Clinical evaluation of a single daily dose of phenylpropanolamine in the treatment of urethral sphincter mechanism incompetence in the bitch

Abstract

The objective of this retrospective study was to determine the efficacy of a single daily oral dose of phenylpropanolamine (PPA) in the treatment of urethral sphincter mechanism incompetence (USMI) in bitches. Nine bitches diagnosed with USMI were treated with a single daily dose [1.5 mg/kg body weight (BW)] of PPA for at least 1 month. Urethral pressure profiles (UPP) were performed in 7 dogs before treatment and repeated in 4 of them after treatment. Treatment with PPA resulted in long-term continence in 8/9 bitches. One dog did not respond to PPA and was treated surgically later. Recheck UPPs showed a significant increase in maximal urethral closure pressure in the 4 bitches after treatment with PPA compared to before treatment. In conclusion, long-term continence can be achieved in bitches affected with USMI after administration of a single daily dose of PPA (1.5 mg/kg BW).

Introduction

Urethral sphincter mechanism incompetence (USMI) is the most common cause of acquired urinary incontinence in the adult bitch (1,2), and occurs most commonly in middle-aged spayed female dogs. Passive urinary leakage is frequently observed when the dog is asleep or recumbent (1). Several etiologies have been proposed to explain this multifactorial condition, such as decreased urethral tone, caudal displacement of the bladder, a shorter urethra, hormonal deficiency, or obesity. In humans, urethral tone is maintained primarily by activation of postsynaptic α-adrenoreceptors (3). In rabbits and dogs, urethral tone is mediated primarily by a α₁-adrenergic receptor subtype that corresponds to the human α_1c-adrenergic receptor (4,5).

Based on this rationale, α₁-adrenergic receptor agonists [most commonly phenylpropanolamine (PPA) and ephedrine] have been used for the treatment of stress urinary incontinence in women (6–8) and for the treatment of USMI in dogs (9–11). Phenylpropanolamine is a partial α₁-agonist drug with a low intrinsic activity and affinity. The efficacy of ephedrine is slightly less predictable than PPA (12) and, in some dogs, effects on the cardiac and central nervous systems can be more pronounced with ephedrine than with PPA (13–15).

In veterinary medicine, PPA is commercially available as PPA hydrochloride syrup, in an immediate-releasing solution. The current recommended dosage and rate of administration of PPA for the treatment of USMI in the dog is 1 to 1.5 mg/kg body weight (BW) every 8 to 12 h (9,16). The reported success rate associated with this treatment ranges from 85% to 97% continence (9,10,16,17), but a decrease in urethral response associated with recurrence of incontinence can be observed after a prolonged administration of PPA (10). Desensitization of the α-adrenergic receptors has been proposed by several authors to explain this observation (18–20), while others have rejected the hypothesis (21). A study in continent female beagle dogs reported a greater increase in urethral pressure values after single daily administration of PPA at a dosage of 1.5 mg/kg BW, compared to 2 to 3 daily administrations (22). Furthermore, a recent pharmacokinetic and urodynamic study in continent female beagle dogs showed that the urethral resistance was increased after single daily PPA administration, but not when PPA was administered every 6 h during the day, despite higher plasma concentrations following more frequent dosing (23).

The objective of this retrospective study, therefore, was to report the clinical efficacy of PPA administered once daily in bitches affected with USMI.

Materials and methods

Animals

Medical records of bitches presented for urinary incontinence and treated with a single daily dose of PPA between 2004 and 2008 were reviewed. Bitches treated with PPA after a previous surgery of the urinary tract as well as bitches diagnosed with neurological disease were excluded from the study. Only bitches diagnosed with acquired USMI were included.

All bitches had a full physical examination, and diagnosis of USMI was made based on breed, history, laboratory results, diagnostic imaging techniques, and urodynamic examination. Laboratory results included urinalysis (n = 6), urine culture (n = 9), hematology (n = 5), and biochemistry profile (n = 6). Diagnostic imaging techniques included abdominal ultrasound (n = 3), intravenous urography (n = 2), and vaginourethrogram (n = 8). Urodynamic examination consisted of urethral pressure profilometry (UPP) (n = 7) followed in some cases by retrograde cystométrie (n = 4). Cystoscopy was performed in 1 bitch to rule out ureteral ectopia.

