Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4–10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats

Abstract

Purpose To determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor (NK2 receptor) agonist, Lys5, MeLeu9, Nle10-NKA(4–10) (LMN-NKA). Methods Cystometry and colorectal pressure measurements were performed in urethane anesthetized, intact and acutely spinalized, female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. Results LMN-NKA (0.1–300 µg/kg) produced dose dependent, rapid (< 60 s), short duration (< 15 min) increases in bladder pressure. In intact rats, doses above 0.3–1 µg/kg induced urine release (voiding efficiency of ~ 70% at ≥ 1 µg/kg). In spinalized rats, urine release required higher doses (≥ 10 µg/kg) and was less efficient (30–50%). LMN-NKA (0.1–100 µg/kg) also produced dose dependent increases in colorectal pressure. No tachyphylaxis was observed, and the responses were blocked by an NK2 receptor antagonist (GR159897, 1 mg/kg i.v.). No obvious cardiorespiratory effects were noted. Conclusions These results suggest that rapid-onset, short duration, drug-induced voiding is possible in acute spinal and intact rats with intravenous administration of an NK2 receptor agonist. Future challenges remain in regards to finding alternative routes of administration that produce clinically significant voiding, multiple times per day, in animal models of chronic SCI.

Underactive Bladder; Review of Progress and Impact From the International CURE-UAB Initiative

“…A Neurokinin-2 receptor (NK2R) agonists are being developed by Dignified as an "on-demand, rapid-onset, short duration, drug-induced, voiding therapy" for patients that require catheterization and do not have BOO [17]. The lead candidate is DTI-100, a short amino acid peptide analog of neurokinin A. DTI-100 produces highly efficient voiding in under 5 minutes of intravenous or subcutaneous administration in > 85% of awake preclinical models including rats, dogs, minipigs, and monkeys.…”

Detrusor underactivity in women: A current understanding

“…It has been well‐documented that endogenous peptide, neurokinin A (NKA), and other neurokinin‐2 (NK2) agonists have the ability to contract bladder and colon smooth muscle preparations from various species, including human . A new NK2 agonist is being developed by Dignify as an “on‐demand, rapid‐onset, short‐duration, and drug‐induced voiding therapy” for patients who require catheterization but do not have bladder outlet obstruction . In a recent study, Kullmann et al found that systemic intravenous administration of an NK2 agonist‐triggered bladder contractions and urine release in both intact rats and those with complete spinal cord transection at the T9‐T10 level when the bladder was filled to a sub‐threshold voiding volume.…”

New technology assessment and current and upcoming therapies for underactive bladder

“…Peptide NK2R agonists may provide an on‐demand voiding therapy in that is both rapid onset, yet short in duration thereby allowing an individual to control when micturition (and/or defecation) occur and reduce or eliminate the need for catheterization (and a bowel program). Although animals studies (to date) have not detected clinically significant increases in bladder pressure (i.e., >40 mm Hg) during voiding cystometry or under bladder isovolumetric cystometry conditions in acute spinal rats, voiding pressures were briefly elevated (up to 60 mm Hg) in anesthetized rats with an intact spinal cord . Studies in individuals with bladder outlet obstruction or detrusor sphincter dyssynergia are planned for these special populations.…”

“…Dignify is developing neurokinin2 receptor (NK2R) agonists as "on-demand, rapid-onset, short-duration, drug-induced, voiding therapy" for individuals who require catheterization and do not have BOO. 12 The lead candidate (DTI-100) is a seven amino acid peptide analog of neurokinin A that produces highly efficient voiding (VE > 85%) within 5 min of intravenous (i.v.) or subcutaneous (s.c.) dosing in >85% of awake rats, dogs, minipigs, and monkeys at doses that are surprisingly well tolerated (Table 3).…”

“…Although animals studies (to date) have not detected clinically significant increases in bladder pressure (i.e., >40 mm Hg) during voiding cystometry or under bladder isovolumetric cystometry conditions in acute spinal rats, voiding pressures were briefly elevated (up to 60 mm Hg) in anesthetized rats with an intact spinal cord. 12 Studies in individuals with bladder outlet obstruction or detrusor sphincter dyssynergia are planned for these special populations.…”