Ketamine-induced Cystitis Research Articles

Management Strategies for Patients with Non-Infectious Cystitis: A Review of the Literature.

The management of noninfectious cystitis continues to evolve as new treatments continue to be developed and investigated. This review aims to synthesize the most recent data regarding management strategies for noninfectious cystitis focused on non-ulcerative, ulcerative, eosinophilic, and ketamine-induced cystitis. Several novel treatments have shown promise as management options including combination antihistamine therapy, phosphodiesterase 5 inhibitors, alpha lipoic acid supplements, and onabotulinumtoxin A. Recent studies have also found pentosan polysulfate sodium to have adverse ophthalmologic effects. For patients with ulcerative cystitis, recent research has shown that fulguration with or without triamcinolone injections should not be delayed. The treatment of noninfectious cystitis should be patient specific based on factors including etiology and symptom profile. Multimodal regimens are often the most effective. Treatment should be started with conservative options and escalated as necessary to oral treatments, intravesical options, or procedural management.

Circ-SFMBT2 sponges miR-224-5p to induce ketamine-induced cystitis by up-regulating metadherin (MTDH).

There is increasing evidence that circular RNAs (circRNAs) play significant roles in various biological processes, yet few reports have examined their roles and molecular mechanisms in ketamine-induced cystitis (KIC). This study examines the possible molecular mechanisms underlying the circRNA-microRNA-mRNA regulatory network in the development of KIC. Transcriptome data were collected, and bioinformatics analysis was conducted to create a circRNA-miRNA-mRNA regulatory network (ceRNA network) associated with the occurrence of KIC. Human bladder epithelial cells (SV-HUC-1) were used in in vitro cell assays. The binding affinity among circ-SFMBT2, miR-224-5p, and Metadherin (MTDH) was identified. To investigate the effects of circ-SFMBT2/miR-224-5p/MTDH on bladder function, KIC mouse models were induced by intraperitoneal injection of ketamine, and gain- or loss-of-function experiments were conducted. Our results demonstrate that MTDH may be a key gene involved in the occurrence of KIC. Both bioinformatics analysis and in vitro cell assays verified that circ-SFMBT2 can competitively bind to miR-224-5p, and miR-224-5p can target and inhibit MTDH. In the bladder tissues of KIC mice, circ-SFMBT2 and MTDH were up-regulated, while miR-224-5p was down-regulated. Animal experiments further confirmed that circ-SFMBT2 can up-regulate MTDH expression by sponging miR-224-5p, thereby exacerbating bladder dysfunction in KIC mice. This study proved that circ-SFMBT2 up-regulates MTDH by competitively binding to miR-224-5p, thereby exacerbating the bladder dysfunction of KIC.

Pathophysiology, clinical presentation, and management of ketamine-induced cystitis.

Ketamine is illegally used as a recreational drug in many Asian countries. Long-term ketamine abusers often develop irritable bladder symptoms that gradually develop into more severe urinary frequency and urgency and eventually into a painful ulcerated bladder. These patients typically have reduced functional bladder capacity, increased bladder sensation, detrusor overactivity, severe urgency, urinary incontinence, and bladder contracture. Ketamine metabolites can cause severe inflammation of the urothelium, urothelial barrier deficits, vascular endothelial fibrinoid changes, increased oxidative stress, and bladder wall fibrosis. A decrease in bladder compliance, urinary tract infection, severe bladder pain with a full bladder, and painful micturition are also common symptoms. Finally, with continued abuse of ketamine, hydronephrosis, ureteral stricture, vesicoureteral reflux, and renal failure may develop. Cessation of ketamine is the mainstay of treatment. Lower urinary tract symptoms usually relapse if patients reuse ketamine after stopping. In cases of severe ketamine cystitis, only augmentation enterocystoplasty can relieve bladder pain and restore normal lower urinary tract function. This article reviews the underlying pathophysiology, clinical characteristics, and management of ketamine cystitis.

