Recent Developments in On-Demand Voiding Therapies

Abstract

One cannot survive without regularly urinating and defecating. People with neurologic injury (spinal cord injury, traumatic brain injury, stroke) or disease (multiple sclerosis, Parkinson's disease, spina bifida) and many elderly are unable to voluntarily initiate voiding. The great majority of them require bladder catheters to void urine and "manual bowel programs" with digital rectal stimulation and manual extraction to void stool. Catheter-associated urinary tract infections frequently require hospitalization, whereas manual bowel programs are time consuming (1 to 2 hours) and stigmatizing and cause rectal pain and discomfort. Laxatives and enemas produce defecation, but onset and duration are unpredictable, prolonged, and difficult to control, which can produce involuntary defecation and fecal incontinence. Patients with spinal cord injury (SCI) consider recovery of bladder and bowel function a higher priority than recovery of walking. Bladder and bowel dysfunction are a top reason for institutionalization of elderly. Surveys indicate that convenience, rapid onset and short duration, reliability and predictability, and efficient voiding are priorities of SCI individuals. Despite the severe, unmet medical need, there is no literature regarding on-demand, rapid-onset, short-duration, drug-induced voiding therapies. This article provides in-depth discussion of recent discovery and development of two candidates for on-demand voiding therapies. The first, [Lys³,Gly⁸,-R-γ-lactam-Leu⁹]-NKA_(3-10) (DTI-117), a neurokinin₂ receptor agonist, induces both urination and defecation after systemic administration. The second, capsaicin (DTI-301), is a transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor agonist that induces defecation after intrarectal administration. The review also presents clinical studies of a combination drug therapy administered via iontophoresis and preclinical studies of neuromodulation devices that induce urination and defecation. SIGNIFICANCE STATEMENT: A safe and effective, on-demand, rapid-onset, short-duration, drug-induced, voiding therapy could eliminate or reduce need for bladder catheters, manual bowel programs, and colostomies in patient populations that are unable to voluntarily initiate voiding. People with spinal injury place more importance on restoring bladder and bowel control than restoring their ability to walk. This paradigm-changing therapy would reduce stigmatism and healthcare costs while increasing convenience and quality of life.

Graphical abstract

Fig. 1.

Effects of LMN-NKA on colorectal activity. (A) Physiograph of bladder pressures in response to ascending doses of LMN-NKA (mg/kg i.v.) recorded under isovolumetric conditions in anesthetized acute spinal (T₁₀) rats. (B and C) Bladder voiding pressure (B) and voiding efficiency (C) in response to ascending doses of LMN-NKA recorded under voiding cystometry conditions in anesthetized spinal-intact rats. The open column P indicates “physiological” bladder voiding pressure during voiding in response to bladder filling before the onset of drug dosing. Black bars indicate bladder pressure responses and voiding efficiency to vehicle (V) and LMN-NKA when the bladder volume was set to 70% bladder capacity. *Indicates significantly different from V, P < 0.05 (adapted from Figs. 2A and 4, Kullmann et al., 2017).

Fig. 2.

Effects of LMN-NKA on colorectal activity. (A) Physiograph of colorectal pressure in an anesthetized rat showing response to LMN-NKA (10 μg/kg i.v.). (B and C) Colorectal pressure area under the curve (AUC) (B) and duration of elevated colorectal pressure (C) in response to cumulative ascending doses of LMN-NKA in anesthetized rats. *Indicates a difference compared with vehicle (V), P < 0.05 (adapted from Fig. 5, Kullmann et al., 2017).

Fig. 3.

Increases in isovolumetric bladder pressure after intravenous, subcutaneous, intramuscular, intranasal, or sublingual routes of administration of LMN-NKA. (A–E) Physiograph tracings of bladder pressure with administration of LMN-NKA via the various routes to individual rats. (F–J) Cumulative dose-response relationships for effects of LMN-NKA on increases in bladder pressure in anesthetized acute spinal (T₁₀) rats (4–21 per group). Intranasal and sublingual dosing were incremental increases due to formulation properties that restricted an exact dose based on body weight. *P < 0.05 compared with vehicle, Dunnett’s multiple comparison test (adapted from Figs. 1 and 2, Marson et al., 2018).

Fig. 4.

Urination (A panels) and defecation (B panels) recorded from awake spinal-intact rats in metabolism cages after vehicle (white bars), LMN-NKA 10 μg/kg subcutaneous (gray bars), and LMN-NKA 100 μg/kg subcutaneous (black bars) administered twice daily for 5 consecutive weeks. *Indicates a significant difference compared with vehicle and 10-μg dose; # indicates a significant difference compared with vehicle (adapted from Fig. 1, Marson et al., 2020).

Fig. 5.

Physiograph tracings of arterial pressure (top) and colorectal pressure (bottom) showing that LMN-NKA (100 μg/kg i.v.) induced hypotension and colorectal contractions and that the NK₁R antagonist CP-99,994 (1 mg/kg i.v.) blocked the LMN-NKA–induced hypotension but did not block the LMN-NKA–induced colorectal contractions in an anesthetized monkey (adapted from Fig. 4, Rupniak et al., 2018a).

