Inhibitor Report for: Distigmine

AIM: The efficacy of cholinergic drugs for reduction of post-voiding residual volume (PVR) in patients with underactive bladder is still controversial. This study was performed to examine whether cholinergic drugs have such an effect on PVR.
METHODS: Patients with underactive bladder treated for more than two months with cholinergic drugs, which were later discontinued, were extracted retrospectively based on their charts. The changes in PVR, cholinesterase activity (ChE), renal function, and voiding function before and after discontinuation of cholinergic drugs were reviewed and analyzed.
RESULTS: Twenty-nine patients were included in this study. In multiple linear regression analysis, the discontinuation of distigmine bromide (DB) was indicated as a significant covariate for PVR increase and ChE increase, while bethanechol chloride (BC) was not a significant covariate. The increase in ChE was significantly correlated with both PVR and voided volume after discontinuation of cholinergic drugs. CONCLUSION: DB could reduce PVR via a decrease in ChE. However, BC at doses up to 60 mg did not reduce PVR. DB may be recommended for the reduction of PVR in patients with underactive bladder.

A randomized phase-I study was performed in a clinical setting in 24 healthy young male subjects, aged 20 to 35 years, to investigate the influence of Ubretid on AChE inhibition following oral and i.m. administration in one of three medication schemes: -single oral (10 mg) and i.m. (0.5 mg) medication (randomized crossover), -multiple oral dosing (5 mg on trial days 1, 2, 3, 5, 7, 9, 11 and 13), -multiple oral dosing (5 mg on trial days 5 to 14) with initial i.m. loading doses (0.5 mg i.m. on trial days 1, 2 and 4). The multiple dosing schemes were chosen as they are both frequently used in clinical practice. The results of the AChE inhibition after Ubretid can be summarized as follows: repeated Ubretid administration as used in this trial did not lead to a cumulation of AChE inhibition. Statistical testing (page test) of maximum AChE inhibition on the last medication days gave no indication of an increased AChE inhibition towards the end of treatment. Compared with the i.m. administration, the Ubretid tablet had a bioavailability of 2.2 +/- 1.1% (mean +/- STD).

Distigmine is a cholinesterase (ChE) inhibitor used for the treatment of detrusor underactivity in Japan. Distigmine's pharmacological effects are known to be long-lasting, but the duration of its effect on urinary bladder contractile function has not been fully elucidated. The present study aimed to determine these effects in relation to the plasma concentrations of distigmine and its inhibition of ChE activities in blood, plasma, and bladder tissue. Intravesical pressures were recorded in anesthetized guinea-pigs for 12 h after the intravenous administration of saline or distigmine (0.01-0.1 mg/kg). Plasma distigmine concentrations were measured by liquid chromatograph-tandem mass spectrometry (LC-MS/MS), while ChE activities were assayed using 5,5'-dithiobis(2-nitrobenzoic acid). Distigmine (0.1 mg/kg) significantly increased the maximum intravesical pressure at micturition reflex for 12 h post-administration. In contrast, plasma distigmine was only detectable for 6 h post-administration in these animals and a one-compartment model calculated an elimination half-life of 0.7 h. However, bladder and blood acetylcholinesterase activities were significantly inhibited for 12 h after distigmine administration, although plasma ChE activities were not affected. The pharmacodynamic effects of distigmine thus persisted after its elimination from the circulation, indicating that it may bind to bladder acetylcholinesterase, producing sustained enzyme inhibition and enhancement of bladder contractility.