A dedicated outpatient clinic for ketamine-induced cystitis: first results

SamenvattingRecreatief ketaminegebruik neemt toe in Nederland. Ketaminemisbruik kan leiden tot schade aan de urinewegen, waardoor urogenitale klachten ontstaan met forse impact op de kwaliteit van leven. Dit artikel gaat over de eerste Nederlandse themapoli met diagnose- en behandelprotocol voor patiënten met ketamine-geïnduceerde urogenitale klachten. Tot op heden zagen we 30 patiënten, van wie 10% betrokkenheid had van de hoge urinewegen. Aanvullende diagnostiek en behandeling waren gefocust op preservatie van nierfunctie. De overige 90% werd gecounseld met als doel te stoppen met ketaminegebruik. Urogenitale klachten werden medicamenteus behandeld. 71% van deze patiënten slaagde erin binnen drie maanden te stoppen met ketaminegebruik en had significant (p < 0,05) vaker afname van klachten dan de groep die niet stopte. Het is belangrijk ketaminemisbruik te erkennen als mogelijke oorzaak van urogenitale klachten bij jonge patiënten, enerzijds vanwege het gevaar voor de hoge urinewegen en anderzijds omdat urogenitale klachten een impactvolle groep aandoeningen is die reversibel is bij stoppen met ketamine.

Current approaches for the treatment of ketamine-induced cystitis.

Ketamine is a dissociative anesthetic, historically used in a clinical setting for the induction and maintenance of anesthesia. Ketamine usage can produce undesirable psychological manifestations including hallucinations and long-term psychotomimetic effects. As a results of its fast onset and short period of action, ketamine is widely used as a recreational drug. Chronic abuse of ketamine can lead to significant urinary system complications including ketamine-induced cystitis (KIC). Common side effects of chronic ketamine abuse are urinary pain and discomfort and decreased bladder compliance and voiding pressure. Cessation of ketamine use is associated with improvement of symptoms however the exact pathophysiology of KIC remains unknown, complicating the ability of clinicians to treat this condition. A literature search was performed using the National Center for Biotechnology Information (NCBI) Pubmed database up to May 2021. Animal models of KIC are necessary to further our understanding of KIC pathophysiology and explore potential treatment options. In all cases, cessation of ketamine use is the first line of treatment and is most effective in managing KIC. In addition to cessation, treatment plans must be tailored to the individual, based on the severity of symptoms and disease progression, and include options such as: oral anti-inflammatories, intravesical treatment and in the most severe cases, surgical intervention. KIC is a painful condition that currently lacks standardized treatment methods. Both animal models of KIC and clinical trials to further elucidate the mechanism of KIC pathophysiology must be explored to create targeted treatment plans.

Using a Rat Model to Translate and Explore the Pathogenesis of Ketamine-Induced Cystitis

Purpose: Ketamine abusers may develop severe ulcerative cystitis along with irritative bladder symptoms. A reliable animal model may benefit the understanding of pathophysiologies and the development of therapeutic strategies for ketamine-induced cystitis (KIC). We used a popular rat model of KIC to validate the micturition behavior, functional brain images, and possible molecular mechanisms of this model. Materials and Methods: Female Sprague–Dawley rats were distributed to control (saline) and ketamine-treated rats (25 mg/kg/day for 28 days). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Potential bladder transcripts involved in KIC were screened by using next-generation sequencing. Results: In contrast to the control, the ketamine-treated rats developed bladder overactivity accompanied by enhanced fMRI signals in periaqueduct and caudal putamen areas. Alterations in bladder transcripts, including eleven genes involving in regulating NF-κB signaling of bladder inflammation, and Crhr2 gene overexpression associating with vascular endothelial growth factor signaling of bladder ischemia were found in ketamine-treated rats. Both categories could be attributed to neurogenic inflammation induced by the direct toxicity of urinary ketamine and its metabolites. Conclusion: Our study results suggest this animal model could mimic irritative bladder symptoms associated with central sensitization in KIC. Through the bladder transcripts analysis, we highlight the neurogenic inflammation underlying the pathophysiologies of KIC in rats.

Ketamine-Induced Cystitis: A Comprehensive Review of the Urologic Effects of This Psychoactive Drug

Ketamine is a common medical anesthetic and analgesic but is becoming more widely used as a recreational drug. Significant side effects on the urinary tract are associated with frequent recreational ketamine use most notably ketamine-induced cystitis (KIC). Regular ketamine consumption has been shown to increase the risk of cystitis symptoms by 3- to 4-fold, and cessation of ketamine use is usually associated with improvement of symptoms. Common KIC-related problems are urinary pain and discomfort, bladder epithelial barrier damage, reduced bladder storage and increased pressure, ureter stenosis, and kidney failure, all of which significantly impact patients' quality of life. Furthermore, it becomes a vicious cycle when KIC patients attempt to manage their urinary pain with increased ketamine use. The precise pathophysiology of KIC is still unknown but several theories exist, most of which highlight the inflammatory signaling pathways leading to bladder epithelium damage due to presence of ketamine in the urine. Empirical treatment options for KIC are available and consist of ketamine cessation, noninvasive therapies, and surgery, and should be decided upon based on the time course and severity of the disease. Of note, cessation of use is strongly recommended for all KIC patients, and should be supplemented with motivational interviews and psychological and social support. It is crucial for clinicians to be familiar with KIC diagnosis and treatment, and to be prepared to have informed discussions with ketamine-using patients about the potential health consequences of ketamine.