Fig. 6.

Plasma concentrations of DTI-117 after intramuscular dosing in conscious minipigs (n = 6 for each dose). Doses of 0.1 mg/kg (open circles) or 1 mg/kg (closed circles) were administered at time = 0. Values are mean + S.E.M. (for methods, see Supplemental Material 1).

Fig. 7.

(A) Physiograph tracings showing arterial, bladder, and colorectal pressure responses to intramuscular administration of 100 μg/kg DTI-117 in an anesthetized dog. Notice robust response of colorectum and bladder and absence of hypotension. (B) Urination, defecation, and emesis response rates recorded in awake dogs after intramuscular administration of vehicle (one male, one female) or DTI-117 (two males, two females) twice daily for 14 days with 30-minute observations once per day on weekdays (i.e., 28 injections and 10 observation periods per animal). (C) Data pooled from a total of 23 male and 23 female awake dogs administered vehicle (saline) or DTI-117 once or twice per day with injections 4 hours apart. Injection sequences were repeated in dogs after at least 3 days between dosing. Animals included in Panel B graphs are included in Panel C. The “n” above each column refers to the number of observations conducted at each dose, including repeated dosing to the same dog. No differences were noted between sexes or between the different dosing protocols. Animals were observed for at least 30 minutes or until dogs fully recovered from adverse events (for methods, see Supplemental Material 2).

Fig. 8.

(A and B) Physiograph tracings from an anesthetized spinal-intact (A) and an acute T₄ spinal cord–injured (aSCI) rat (B) showing responses of colorectal and arterial pressure to cumulative ascending concentrations of intrarectal capsaicin. (C and D) Concentration response graphs showing mean peak colorectal pressure (C) and AUC of colorectal pressure (D) in anesthetized rats (six males, 6 females). (E) Capsaicin-induced defecation response rates after single intrarectal administration of various concentrations of capsaicin to awake rats. *Indicates a statistical difference from vehicle, P < 0.001. Percentages are in parentheses. *Indicates responder rates significantly different to vehicle, P < 0.05 (for methods, see Supplemental Material 3).

Fig. 9.

Desensitization to repeated intrarectal administration of capsaicin in anesthetized acute T₄ SCI (aSCI) rats. (A) Physiograph tracings from an anesthetized rat that was administered 200 μl of a 1% capsaicin solution intrarectally three times. (B and C) Changes in colorectal peak pressure and AUC, respectively, produced by the first intrarectal capsaicin instillation and a second instillation 60 minutes after the first. *Indicates P < 0.05 compared with the previous response to capsaicin (for methods, see Supplemental Material 3).

Fig. 10.

Physiograph tracings showing blockade of capsaicin effects by the muscarinic cholinergic receptor antagonist atropine but not by the NK2 receptor antagonist GR 159897. (A) Administration of the muscarinic cholinergic receptor agonist bethanechol (A1) produces colorectal contractile activity. After administration of atropine (0.5 mg/kg), colorectal contractions in response to capsaicin (A2) and bethanechol (A3) are completely blocked. Atropine has no effect on colorectal contractions to the NK2 receptor agonist LMN-NKA (A4). (B) Administration of LMN-NKA produces colorectal contractile activity (B1). After administration of GR 159897, colorectal contractions to capsaicin are unaffected (B2), but contractions produced by LMN-NKA (B3) are completely blocked (for methods, see Supplemental Material 3).

Fig. 11.

Physiograph tracings showing induction of colorectal contractions in response to intrarectal instillation of three other TRPV1R agonists: oleoyldopamine (OLDA), oleoylethanolamide (OEA), and nonivamide. The wide black arrows indicate when a cotton plug saturated with each agonist is inserted into the rectum and the concentration of each agonist. The black downward arrows indicate when the cotton plug was removed. *Indicates that the colorectal balloon catheter was expelled (for methods, see Supplemental Material 3).

Fig. 12.

Reproducibility of capsaicin-induced defecation during repeated administration tested on 2 consecutive days each week for 3 weeks. (A–C) Pooled data across all 6 days of observation recording number of fecal pellets (A), fecal weight (B), and latency to onset of defecation (C) for each concentration of capsaicin (n = 6 rats per group). (D and E) Each individual day’s observation recording number of fecal pellets (D) and fecal weight (E) in the same groups of animals plotted in A–C. Notice that each successive day’s responses are the same as the previous day but across 3 weeks all responses (including vehicle) declined, suggesting that the animals were still being habituated. *Indicates a statistically significant difference from vehicle (for methods, see Supplemental Material 4).

Fig. 13.

(A and B) Physiograph tracings of colorectal pressure in a rat response to 2% capsaicin (black arrows) in a TEW (10% Tween-80, 9.5% ethanol, 80.5% water) solution–soaked cotton ball (A) or in a cocoa butter suppository (B). Notice similar responses. (C and D) Graphs of plasma concentrations of capsaicin after instillation of capsaicin in a TEW solution (C) or in a cocoa butter suppository (D) in three male and three female anesthetized rats. No sex differences were found (for methods, see Supplemental Material 4).