Om P. Khanna

Disorders of micturition Neuropharmacologic basis and results of drug therapy

The clinical use of various pharmacologic agents in problems of micturition is based on the new concepts of intrinsic urethrovesical innervation, presence and regional predominance of autonomic neuroreceptors, and experimental evidence of the effects of various drugs on the bladder and the urethra. A new concept, relating to the processes that control bladder filling and emptying, is coming into being and replacing the traditional concept based on anatomic grounds alone. On the basis of the published data, and from personal experience both experimental and clinical, pharmacologic agents singly or in combination can be effectively and safely used in various problems of micturition such as incontinence (enuresis, stress incontinence in women, postprostatectomy, urgency incontinence), and functional outflow obstruction caused by neurologic or non-neurologic disease processes.

Cholinergic and adrenergic neuroreceptors in urinary tract of female dogs. Evaluation of function with pharmacodynamics.

Our preliminary pharmacodynamic studies on the lower urinary tract of adult female dogs indicate that cholinergic and adrenergic (alpha and beta) neuroreceptors in the urethra appear to coordinate the detrusor and urethral function during micturition. Urethral resistance measured as urethral pressure was easily altered with various pharmacologic agents. However, only bethanechol elicited detrusor response measured as intravesical pressure. The possible clinical usefulness of various drugs is outlined. Our results indicate the therapeutic value of ephedrine sulfate and propranolol in stress urinary incontinence; phenoxybenzamine in neurogenic vesical dysfunction and functional outlet obstruction; phenoxybenzamine plus bethanechol in atonic neurogenic bladder; and imipramine in enuresis.

Effects of phenoxybenzamine hydrochloride on canine lower urinary tract Clinical implications

The results of our study show that phenoxybenzamine hydrochloride, a potent long-acting alpha-adrenergic blocker, has clearly demonstrable effects on urethral function. In a dose of 0.5 mg. per kilogram of body weight it caused a significant lowering of the resting urethral pressure, a decrease in the arterial pressure, and no change in the intravesical pressure. Higher doses caused similar but more pronounced and prolonged effects. The combined use of phenoxybenzamine and bethanechol increased the intravesical pressure and decreased the urethral pressure. It appears that the predominant mechanism of urethral resistance is alpha-adrenergic activity in smooth muscle. A review of the medical literature, our experimental studies, and limited clinical application lead uo to conclude that phenoxybenzamine could be useful in treating neurogenic vesical dysfunction of various types, urethral syndrome, urgency incontinence, functional outlet obstruction with or without vesicoureteral reflux, drug-related obstructive urinary symptoms, partial prostatic obstruction, and ureteral colic. The combination of phenoxybenzamine and bethanechol could be used in managing patients with atony of the bladder of neuropathic or myopathic origin.

Histamine receptors in urethrovesical smooth muscle.

Through the method of pharmacologic antagonism, the contractile effect of histamine was studied simultaneously on isolated smooth muscle preparations obtained from the body and base of the bladder and from the proximal urethra of the guinea pig. Histamine had a contractile effect mediated specifically through H1 receptors, with no H2 activity. This effect was most marked in the body of the bladder, comparatively moderate in the base, and slight in the proximal urethra. It appears that histamine effect is not mediated through either a cholinergic or an adrenergic mechanism. Clinical implications are discussed.

Effects of prostaglandins on vesicourethral smooth muscle of rabbit therapeutic implications

The effects of PGF 2-alpha and PGE2 on the vesicourethral smooth muscle of the rabbit were studied in vitro. PGF2-alpha had potent contractile effects on the bladder body and comparatively less in the bladder base and the proximal urethra. PGE2 contractile effects were two times greater than PGF 2-alpha on the bladder body but minimal or absent on the base and the urethra. The effects of PGF2-alpha and PGE2 seem to be mediated through a prostaglandin receptor as indicated by competitive antagonism of both prostaglandins by N-0164, a synthetic phenyl phosphonate. It also appears that the effects of PGF2-alpha PGE2 may not be mediated through muscarinic, adrenergic, nicotinic, or histaminic receptors or direct smooth-muscle action. The therapeutic implications of PGE2 in the patients with problems of bladder emptying are discussed.

Vesicourethral smooth muscle: Function and relation to structure

The effects of acetylcholine and norepinephrine on the longitudinal and circular smooth muscle strips from the rabbit bladder body, bladder base, and proximal urethra have been studied and compared. Based on the functional responses that were obtained, it was concluded that the vesicourethral structure can consist of three muscular systems. One system consists of the acetylcholine sensitive detrusor, the deep bladder base, and the longitudinal smooth muscle layer of the urethra. The second muscle system comprises the norepinephrine-sensitive detrusor muscle, the superficial bladder base, the bladder neck, and part of the longitudinal urethral smooth muscle. The third muscle system is the circular urethral musculature, unrelated to the detrusor circular muscle.

Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guérin or adriamycin.

We evaluated 155 patients with superficial bladder cancers (Stages Ta, T1, and TIS) and treated them with either intravesical bacillus Calmette-Guérin (Tice strain) (BCG) or doxorubicin hydrochloride (Adriamycin), in a multicenter nonrandomized study. At present 140 of these patients in treatment Groups I and II are being followed up. With additional follow-up, BCG continued to produce a higher percentage of complete remissions (71%) than doxorubicin (54%). The percentage of incomplete remission with BCG (7%) was half that with doxorubicin (14%). Half of the patients whose initial therapy failed had complete remission after additional therapy. However, for patients with recurrence, additional follow-up shows a recurrence rate per 100 patient-months for BCG (1.0) only slightly lower than that for doxorubicin (1.1). The percentage of progressions continued to be higher with BCG (8.5%) than with doxorubicin (5%), but the difference between these results for the two drugs proved slightly less than we reported previously. Of the patients in this study, 2.5 percent (all treated with BCG) required cystectomy. A comparison of the results of our study with those of 13 other studies using BCG to treat bladder cancer indicates that therapy beyond an initial course of 6 weekly treatments increases the percentage of complete response. All of the studies showed that the greatest improvement in percentage of complete response occurred with the second course of treatment. The value of maintenance therapy cannot yet be determined, since few studies have used that protocol. The percentage of patients requiring cystectomy in studies with fewer than 20 treatments was 2.2 times higher than in studies with more than 20 treatments.

Imipramine hydrochloride: pharmacodynamic effects on lower urinary tract of female dogs.

Our study of the pharmacodynamics of imipramine hydrochloride of the female canine lower urinary tract indicates the primary mode of action to be the stimulation of alpha adrenergic neuroreceptors in the bladder neck and urethra. This stimulation results in increased resting urethral pressure, adequate sphincter closure, possibly an increase in the bladder capacity and efficient urinary control. Imipramine had no anticholinergic effect on the bladder and the urethra. It also appears unlikely that in enuretic patients imipramine acts by central augmentation of the adrenergic system. No change was noticed in the intravesical or arterial pressures.

Effects of calcium and verapamil on vesicourethral smooth muscle of rabbits.

Isolated smooth muscle strips from the rabbit bladder body, bladder base, and proximal urethra were contracted with ionic calcium (Ca2+) alone and with the calcium-selective ionophore A23187, acetylcholine, norepinephrine, adenosine triphosphate (ATP), and direct electrical stimulation. The effects of Ca2+ and the calcium entry blocker verapamil on spontaneous muscle activity and on contractions induced by these agonists were examined. Ca2+ -free Tyrodes solution and verapamil, 1 x 10(-7)M and above, relaxed all of the vesicourethral smooth muscle strips. In addition verapamil, 1 x 10(-8) to 1 x 10(-6) M depending on the particular stimulant employed, noncompetitively inhibited smooth muscle contractions elicited by Ca2+, acetylcholine, norepinephrine, ATP, and direct electrical stimulation. It was concluded that transmembrane Ca2+ influx was important not only in the maintenance of tone and spontaneous phasic muscle activity, but also for the activation of contractions induced by all of the stimulants tested. The data also suggest that intracellular Ca2+ fraction(s) participate in the contractile responses to acetylcholine and norepinephrine challenge, but not to contractions evoked by ATP or electricity.

Does bacillus Calmette-Guérin immunotherapy accelerate growth and cause metastatic spread of second primary malignancy?

In our study, 29 of 150 patients with bladder cancer also had other associated primary malignancies, 10 of which were manifested after intravesical treatment with bacillus Calmette-Guérin (BCG). Second primary malignancies developed in 5 of these patients within three months of the start of BCG therapy. All 5 showed acceleration of the second primary tumor, and distant metastatic lesions developed in 4. In the other 5 patients nonbladder primary malignancies developed eight months or more after intravesical BCG therapy started, but did not show acceleration or spread. Twenty patients with other primary malignancies that had developed months to years before intravesical therapy did not show acceleration or spread of those tumors. We have seen enough cases of patients who received intravesical BCG at the time of growth and spread of second primary malignancies to warrant concern. Animal and human studies of BCG use for treatment of malignancy indicate that the temporal relationship between the starting point of tumor development and the starting point of BCG treatment is crucial in determining whether BCG will eradicate or exacerbate the tumor. We have therefore instituted a change in our treatment until the question of whether or not BCG causes the appearance and spread of these second malignancies is answered.