Distigmine bromide (distigmine), a reversible, long-lasting cholinesterase (ChE) inhibitor, is used for the treatment of underactive bladder in Japan and has been shown to potentiate urinary bladder (UB) contractility. We studied the duration of distigmine's potentiating effects on acetylcholine (ACh)-induced UB contraction and its inhibitory effects on ChE activity, and compared that with those of other ChE inhibitors (neostigmine, pyridostigmine, and ambenonium). The duration of potentiating/inhibitory effects of ChE inhibitors, including distigmine, on ACh-induced guinea pig UB contraction/ChE activity was evaluated for 12 h following washout. Dissociation rate constants (k) of the inhibitors were also tentatively calculated based on the time courses of their ChE inhibitory effects. The potentiating effect of distigmine (10-6 M) on ACh-induced UB contraction and its inhibitory effect on ChE activity were significantly sustained 12 h after washout. The potentiating effect of other ChE inhibitors on ACh-induced UB contraction, however, was sustained only until 3 h after washout. The ChE inhibitory effects of these inhibitors dissipated in a time-dependent manner after washout, with more than 75% of ChE activity restored by 4 h after washout. The k values of ChE inhibitors approached 0.50 h-1, except for distigmine, where k could not be determined. Compared with that of other ChE inhibitors, the potentiating effect of distigmine on UB contractile function was significantly more sustainable following washout, which was likely associated with its corresponding long-lasting ChE inhibitory effect. Distigmine may associate more strongly with UB ChE than other ChE inhibitors, which would partly explain its sustained effects.

Distigmine bromide (distigmine) is a reversible carbamate group cholinesterase (ChE) inhibitor. Although mainly used clinically for the treatment of myasthenia gravis, distigmine is also indicated for detrusor underactivity in Japan. According to the pharmacological classification of distigmine, its therapeutic effect against detrusor underactivity appears to be produced by enhanced urinary bladder smooth muscle (UBSM) contractility due to an increased concentration of acetylcholine between parasympathetic nerve endings and UBSM cells. However, ATP as well as acetylcholine is also released from parasympathetic nerve endings that dominate UBSM. The present study was thus carried out to investigate the potentiating effects of distigmine on the two UBSM contractile components in response to parasympathetic nerve stimulation induced by electrical field stimulation (EFS). In isolated guinea pig UBSM tissues, EFS (1-16Hz) produced tetrodotoxin-sensitive, frequency-dependent contractions. The contractile responses to EFS were largely diminished by atropine (10-6M), and the remaining contractile components in the presence of atropine were virtually abolished by alpha,beta-methylene adenosine triphosphate (alpha,beta-mATP) (10-4M). Distigmine (10-6M) significantly potentiated EFS-induced contractile components generated in the presence of alpha,beta-mATP (10-4M), but did not potentiate EFS-induced contractile components generated in the presence of atropine (10-6M). These findings clearly indicate that distigmine strongly potentiates UBSM contraction selectively induced by parasympathetic nerve-derived acetylcholine, suggesting a potential mechanism by which distigmine restores detrusor underactivity.

To elucidate the mechanism whereby distigmine, an underactive bladder remedy, potentiates urinary bladder contractions long-lastingly, the inhibition of recombinant human acetylcholinesterase (rhAChE) by distigmine was investigated. A centrifugal ultrafiltration device, Nanosep(R) 10K, was used to separate rhAChE and a bound inhibitor from an unbound inhibitor, reaction substrate, and reaction product. This allowed the same aliquot of rhAChE to be repeatedly assayed for up to 48 h to confirm the long-lasting binding of an inhibitor. Cholinesterase (ChE) inhibitors, distigmine, pyridostigmine, neostigmine, and ambenonium, were tested. The dissociation rate constant (kdiss) and dissociation half-life (t1/2) of each inhibitor were determined based on the changes in rhAChE activity. Within 2-4 h after removing pyridostigmine, neostigmine, or ambenonium, the rhAChE activity was restored to the control levels. The kdiss values for pyridostigmine, neostigmine, and ambenonium were calculated to be 0.51+/-0.05, 0.66+/-0.03, and 1.41+/-0.08 h-1, and the t1/2 values were calculated to be 1.36, 1.05, and 0.49 h, respectively. With distigmine, the rhAChE activity initially dropped to 17% of that in the control and then slowly recovered to only 50% by 48 h after drug removal. The kdiss and t1/2 values of distigmine were calculated to be 0.012+/-0.001 h-1 and 57.8 h, respectively. Based on the t1/2 values, distigmine was judged to dissociate from acetylcholinesterase (AChE) 40-120-fold slower than the other ChE inhibitors did. This may explain the long-lasting potentiation of urinary bladder contractions and motility by distigmine as a treatment for an underactive bladder.