Transcriptomic analysis of bladder tissue in a rat model of ketamine-induced bladder fibrosis.

Ketamine-induced cystitis (KIC) is a disease caused by ketamine that can cause lower urinary tract symptoms (LUTS). Its end-stage is bladder contracture, which is related to bladder fibrosis and poses a serious burden to patient lives. We established a KIC model in female Sprague Dawley rats and verified bladder fibrosis in the model by Masson trichrome staining and western blot analysis. The bladders of the rats from the ketamine and control groups were used to perform transcriptome analysis. In particular, association analysis with metabolomics was also used to determine the potential mechanisms of ketamine-induced bladder fibrosis. A total of 685 differentially expressed messenger RNAs, 71 differentially expressed long noncoding RNAs, 23 differentially expressed microRNAs, and 68 differentially expressed circular RNAs were identified. We found that ribosome, Wnt signaling, vascular endothelial growth factor signaling, cytoskeleton organization, and cytoskeletal protein binding may be potential pathways in ketamine-induced bladder fibrosis as identified by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. In addition, the mitogen-activated protein kinase pathway appeared to be closely related to the development of ketamine-induced bladder fibrosis according to association analysis. In this study, using transcriptomic and correlation analyses of metabolomics, we identified pathways that may be potential targets for the prevention and treatment of ketamine-induced bladder fibrosis.

Ketamine Induced Bladder Fibrosis Through MTDH/P38 MAPK/EMT Pathway.

Purpose: Ketamine is an anesthetic in clinical, but it has also been used as an abusing drug due to its low price and hallucinogenic effects. It is proved that ketamine abusing would cause multiple system damage including the urinary system, which is called ketamine-induced cystitis (KIC). Bladder fibrosis is late stage in KIC and threaten abusers’ life. This study aimed to investigate the molecular mechanism of ketamine-induced bladder fibrosis. Methods: Female Sprague Dawley (SD) rats were randomly divided into 3 groups. 2 groups were treated with tail vein injection of ketamine (25 mg/kg/day, 50 mg/kg/day ketamine hydrochloride solution, respectively) for 12 weeks, whereas the control group was treated with normal saline solution. In each group, rat bladders were extracted and samples were examined for pathological and morphological alterations via hematoxylin and eosin (HE) staining, Masson’s trichrome staining and immunohistochemistry (IHC). SV-HUC-1 cells were treated with different concentrations of ketamine solution (0, 0.1, 0.5, 1 mmol/L). Rat bladder and SV-HUC-1 cells were extracted protein and RNA for Western blot and RT-PCR detection. Metadherin (MTDH) siRNAs and overexpression plasmids were used to knock down and overexpress the relative genes. P38 mitogen-activated protein kinase (MAPK) inhibitor was utilized to inhibit the MAPK pathway. Results: Rats in the ketamine group exhibited fibrosis compared to rats of the control group and fibrosis were also markedly upregulated in SV-HUC-1 cells after treated with ketamine, which were ketamine concentration-dependent. After treating with ketamine in SV-HUC-1 cells, there was an increase expression of MTDH, epithelial-mesenchymal transition (EMT) markers, P38 MAPK. MTDH knockdown would suppresses P38 MAPK/EMT pathway to inhibit fibrosis, however, MTDH overexpression could promote the pathway in SV-HUC-1 cells. Conclusion: In rats and SV-HUC-1 cells ketamine-treated models, MTDH can regulate EMT through the P38 MAPK pathway to regulate the process of bladder fibrosis.

Rodent models of ketamine-induced cystitis.

Long-term or recreational use of ketamine affects the urinary system and can result in ketamine-induced cystitis (KIC). Rodent models of KIC are important to study KIC pathophysiology and are paramount to the future development of therapies for this painful condition. This review aims to provide a summary of rodent models of KIC, focusing on disease induction, experimental methods, and pathological features of the model. A literature search was performed using the National Center for Biotechnology Information (NCBI) Pubmed database up to March 2021. 20 articles met the inclusion criteria and were finally selected. There are considerable variations in the rodent models used for studying KIC in terms of the strain of the animal being used; dose, duration, and route of ketamine administration to induce KIC, and assessment of pathological features. KIC remains difficult to fully recapitulate in humans. Improved characterization of KIC models and the experimental parameters and meticulous discussion on translational limitations are required to improve the translational value of research using rodent models of KIC.

