be causally related to priapism to be 
contra-indicated for use in males. It is to be recognized that induction 
of the abnormal penile erection of priapism would not be considered as a 
desirable treatment for male impotence. It should also be understood that 
known agents associated with priapism are not effective in the induction 
of useful erectile activity in impotent males. 
Also found among the many drugs reported to be associated in cases of 
priapism is trazodone. Representative of these reports are the following: 
(1) Anon., The Medical Letter, 20(658), Mar. 30, 1984, page 35. 
(2) Aronoff, The Lancet, Apr. 14, 1984, page 856. 
(3) Lansky, et al., J. Clin. Psychiatry, 45:232-233, 1984. 
(4) Scher, et al., Am. J. Psychiatry, 140:1362-1363, 1983. 
(5) Raskin, ibid., 142:1, 1985. 
While the incidence of trazodone-associated priapism or undesired abnormal 
erectile activity is very low, nonetheless, these reports would act to 
teach away from the use of trazodone in treating male impotence, 
especially since other agents associated with priapism have not been found 
to be useful in this regard. As the study of the relationship of trazodone 
and erectile activity has proceeded, however, it has been discovered that 
trazodone unexpectedly can produce useful erectile activity in male 
mammals. This surprising finding has led to the instant unobvious 
invention. 
In summary, trazodone and its pharmaceutically acceptable salts have 
heretofore been reported as having only unwanted abnormal and potentially 
harmful effects on erectil function of male patients. There exists nothing 
in the prior art which teaches or suggests that trazodone would be useful 
in the treatment of impotence in males with compromised penile erection 
function. 
SUMMARY OF THE INVENTION 
The process of the present invention is intended for treatment of male 
impotence. The process essentially involves administration of trazodone, 
or a pharmaceutically acceptable acid addition salt thereof, to a male 
mammal in need of such treatment. For use in the instant process oral 
administration of trazodone hydrochloride from about 50 to 400 mg per day 
is anticipated as being the preferred dosage regimen. Dosage adjustment is 
to be made depending on the response seen in each individual.

DETAILED DESCRIPTION OF THE INVENTION 
Erectile impotence has been defined by Masters and Johnson (W. H. Masters, 
V. E. Johnson; Human Sexual Inadequacy, Little, Brown and Company, Boston, 
1970, page 157) as the "inability to achieve or maintain an erection [of] 
quality sufficient to accomplish successful coital connection". Since 
erectile impotence can result from a variety of underlying causes ranging 
from purely psychogenic to completely physical dysfunctioning, it would be 
unrealistic to expect a single treatment modality to be effective in all 
cases. In current medical practice, impotence is treated by determining 
the underlying cause or causes and then treating them whenever possible. 
When irreversible organic impotence is found, however, penile prosthesis 
implantation is considered the most beneficial treatment. For psychogenic 
causes of impotence, the underlying condition is treated with 
psychopharmacologic agents and/or behavioral therapies. In a majority of 
cases, identification of the underlying causes of male impotence is either 
very complex or cannot be determined with certainty. Currently, refractory 
cases of organic impotence, resulting from neurologic causes, for example, 
can be identified by a comprehensive diagnostic approach which includes 
nocturnal penile tumescence monitoring and laboratory testing. 
The technique of nocturnal penile tumescence monitoring makes use of bursts 
of autonomic central nervous system activity which occur regularly every 
90 to 110 minutes during sleep. These periods are characterized by a 
variety of objective physiologic changes which include rapid eye movement 
(REM), increased respiration, increased heart rate, and penile erection. 
When organic impotence is present, nocturnal penile tumescence will fail 
to occur or be abnormally diminished. If the problem is not due to 
physical dysfunction, a normal nocturnal penile tumescence pattern will be 
observed. 
A study in monkeys demonstrated that trazodone produced penile tumescence 
in 40% of the animals tested. The tumescence seen with trazodone developed 
within 10 minutes and lasted for about 50-60 minutes. Spontaneous 
detumescence is associated with normal erectile activity as opposed to the 
abnormal erectile activity of priapism. Following study in monkeys, 
trazodone was demonstrated to cause significant increase in nocturnal 
penile tumescence in three of six normal male volunteers. This study on 
sleep-related erections in normal males was placebo-controlled and 
compared the effects of trazodone and trimipramine. The increased erectile 
activity in the study subjects was seen only with trazodone, thus tending 
to confirm the monkey study which indicates that trazodone may produce or 
enhance erectile activity in a significant proportion of Anthropoidea and 
might be useful in treatment of human male impotence. 
Analysis of reported episodes of unusual erectile activity for depressed 
male patients being administered trazodone indicates that in some 
instances the patient or physician has considered the erectile activity to 
be beneficial. Several of these clinical cases are summarized in Table 1. 
TABLE 1 
______________________________________ 
Beneficial Erectile Activity With Trazodone 
Ex. Age Dosage 
No. Pt. File No 
(Years) (mg.) Remarks 
______________________________________ 
1 39-MGE-0128 
59 100-200 
Pt. was semi-impotent 
prior to therapy with 
trazodone. 
2 39-MKE-0097 
50 50-250 
Although erections 
persist following inter- 
course, pt. continues 
with medication, reporting that the 
"benefit outweighs the 
effect. . ." 
3 39-MLA-0043 
57 150 Pt. had first erection in 
5 years within 2 days of 
trazodone treatment. No 
erections since tra- 
zodone discontinued. 
4 39-MHD-0006 
44 unknown 
Pt. had a fibrotic mass at 
the base of the penis 
and was impotent prior to 
trazodone therapy. 
5 75-SRUSA- 50 100 Pt. had loss of libido for 
MO385-0284 several years. Sexual 
functioning returned 
after starting on 
trazodone. 
6 87-SRUSA- 52 75-100 
Pt. had been impotent 
MO785-0235 for last 5 years. Within 
3 days of trazodone treat- 
ment, pt. experienced a 
return of sexual 
function. 
7 39-MLD-0032 
44 200-400 
MD reports that pt. is 
happy with his increased 
erectile activity and 
wished to remain on 
trazodone. 
______________________________________ 
Administration of trazodone according to the present invention may be made 
by the parenteral, oral, or rectal routes. The oral route is preferred, 
however. The clinical dosage range for the treatment of male sexual 
impotence is about the same as for antimdepressant usage, that is, from 
about 50 mg up to about 400 mg per day. It is recommended that trazodone 
be given accompanied by some food and starting at the level of 50 mg per 
day. Preferably, the drug should be taken at bedtime. The drug may then be 
increased by 50 mg increments, as tolerated, every 3 to 7 days. As the 
total dosage increases, the drug may be administered in divided doses. No 
more than 300 mg of trazodone is to be given as a single dose. Male 
patients being treated with trazodone for impotence should be monitored 
carefully by their attending physician during the dose-titration period of 
treatment. Since the dosage should be tailored to the individual patient, 
the usual practice is to commence with a dose of about 50 mg per day 
administered at bedtime and then to increase the dose every 3 to 7 days by 
50 mg at each dosage time until the desired response is observed or until 
the patient exhibits side effects. Administration of the daily dosage in 
divided doses may be recommended in some instances. The emergence of side 
effects such as dizziness, drowsiness, or prolonged or inappropriate 
penile erection serves as indication to the attending physician or health 
specialist that a discontinuation or reduction in the amount of trazodone 
administered would be appropriate.