A 54-year-old female experienced rapid respiratory failure while being transported in an ambulance to our emergency department for evaluation and management of constipation and abdominal pain. The patient was on treatment with distigmine bromide for postoperative urination disorder and magnesium oxide for constipation. Increased salivary secretions, diminished respiratory excursion, type 2 respiratory failure (PaCO2 : 65 mmHg), low serum cholinesterase, and hypermagnesemia were detected. Imaging studies revealed that the patient had bilateral aspiration pneumonia, fecal impaction in the rectum, and a distended colon causing ileus. The patient was mechanically ventilated and was weaned off the ventilator on day 3. Therapeutic drug monitoring after discharge revealed that the serum level of distigmine bromide on admission was markedly elevated (377.8 ng/mL vs. the normal therapeutic level of 5-10 ng/mL). Distigmine bromide induced a cholinergic crisis with a resultant increase in airway secretions and respiratory failure. In this particular case, orally administered distigmine bromide was excessively absorbed because of prolonged intestinal transit time secondary to fecal impaction and sluggish bowel movement; this caused a cholinergic crisis and hypermagnesemia contributing to respiratory failure. Clinicians should be aware that bowel obstruction in a patient treated with distigmine bromide can increase the risk of a cholinergic crisis.

BACKGROUND/AIMS: To evaluate the effects of silodosin (alpha1A-adrenoceptor antagonist) and distigmine (acetylcholinesterase inhibitor), alone or in combination, on voiding dysfunction in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model, by pressure flow study.
METHODS: Male ZDF rats were anesthetized with urethane and a catheter was implanted into the bladder through the dome. Saline was continuously infused into the bladder at 6 ml/h to induce the micturition reflex. Intravesical pressure and micturition volume were recorded continuously and various urodynamic parameters were calculated using a waveform analysis system.
RESULTS: Increased bladder capacity, residual volume, and urethral resistance and decreased maximum detrusor contraction velocity and urine flow rate, considered to be detrusor underactivity-like symptoms, were observed in ZDF rats. Although both silodosin and distigmine improved impaired voiding function, administration of both drugs in combination was more effective than either drug alone.
CONCLUSIONS: ZDF rats showed symptoms suggestive of detrusor underactivity, and silodosin tended to ameliorate these symptoms in ZDF rats. These results suggested that an alpha1A-adrenoceptor antagonists may be effective against the voiding disorder accompanying not only bladder outlet obstruction but also deficiency of bladder function. Moreover, combined administration of an alpha1A-adrenoceptor antagonist with an acetylcholinesterase inhibitor may have additive efficacy in clinical use. (c) 2015 S. Karger AG, Basel.

AIM: The efficacy of cholinergic drugs for reduction of post-voiding residual volume (PVR) in patients with underactive bladder is still controversial. This study was performed to examine whether cholinergic drugs have such an effect on PVR.
METHODS: Patients with underactive bladder treated for more than two months with cholinergic drugs, which were later discontinued, were extracted retrospectively based on their charts. The changes in PVR, cholinesterase activity (ChE), renal function, and voiding function before and after discontinuation of cholinergic drugs were reviewed and analyzed.
RESULTS: Twenty-nine patients were included in this study. In multiple linear regression analysis, the discontinuation of distigmine bromide (DB) was indicated as a significant covariate for PVR increase and ChE increase, while bethanechol chloride (BC) was not a significant covariate. The increase in ChE was significantly correlated with both PVR and voided volume after discontinuation of cholinergic drugs. CONCLUSION: DB could reduce PVR via a decrease in ChE. However, BC at doses up to 60 mg did not reduce PVR. DB may be recommended for the reduction of PVR in patients with underactive bladder.

It is not uncommon for patients with spinal cord injury to have both detrusor overactivity during the storage phase and detrusor underactivity during the voiding phase. However, there has been no information about the efficacy of combined treatment with cholinesterase inhibitors and anti-muscarinic agents for this condition. Therefore, the effect of co-administration of distigmine bromide (a cholinesterase inhibitor) and propiverine hydrochloride (an anti-muscarinic agent) on bladder activity was examined in rats with spinal cord injury. Rats were anesthetized with isoflurane and the lower thoracic spinal cord was transected. The bladder was emptied by abdominal compression twice a day for 14 days after surgery. A total of 4 weeks after surgery, the animals were anesthetized with urethane, and the effect of intravenous injection of distigmine (0.01-1 mg/kg) followed by propiverine (1 mg/kg) on continuous cystometry parameters was examined. After injection of distigmine (0.1 and 1 mg/kg), the maximum bladder contraction pressure was significantly increased, and the duration of bladder contraction and the interval between bladder contractions were significantly prolonged. The baseline bladder pressure was not changed by injection of distigmine. After the addition of propiverine, the interval between bladder contractions was significantly further prolonged without any change of the maximum contraction pressure, baseline pressure or duration of bladder contraction. The residual volume after voiding bladder contraction was less than 0.1 mL in all animals. In conclusion, co-administration of distigmine with propiverine might improve both bladder underactivity during the voiding phase and bladder overactivity during the storage phase.