Intravesical Instillation of Norketamine, a Ketamine Metabolite, and Induced Bladder Functional Changes in Rats

This study aimed to determine the mechanism of ketamine-induced cystitis without metabolism. A total of 24 adult male Sprague-Dawley rats were separated into control, ketamine, and norketamine groups. To induce cystitis, rats in the ketamine and norketamine groups were treated with intravesical instillation of ketamine and norketamine by mini-osmotic pump, which was placed in subcutaneous space, daily for 24 h for 4 weeks. After 4 weeks, all rats were subjected to bladder functional tests. The bladders were collected for histological and pathological evaluation. Compared to control, ketamine treatment demonstrated an increase in the bladder weight, high bladder/body coefficient, contractive pressure, voiding volume, collagen deposition, reduced smooth muscle content, damaged glycosaminoglycan layer, and low bladder compliance. Compared to ketamine, norketamine treatment showed more severe collagen deposition, smooth muscle loss, damaged glycosaminoglycan layer, and increased residual urine. Intravesical administration of ketamine and norketamine induced cystitis with different urodynamic characteristics. Norketamine treatment caused more severe bladder dysfunction than ketamine treatment. Direct treatment of the bladder with norketamine induced symptoms more consistent with those of bladder outlet obstruction than ketamine cystitis. Detailed studies of cellular mechanisms are required to determine the pathogenesis of ketamine cystitis.

Autophagy Alters Bladder Angiogenesis and Improves Bladder Hyperactivity in the Pathogenesis of Ketamine-Induced Cystitis in a Rat Model.

Simple SummaryLong-term ketamine abuse may increase urinary frequency, nocturia, urgency, bladder pain, dysuria, and sometimes hematuria. Evaluation of the pathophysiological mechanism of bladder voiding dysfunction in ketamine-induced cystitis (KIC) patients is a critical step for therapy. This study uses autophagy inducer (rapamycin, mTOR inhibitor) and inhibitor (wortmannin, PI3K-III inhibitor) to identify the role of autophagy in bladder angiogenesis alteration and bladder hyperactivity improvement.The present study attempts to elucidate whether autophagy alters bladder angiogenesis, decreases inflammatory response, and ameliorates bladder hyperactivity—thereby influencing bladder function in ketamine-induced cystitis (KIC). In our methodology, female Sprague-Dawley (S-D) rats were randomly divided into the control group, the ketamine group, the ketamine+rapamycin group, and the ketamine+wortmannin group. The bladder function, contractile activity of detrusor smooth muscle, distribution of autophagosome and autolysosome, total white blood cells (WBCs) and leukocyte differential counts, the expressions of autophagy-associated protein, angiogenesis markers, and signaling pathway molecules involved in KIC were tested, respectively. The data revealed that treatment with ketamine significantly results in bladder overactivity, enhanced interstitial fibrosis, impaired endothelium, induced eosinophil-mediated inflammation, swelling, and degraded mitochondria and organelles, inhibited angiogenesis, and elevated the phosphorylation of Akt. However, treatment with rapamycin caused an inhibitory effect on vascular formation, removed ketamine metabolites, decreased the eosinophil-mediated inflammation, and ameliorated bladder hyperactivity, leading to improve bladder function in KIC. Moreover, wortmannin treatment reduced basophil-mediated inflammatory response, improved bladder angiogenesis by increasing capillary density and VEGF expression, to reverse antiangiogenic effect to repair KIC. In conclusion, these findings suggested that autophagy could modulate inflammatory responses and angiogenesis, which improved bladder function in KIC.