Urodynamic examination

Anesthesia was induced with an IV bolus of propofol (Propovet; Abbott Lab, Queenborough, Kent, United Kingdom), 4 mg/kg BW and was maintained with a continuous IV infusion of propofol at a dosage sufficient to maintain a light plane of anesthesia (between 5 and 30 mg/kg/h). The infusion rate was adapted individually to be as low as possible while allowing maintenance of the dog in recumbency. The dogs were then placed in right lateral recumbency (24). Three successive UPPs were then performed as described elsewhere (25). When performed, retrograde filling cystometry at a rate of 10 mL/min was done after the UPP, as previously described (25). The following variables were recorded from the UPP measurements: maximum urethral pressure (MUP), maximum urethral closure pressure (MUCP, the difference between MUP and bladder pressure), and integrated pressure (IP, area under the functional profile length curve, representing urethral resistance). Definitions are in accordance with those of the International Continence Society (26). The functional profile length (FPL) was defined as the length of the urethra along which the urethral pressure exceeds the intra-vesical pressure. The following variables were determined from the cystometric measurements: threshold pressure (bladder pressure at the time of micturition), threshold volume (volume of saline solution infused when micturition reflex was detected), and compliance. Compliance was calculated by:

$$(\text{threshold\hspace{0.17em}volume}-{\text{V}}_0)/(\text{threshold\hspace{0.17em}pressure}-{\text{P}}_0)$$ Equation 1

where: V₀ and P₀ are the bladder volume and bladder pressure, respectively, at the start of cystometry.

Treatment

Bitches were treated with a single daily dose of PPA hydrochloride syrup (Propalin; Vétoquinol, Paris, France), at 1.5 mg/kg BW. The bitches were initially treated for 3 to 4 wk before recheck. If the owner agreed, a recheck UPP was repeated at the time of clinical recheck. The UPP was performed again at various later times. A questionnaire was used for long-term follow-up evaluation by telephone.

Statistics

The influence of treatment on the values of the urodynamic parameters (MUCP, FPL and IP) was studied using the mixed procedure of the SAS statistical software (SAS version 9.1; SAS Institute, Cary, North Carolina, USA). A value of P < 0.05 was considered significant.

Results

Nine spayed female dogs met the inclusion criteria. Members of the following breeds were enlisted: 2 Doberman pinschers, 1 Belgian sheepdog (Groenendael), 1 Gordon setter, 1 malinois sheepdog, 1 Rhodesian ridgeback, 1 Tibetan mastiff, and 2 mixed breed dogs. Ages ranged from 1 to 9 y (mean: 4.6 y). Body weights ranged from 15.5 to 41 kg (mean: 30 kg).

Clinical signs included urine leakage during sleep (n = 7) and/or effort (n = 3). Frequency of urine leakage varied from once to multiple times a day. Duration of clinical signs prior to presentation ranged from 3 mo to 3 y (mean: 16.4 mo). Time interval between neutering and the onset of clinical signs ranged from a few days to 7 y (mean: 23.5 mo). Five bitches became incontinent within 1 y of neutering.

Six bitches had never received any treatment prior to presentation. Three bitches had previously been treated with oestriol without any improvement, and 2 of those 3 had also received PPA (2.5 mg/kg q12h for dog 5 and 0.15 mg/kg q24h for dog 6), but without any success.