Distigmine bromide (3, 3'-[hexamethylenebis (methyliminocarbonyloxy)] bis (1-methylpyridinium) dibromide), an acetylcholinesterase (AChE) inhibitor, produced a time-dependent and dose-dependent increase in acetylcholine (ACh) levels in the medial prefrontal cortex of rats. The overt cholinergic behaviours, such as tremor, fasciculation and lacrimation, were also elicited by distigmine bromide. The onset and duration of these behaviours were reflected in the microdialysis data showing that distigmine bromide enhances cholinergic neurotransmission in rat brain. The dose of distigmine bromide eliciting increase in ACh in the medial prefrontal cortex of rats correlated well with its dose for the induction of the cholinergic behaviours. Furthermore, distigmine bromide was an equipotent inhibitor of AChE and butyrylcholinesterase (BuChE) activities in the present study. From these findings, it is suggested that distigmine bromide may produce centrally mediated behavioural signs by increasing the ACh levels in the brain, resulting from its AChE and BuChE inhibitions.

INTRODUCTION: Distigmine, a long-acting anti-cholinesterase, is associated with side effects such as Parkinsonism, cholinergic crisis, and rhabdomyolysis. We report a spinal cord injury patient, who developed marked hydronephrosis and hydroureter after distigmine therapy, which led to a series of complications over subsequent years. CASE PRESENTATION: A 38-year-old male developed T-9 paraplegia in 1989. Intravenous urography, performed in 1989, showed normal kidneys, ureters and bladder. He was prescribed distigmine bromide orally and was allowed to pass urine spontaneously. In 1992, intravenous urography showed bilateral marked hydronephrosis and hydroureter. Distigmine was discontinued. He continued to pass urine spontaneously. In 2006, intravenous urography showed moderate dilatation of both pelvicalyceal systems and ureters down to the level of urinary bladder. This patient was performing self-catheterisation only once a day. He was advised to do catheterisations at least three times a day. In December 2008, this patient developed haematuriawhich lasted for nearly four months.. He received trimethoprim, then cephalexin, followed by Macrodantin, amoxicillin and ciprofloxacin. In February 2009, intravenous urography showed calculus at the lower pole of left kidney. Both kidneys were moderately hydronephrotic. Ureters were dilated down to the bladder. Dilute contrast was seen in the bladder due to residual urine. This patient was advised to perform six catheterisations a day, and take propiverine hydrochloride 15 mg, three times a day. Microbiology of urine showed Klebsiella oxytoca, Pseudomonas aeruginosa, and Enterococcus faecalis. Cystoscopy revealed papillary lesions in bladder neck and trigone. Transurethral resection was performed. Histology showed marked chronic cystitis including follicular cystitis and papillary/polypoid cystitis. There was no evidence of malignancy. CONCLUSION: Distigmine therapy resulted in marked bilateral hydronephrosis and hydroureter. Persistence of hydronephrosis after omitting distigmine, and presence of residual urine in bladder over many years probably predisposed to formation of polypoid cystitis and follicular cystitis, and contributed to prolonged haematuria, which occurred after an episode of urine infection. This case illustrates the dangers of prescribing distigmine to promote spontaneous voiding in spinal cord injury patients. Instead of using distigmine, spinal cord injury patients should be advised to consider intermittent catheterisation together with oxybutynin or propiverine to achieve complete, low-pressure emptying of urinary bladder.