Association of urinary ketamine and APOA1 levels with bladder dysfunction in ketamine abusers revealed via proteomics and targeted metabolite analyses

Chronic ketamine abuse is associated with bladder dysfunction and cystitis. However, the effects of ketamine abuse on the urinary proteome profile and the correlations among urinary proteins, urinary ketamine (and metabolites) and clinicopathological features of ketamine-induced bladder dysfunction remain to be established. Here, we recruited 56 ketamine abusers (KA) and 40 age-matched healthy controls (HC) and applied the iTRAQ-based proteomics approach to unravel quantitative changes in the urine proteome profile between the two groups. Many of the differentially regulated proteins are involved in the complement and coagulation cascades and/or fibrotic disease. Among them, a significant increase in APOA1 levels in KA relative to control samples (392.1 ± 59.9 ng/ml vs. 13.7 ± 32.6 ng/ml, p < 0.0001) was detected via ELISA. Moreover, urinary ketamine, norketamine and dehydronorketamine contents (measured via LC-SRM-MS) were found to be positively correlated with overactive bladder syndrome score (OABSS) and APOA1 levels with urinary RBC, WBC, OABSS and numeric pain rating scale in KA. Collectively, our results may aid in developing new molecular tool(s) for management of ketamine-induced bladder dysfunction. Moreover, information regarding the differentially regulated proteins in urine of KA provides valuable clues to establish the molecular mechanisms underlying ketamine-induced cystitis.

Aldh2 gene reduces oxidative stress in the bladder by regulating the NF-κB pathway in a mouse model of ketamine-induced cystitis.

Aldehyde dehydrogenase 2 (aldh2) serves an important role in the development of organ injury. Therefore, the present study investigated the effects of aldh2 on the oxidative stress response in a mouse model of ketamine-induced cystitis (KIC). A total of 60 8-week-old male Institute of Cancer Research wild-type (WT) mice and 45 aldh2 knock-out (KO) mice were randomized to receive low-dose ketamine (30 mg/kg), high-dose ketamine (60 mg/kg) or normal saline (controls). At 4, 8 and 12 weeks post-injection, bladder tissues were harvested and used to investigate the protective mechanisms of aldh2 on bladder function. The results demonstrated that aldh2 KO mice exhibited significant weight loss following chronic ketamine injection compared with that in WT mice. Furthermore, ketamine treatment increased the urination rate (P<0.05), pathological score (P<0.05), levels of the oxidative stress product malondialdehyde (P<0.05) in addition to reducing the expression of the anti-oxidative stress enzyme superoxide dismutase (P<0.05) and glutathione-SH (P<0.05). Oxidative stress in aldh2 KO mice was also found to significantly enhance the expression of proteins associated with the NF-κB signaling pathway, which promoted the expression of inducible nitric oxide synthase (P<0.05) and cyclooxygenase-2 (P<0.05) further. Finally, aldh2 KO mice demonstrated higher severity of fibrosis in the submucosal and muscular layers of the bladder. In conclusion, the present study suggests that aldh2 serves a protective role in preventing inflammation and fibrosis in KIC.

Evaluation of the impact of platelet rich plasma and hyaluronic acid on ketamine-induced cystitis in albino rats : A histological and immunohistochemical study.

Background: ketamine induced cystitis (KIC) is commonly occurred in ketamine abusing individuals. It is associated with damage in the lining of the bladder and lower urinary tract symptoms. Platelets rich plasma (PRP) is attractive therapeutic line in regenerative medicine. Hyaluronic acid (HA) has many beneficial therapeutic effects in treatment of different types of cystitis.Objective: to evaluate the effect of PRP and HA on ketamine induced cystitis in adult male rats.Materials and Methods: Forty- four adult male rats were divided into five groups: Group I: control rats. Group II: Ketamine group. Group III: Recovery group. Group IV: Ketamine and PRP treated group. Group V: Ketamine and HA treated group. Specimens from the body of the urinary bladder were processed and examined histologically and immunohistochemically. Morphometrical studies and statistical analysis were conducted.Results: Groups II and III showed focal areas of degeneration and ulceration with apparently decreased thickness of the urothelium. Cellular infiltration and dilated congested blood vessels of the lamina propria were also observed. A significant increase of the collagen fibers in the lamina propria and between the muscle bundles. Nuclear factor kappa B (NF-κB) immunoreaction was significantly increased but there was a non-significant increase of antiproliferating cell nuclear antigen (PCNA) immunopositive nuclei among urothelium and a significant decrease of desmin, compared to group I. Groups III and IV showed improvement of most of the histological and immunohistochemical changes described before.Conclusion: The intravesical injection of PRP and HA provide a positive impact on treatment of KIC. HA therapy is a more efficient mean as it provides a better improvement in healing of urothelium and promotes more rapid tissue regeneration.

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate ketamine-induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model.

We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1β [IL-1β], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-β1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.