Hematologic profiles were available for 5 bitches and all were within normal limits. Biochemistry profiles were available for 6 bitches. Dog 4 had elevated alkaline phosphatases (113 U/L, normal range: 14 to 39 U/L). Dog 5 had elevated total cholesterol (3.59 g/L, normal range: 0.8 to 3.00 g/L). Dog 7 had increased BUN (0.71 g/L, normal range: 0.13 to 0.51 g/L), increased creatinine (15.3 mg/L, normal range: 4 to 15 mg/L), increased alkaline phosphatases (648 U/L), and increased total cholesterol (4.12 g/L, normal range: 0.8 to 3.00 g/L). Abdominal ultrasound of that dog revealed an enlarged and hyperechoic pancreas. The dog developed vomiting and diarrhea 10 d later, associated with an elevation of hepatic enzymes. Hepatic and pancreatic biopsies taken laparoscopically were within normal limits and the dog was treated symptomatically. The owners declined further investigation for the urinary incontinence and the dog was treated with PPA empirically.

Urinalyses were available for 6 bitches and were within normal limits. Urine specific gravity ranged from 1.015 to 1.028. Urine cultures performed in 9 bitches were negative. None of those bitches had received antibiotics prior to urine culture.

Diagnostic imaging techniques used on the 9 dogs included vaginourethrogram, abdominal ultrasound, and intravenous urography. Vaginourethrograms were within normal limits in 7 dogs and revealed a pelvic bladder in 1 bitch. Abdominal ultrasound revealed the presence of sediment in the urinary bladder of dog 5 and an enlarged and hyperechoic pancreas in dog 7. Intravenous urographies were within normal limits.

Urodynamic examination in 7 dogs included UPP in all of them and cystometry in 4 dogs. Bladder compliance ranged from 12.3 and 19.5 mL/cm H₂O (mean: 16.4 mL/cm H₂O). Compliance could not be calculated in dog 6 due to constant urine leakage during cystometry, even with a low volume of infused saline. Besides the UPPs performed prior to treatment, UPPs were repeated after 1 mo of treatment in 4 dogs and performed a third time in 3 dogs. Values of MUCP, FPL, and IP are presented in Table 1. Before treatment, UPP showed a low MUCP and low IP in all 7 bitches (Figure 1a). Mean pretreatment MUCP was 19 ± 9 cm H₂O, mean FPL was 7.8 ± 1.7 cm, and mean IP was 106 ± 61 cm² H₂O. All the dogs were continent at the time of the first recheck UPPs (n = 4). Mean MUCP of the 4 dogs at the first recheck was 31 ± 21 cm H₂O, mean FPL was 7.2 ± 1.6 cm, and mean IP was 110 ± 34 cm² H₂O. When considering those 4 dogs, values of MUCP were significantly increased at the first recheck compared to before treatment (P < 0.05) (Figure 1b). FPL was significantly decreased after treatment compared to before treatment (P < 0.05). The 3 dogs which had a second recheck were continent at the time of the second UPP. Mean MUCP of the 3 dogs at the second recheck UPP was 35 ± 17 cm H₂O, mean FPL was 7.1 ± 1.9 cm, and mean IP was 134 ± 87 cm² H₂O. Integrated pressure was increased at the first recheck in 2 dogs and at the second recheck in 2 dogs compared to before treatment, but that increase was not significant. In the dogs that had a urine specific gravity rechecked, the value did not change after treatment with PPA.

Table 1.

Mean ± standard deviation (s) values of 3 successive UPP measurements in 7 dogs at t₀, t₁, and t₂. Note that dog 2 had only 1 pretreatment urethral pressure profile (no standard deviation)

	Dog
	1	2	3	4	5	6	9
MUCP ± s(cm H2O)
t0	8 ± 0	7	32 ± 15	24 ± 1	18 ± 5	24 ± 0	16 ± 0
t1	22 ± 6	—	—	16 ± 4	—	29 ± 0	72 ± 6
t2	15 ± 11	—	—	39 ± 15	—	48 ± 1	—
FPL ± s (cm)
t0	7.3 ± 0	7.5	9.1 ± 0.7	6.9 ± 0.1	5.7 ± 0.9	10.3 ± 0.1	7.5 ± 0.2
t1	7.4 ± 1.3	—	—	6.6 ± 0.3	—	9.3 ± 0.1	5.4 ± 0.2
t2	6.1 ± 0.4	—	—	6 ± 0	—	9.9 ± 0	—
IP ± s (cm2 H2O)
t0	53 ± 6	81	144 ± 6	80 ± 7	59 ± 6	209 ± 17	75 ± 2
t1	92 ± 6	—	—	78 ± 9	—	152 ± 7	131 ± 5
t2	38 ± 6	—	—	122 ± 17	—	248 ± 1	—

MUCP — maximal urethral closure pressure; FPL — functional profile length; IP — integrated pressure. t₀ — UPP performed before PPA therapy; t₁ — UPP performed at the first recheck (3 to 4 wk); t₂ — UPP performed at the second recheck (2 to 4 mo).