Distigmine bromide (Ubretid) is a long-acting anti-cholinesterase, widely used for the treatment of underactive neurogenic bladder and myasthenia gravis. Our study concerns a 73-year-old man treated with a potentially life-threatening cholinergic state due to distigmine bromide. He had been administered distigmine bromide orally for over two years at a daily dosage of 10 mg as a treatment for underactive neurogenic bladder. He suddenly developed diarrhea and consciousness disturbance during treatment of his urinary tract infection. Bradycardia and miosis were noted. Blood examination revealed extremely low levels of the plasma cholinesterase activity. The condition was diagnosed as distigmine bromide intoxication. All cholinergic symptoms disappeared in several days after the administration of distigmine bromide was terminated. Cholinergic crisis due to overdosage with anticholinesterases is well known, and the myasthenic patients are usually supervised in the early stages of dosage regulation to guard against the possibility of cholinergic crisis. However the use of oral distigmine bromide, even in therapeutic doses for urinary retention, could result in cholinergic crisis. We therefore conclude that extreme caution must be used in administering distigmine bromide.

The long-acting anticholinesterase, distigmine bromide (Ubretid), is widely used for the treatment of underactive neurogenic bladder. Therefore, we emphasize its hazardable side-effect of cholinergic crisis. A 78-year-old man with duodenal ulcer complained of nocturia, and was administered distigmine bromide 10 mg daily under the diagnosis of mild benign prostatic hypertrophy with underactive neurogenic bladder. It seemed that administration slightly improved his symptom but he developed bradycardia, dyspnea and drowsiness suddenly on the 4th day. Blood examination revealed extremely low cholinesterase in his serum, suggesting distigmine bromide intoxication. He was treated intensively with several intravenous injections of atropine, high-concentration oxygen and transfusion of fresh frozen plasma. Nevertheless, his condition did not recover, resulting in death of "cholinergic crisis" on the 6th day.

AIM The aim of the study was to determine the absolute bioavailability and pharmacokinetics after a single dose oral administration in comparison to i.v. administration of 14C-labelled distigmine-bromide (14C-Ubretid) in healthy male volunteers. RESULTS: After the intravenous administration, distigmine is eliminated from the body by renal excretion (85%), and for a small fraction by biliary excretion in the feces (4%). This situation is reversed after an oral administration, where 6.5% of the dose is recovered from the urine and 88% from the feces. This means that distigmine after oral administration is hardly absorbed, the calculated bioavailability is 4.65%. CONCLUSION: The mean absorption time (MAT) after oral administration was 10 h, influencing the t(1/2alpha) (1.4 vs 4.5 h) and the t(1/2beta) (60 vs 70 h) to higher values than after the i.v. administration (p < 0.05).

Distigmine is widely used for the treatment of dysuria, which is caused by various types of psychotropic medications. Distigmine, however, is also known to induce adverse cholinergic effects, such as diarrhea and salivation, with a decreased level of serum cholinesterase. We evaluated the possibility of using serum acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as specific clinical markers for the adverse cholinergic effects of distigmine. Of the twelve patients treated with distigmine for dysuria caused by psychotropic drugs six patients presented both adverse cholinergic effects and decreased levels of serum AChE and BChE. The other six presented neither of these changes. This study suggests that the values of serum AChE and BChE may be useful markers for the manifestation of adverse cholinergic effects caused by distigmine.

A randomized phase-I study was performed in a clinical setting in 24 healthy young male subjects, aged 20 to 35 years, to investigate the influence of Ubretid on AChE inhibition following oral and i.m. administration in one of three medication schemes: -single oral (10 mg) and i.m. (0.5 mg) medication (randomized crossover), -multiple oral dosing (5 mg on trial days 1, 2, 3, 5, 7, 9, 11 and 13), -multiple oral dosing (5 mg on trial days 5 to 14) with initial i.m. loading doses (0.5 mg i.m. on trial days 1, 2 and 4). The multiple dosing schemes were chosen as they are both frequently used in clinical practice. The results of the AChE inhibition after Ubretid can be summarized as follows: repeated Ubretid administration as used in this trial did not lead to a cumulation of AChE inhibition. Statistical testing (page test) of maximum AChE inhibition on the last medication days gave no indication of an increased AChE inhibition towards the end of treatment. Compared with the i.m. administration, the Ubretid tablet had a bioavailability of 2.2 +/- 1.1% (mean +/- STD).