Augmentation Enterocystoplasty for Patients with Ketamine-induced Cystitis

Purpose: Ketamine abuse has been a worldwide issue recently. Ketamine-induced cystitis (KC) is an annoying urinary tract symptom secondary to long-term ketamine abuse. The aim of our study is to review clinical outcomes of bladder augmentation enterocystoplasty (AE) for the patients with KC. Materials and Methods: We performed bladder AE for eight patients with refractory symptoms of KC (severe bladder pain, micturition pain, urgency, frequency, and contracted bladder). All the patients received conservative treatment at clinics or referred from other hospital. Results: Between 2007 and 2015, eight patients (seven males and one female), aged 26–48 years (mean 32.7 years), underwent AE as indicated. The duration of ketamine abuse ranged from 2 to 15 years (mean 6.8 years). Contracted bladder was noted in all patients, hydronephrosis in two and hydroureter in one under intravenous pyelography. Postoperative hospitalization ranged from 12 to 47 days (mean 22.4 days). Significant increases in estimated glomerular filtration rate (86.43 ± 21.47 vs. 103.14 ± 29.32 ml/min/1.73 m2,P &lt; 0.05), functional bladder capacity (47.75 ± 10.07 vs. 273.13 ± 54.96 ml,P &lt; 0.0001), and pain visual analog score (6.0 ± 1.2 vs. 1.75 ± 0.89,P &lt; 0.0001) were noted after AE. Surgical complications included adhesion ileus, progressive impaired renal function, and enterovesical fistula. All the patients were satisfied with the outcomes of the surgery, based on their responses to the self-report questionnaires. All patients reported marked improvement in micturition pain and urinary frequency, which greatly elevated life quality. Most patients were followed up at the outpatient department within 1 year or were lost to follow-up after surgery. Conclusion: This case series demonstrated that for surgical management of refractory bladder pain and low bladder capacity resulting from KC, AE might be effective. However, cessation of ketamine use is the most important to prevent recurrence of the above symptoms.

Potential Orphan Drug Therapy of Intravesical Liposomal Onabotulinumtoxin-A for Ketamine-Induced Cystitis by Mucosal Protection and Anti-inflammation in a Rat Model

Ketamine abusers may develop ulcerative cystitis and severe lower urinary tract symptoms, which is a medical dilemma. Recently, researchers have found the endemic of ketamine-induced cystitis worldwide. The intravesical administration of liposome-encapsulated onabotulinumtoxinA (Lipotoxin) might facilitate the healing of the damaged urothelium from liposomes, and reduce the urinary symptoms by onabotulinumtoxinA-induced chemo-denervation. Using female Sprague-Dawley rats, we investigated the effects of Lipotoxin on ketamine-induced cystitis. Functional magnetic resonance imaging, metabolic cage study, and cystometry were conducted. Paraffin-embedded sections were stained. The bladder mucosa and muscle proteins were assessed through Western blotting. We observed that repeated intravesical Lipotoxin instillation could improve suburothelial hemorrhage, recover the urothelial tight junction and adhesion proteins (zonula occludens-1 and E-cadherin), ensure less substance P in the urothelium, inhibit the overexpression of inflammatory mediators (IL-6, TNF-α, nuclear NF-κB, and COX-2) in the detrusor, suppress the upregulation of the mucosal TRPV1 and detrusor M2-mAChR, and ameliorate bladder overactivity in the ketamine-treated rats. These data reveal the mechanisms underlying the action of Lipotoxin in ketamine-induced cystitis of rats, which provide a basis of Lipotoxin for further treating ketamine-induced cystitis in humans.

Ketamine and Its Pharmacologic Profile in Psychiatric Disorders

Ketamine is used to treat psychiatric conditions at low doses to minimize risks associated with anesthetic sedation. Dissociative phenomena and minimally increased heart rate and blood pressure are among the most common but transient side effects during intravenous ketamine infusion. When used in common medical practice as an anesthetic, analgesic, and antidepressant, there is little evidence to support nonreversible adverse events. Several retrospective studies have demonstrated that daily, illicit use of ketamine at high doses over a period of years is associated with neurocognitive dysfunction and ketamine-induced cystitis. Although ketamine may have use in special populations, screening for active psychosis, illicit ketamine use, a history of cystitis, and severe or uncontrolled cardiovascular disease is critical when determining the appropriateness of ketamine treatment. [ Psychiatr Ann. 2018;48(4):170–174.]

Epigenetic regulation of COX-2 expression by DNA methylation via NF-KB activation in ketamine-induced ulcerative cystitis

Epigenetic regulation of COX-2 expression by DNA methylation via NF-KB activation in ketamine-induced ulcerative cystitis