^—not done.

Figure 1.

Urethral pressure profiles of dog 9 before PPA therapy (a), and after 1 mo of PPA therapy at 1.5 mg/kg once a day (b). Note the low maximal urethral pressure before treatment. At the recheck, the dog had received PPA the morning of the UPP. Note the increased maximal urethral pressure responsible for the increased integrated pressure.

Pura: Urethral pressure.

At long-term follow-up, 8 bitches were continent after single daily administration of PPA. In dog 9, PPA administration was discontinued after a few mo and the dog remained continent without any medication. Five bitches (dogs 2, 3, 6, 7, and 8) remained on PPA once a day and were continent 4 to 36 mo after the start of the treatment (mean: 20.8 mo). Dog 1 received PPA every other day after the first recheck and remained continent at that dosage until 4.4 y after starting PPA therapy. Dog 4 received PPA every other day after the first recheck then every 3 d after the second recheck and remained continent for a few mo. She then had to return to the initial dosage of PPA once a day to remain continent. Dog 5 did not improve with PPA therapy and was treated surgically later on. No side effects were reported in any dog.

Discussion

This retrospective study demonstrates the efficacy of the administration of a single daily dose of PPA to treat bitches with USMI. Phenylpropanolamine was effective in maintaining continence in 88.9% of the affected bitches. Only 1 bitch failed to respond to medical treatment and was therefore treated surgically. This success rate is comparable to those in previous studies reporting a continence rate of 85% to 97% after administration of PPA 2 or 3 times a day (9,10,16,17).

The rationale for choosing our dosage regimen is based on previous experimental studies demonstrating the urodynamic advantage of a single daily administration of PPA, with a greater increase in urethral pressure values observed after a single administration of PPA, compared with 2 to 3 administrations daily (22). This observation was confirmed in a recent pharmacokinetic and urodynamic study in continent female beagles, in which a significant increase in urethral resistance was observed at T_max after 1 wk of once daily administration, but not when PPA was administered every 6 h during the day, despite higher plasma concentrations following more frequent dosing (23). This finding could potentially be due to desensitization of the urethral α-adrenergic receptors, which has been described in dogs treated multiple times daily with PPA or in dogs receiving prolonged treatment (10). Desensitization of urethral α-adrenergic receptors is controversial. Prolonged administration of α-adrenoreceptor agonists may cause a right shift in the dose-response curve and reduce the maximum response (18–20,27). Other investigators have, however, rejected that finding and contended that repetitive administration of an agonist at a dose that significantly increases the urethral pressure does not desensitize functional urethral α-adrenergic receptors in vivo (21). In the present study, 7 dogs remained on long-term PPA therapy. Only 1 bitch developed incontinence while receiving PPA every 3 d. Whether the degree of “desensitization” is decreased with single daily administrations of PPA compared with multiple daily administrations is still unknown.

The reason why bitches remain continent between PPA administrations during a single daily administration protocol is unknown. Indeed, it has been shown that plasma concentration in PPA and the urethral resistance increase significantly 2 h after PPA administration, and then decrease progressively to reach baseline values after 24 h in healthy beagle dogs. The maximal plasma concentration (C_max ) was reached 2 h after PPA administration (T_max ) and the half-life was 4 h (23).

An increase in IP values was observed in only 2 dogs after 1 mo of treatment with a single daily dose of PPA. This does not corroborate the results from previous experimental studies (22,23). Because of the retrospective nature of the present study, the exact time frame between the PPA administration and the UPP was unknown. It may be possible that the UPP was performed before administration of the daily dose of PPA. As previously reported (23), the time at which the UPP is performed in regards to the PPA administration may modify the urodynamic parameters. After a single administration of PPA, a significant increase in urethral resistance was observed for up to 8 h, followed by a rapid decrease (23). Variations in the depth of anesthesia between various dogs and between various measurements in the same dog could also be responsible for variations in urodynamic parameters, although the same anesthetic protocol was always used with the goal of maintaining a light and stable depth of anesthesia. The range of our propofol infusion rates is quite large because rates had to be adapted individually depending on the depth of anesthesia obtained. The rate had to be increased if the dog was not willing to stay in lateral recumbency or was moving too much. However, in a study comparing the effect of propofol and sevoflurane on the urethral pressure profile in healthy female dogs, the mean maximum urethral closure pressure of awake dogs was not significantly different from that of dogs anesthetized with propofol at rates of 0.4, 0.8, and 1.2 mg/kg/min, which are still higher than our infusion rates (0.08 to 0.5 mg/kg/min) (28).

In a study comparing the effect of phenylpropanolamine and pseudoephedrine on the urethral pressure profile of incontinent female dogs, there was a significant increase in the MUCP (17.8 +/− 9.48 cm H₂O pre-treatment versus 24.9 +/− 12.7 cm H₂O post-treatment) and IP (44.1 +/− 22.2 cm² H₂O pre-treatment versus 76.9 +/− 42.3 cm² H₂O post-treatment) after 4 wk of PPA therapy (1.5 mg/kg, PO, q8h), whereas there was no significant change in the FPL (6.6 +/− 1.64 cm pre-treatment versus 7.36 +/− 3.13 cm post-treatment) after 4 wk of PPA (29). Those results are in accordance with the results herein for the increased MUCP after PPA, but not for the increased IP, which was not observed in our study. Possible explanations may be the timing of UPP measurement, variability in the depth of anesthesia, or simply variability between UPP measurements in such a small number of dogs.

Rechecks were usually scheduled 3 to 4 wk after starting PPA therapy. It has been shown that maximum urodynamic effects of PPA are observed by 7 d of treatment, with no further increases in measured variables after 2 wk of treatment (22). Therefore, dogs could have been rechecked earlier, but 3 to 4 wk was judged to be more convenient for owners.

Due to the retrospective nature of this study, the efficacy and the values of urodynamic parameters were not compared between different dosage regimens. Whether PPA is more efficient clinically when used once a day compared to 2 or 3 times a day is therefore unknown. However, a single daily administration is obviously more convenient and less expensive for owners.

Side effects were not recorded in any dogs in this study. The main side effects of PPA reported in women and experimentally in dogs and rabbits include hyperexcitability and arterial hypertension, although they have been rarely reported clinically at recommended dosage in bitches (9,10,13,30–32). Recent studies, however, have reported a significant increase in arterial pressure and a compensatory decrease in heart rate in conscious healthy beagle dogs after administration of PPA once or 3 times daily (22). Drugs that are capable of inducing tachycardia in animals receiving α-adrenergic agents, therefore, should be used with caution, particularly if arterial blood pressure increases. Alpha-adrenergic agents should also be used with caution in dogs susceptible to exaggerated vagal tone (such as brachycephalic breeds), because such dogs could over-respond to arterial hypertension and have vagally mediated syncope (33). It must be acknowledged that direct or indirect arterial pressure measurements were not recorded in this retrospective study.

The study is limited by its retrospective nature and the small number of dogs, especially the limited number of UPPs performed after treatment with PPA. Statistical data, therefore, have a limited power and should be interpreted with caution.

In conclusion, it appears that single daily administration of PPA at a dosage of 1.5 mg/kg BW resulted in long-term continence in 8 out of 9 bitches suffering from USMI. The efficacy of such a regimen, however, should be confirmed on a larger number of dogs. This administration regimen would be obviously more convenient and less expensive for owners. A prospective study comparing the urodynamic effects and the clinical efficacy of PPA administered once versus 2 or 3 times a day in a larger number of dogs would also be useful. CVJ