Characterization of Patients with Chronic Obstructive Pulmonary Disease Initiating Single-Inhaler Long-Acting Muscarinic Antagonist/Long-Acting ß2-Agonist Dual Therapy in a Primary Care Setting in England.

Purpose: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-inhaler dual therapies remain unclear. We aimed to describe characteristics, prescribed treatments, healthcare resource use (HCRU) and costs of patients with COPD who initiated single-inhaler long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy in primary care in England. Patients and Methods: Retrospective study using linked data from Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. Patients with COPD with ≥1 single-inhaler LAMA/LABA prescription between June 2015 and December 2018 (index) were included. Demographic and clinical characteristics, prescribed treatments, HCRU and costs were evaluated in the 12 months pre-index. Data are presented for patients not receiving concomitant inhaled corticosteroids at index (non-triple users). Results: Of 10,991 patients initiating LAMA/LABA, 9888 were non-triple users, of whom 21.3% (n=2109) received aclidinium bromide/formoterol, 18.1% (n=1785) received indacaterol/glycopyrronium, 12.0% (n=1189) received tiotropium bromide/olodaterol and 48.6% (n=4805) received umeclidinium/vilanterol. Demographic and clinical characteristics were similar across indexed therapies. LAMA monotherapy was the most frequently prescribed respiratory therapy at 12 (18.4-25.8% of patients) and 3 months (23.9-33.7% of patients) pre-index across indexed therapies; 42.5-59.0% of patients were prescribed no respiratory therapy at these time points. COPD-related HCRU during the 12 months pre-index was similar across indexed therapies (general practitioner consultations: 62.0-68.6% patients; inpatient stays: 19.3-26.1% patients). Pre-index COPD-related costs were similar across indexed therapies, with inpatient stays representing the highest contribution. Mean total direct annual COPD-related costs ranged from £805-£1187. Conclusion: Characteristics of patients newly initiating single-inhaler LAMA/LABA dual therapy were highly consistent across indexed therapies. As half of non-triple users were not receiving respiratory therapy one year prior to LAMA/LABA initiation, there may be an opportunity for early optimization of treatment to relieve clinical burden versus current prescribing patterns in primary care in England.

Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: A systematic review and meta-analysis.

BACKGROUND: In symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978). METHODS: We searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest. RESULTS: We identified a total of three RCTs (N = 632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV1 (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies. CONCLUSIONS: In the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV1 in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.

Efficacy of Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhaler (BGF MDI) Versus Other Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting ß2-Agonist (ICS/LAMA/LABA) Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

INTRODUCTION: Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA). METHODS: A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St. George's Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12-24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. RESULTS: Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario. CONCLUSION: This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.

Risk of Parkinson disease in Sjögren syndrome administered ineffective immunosuppressant therapies: A nationwide population-based study.

To determine the incidence and risk of Parkinson disease (PD) in patients with Sjögren syndrome (SS) according to a nationwide population-based database.In total, 12,640 patients in the SS cohort and 50,560 in the non-SS cohort were enrolled from Taiwan's National Health Insurance Research Database from 2000 to 2010. We used the Cox multivariable proportional hazards model to determine the risk factors for PD in the SS cohort.We observed an increased incidence of PD in patients with SS, with a crude hazard ratio (HR) of 1.40 and an adjusted HR (aHR) of 1.23. The cumulative incidence of PD was 1.95% higher in the SS cohort than in the non-SS cohort. The SS cohort had an elevated HR under medication use, namely cevimeline and pilocarpine (crude HR, 1.28), hydroxychloroquine (crude HR, 1.43; aHR, 1.46), and methylprednisolone (crude HR, 2.21; aHR, 1.49). Patients receiving other non-hydroxychloroquine immunosuppressant therapies had a lower risk (aHR, 0.86) of PD. Furthermore, patients with SS aged 20 to 49 years had a 1.93-fold higher risk of PD than did those without SS (aHR, 1.93). The risk of PD was higher (aHR, 2.20) in patients with SS without comorbidities than in those with comorbidities. The aHR of PD significantly increased when the follow-up period exceeded 9 years (aHR, 1.93).We determined an increased risk of PD in patients with SS. Further investigation is warranted to determine the possible underlying mechanisms and the potential role of non-hydroxychloroquine immunosuppressants in ameliorating PD.

Interventions for dry mouth and hyposalivation in Sjögren's syndrome: A systematic review and meta-analysis.

OBJECTIVES: Systematic review with meta-analysis of interventions for dry mouth symptoms and hyposalivation of Sjögren's syndrome (SS). MATERIALS AND METHODS: We searched MEDLINE, Cochrane Central and EMBASE up to February 2018 for randomized trials of interventions for dry mouth and hyposalivation of SS. The primary outcome was the mean change in xerostomia symptoms. The secondary outcomes included changes in salivary flow and quality of life. We used the Cochrane risk of bias tool for individual studies and the GRADE method to summarize the quality of evidence across studies for the included outcomes. RESULTS: Thirty-six studies (3,274 patients) were included in the systematic review. Results from the meta-analyses showed high-quality evidence that pilocarpine was superior to placebo in reducing dry mouth symptoms. We found moderate quality of evidence that pilocarpine, rituximab and interferon-alpha were more effective than placebo in increasing salivary flow, with the relevant effect size being large for pilocarpine, and notably smaller for rituximab and interferon-alpha. CONCLUSION: Clinicians should be very confident in the beneficial effects of pilocarpine upon dry mouth symptoms of SS and moderately confident that pilocarpine, rituximab and interferon-alpha can have beneficial effects upon salivary flow. Adverse events are common. The use of other treatment modalities cannot be supported on the basis of current evidence.

Salivary hypofunction: An update on therapeutic strategies.

OBJECTIVE: To perform a literature review addressing the therapeutic strategies for salivary hypofunction. BACKGROUND: Qualitative and quantitative salivary dysfunctions predispose to changes in the oral mucosa and teeth, cause impairment to oral functions and negative impact on quality of life. MATERIALS AND METHODS: A MEDLINE/PubMed search was conducted using the terms "Xerostomia" AND, "Saliva Artificial" OR, "Citric Acid," "Malic Acid," "Chewing Gum," "Acupuncture" OR, "Pilocarpine" OR, "Bethanechol" OR, "Cevimeline" OR, "Hyperbaric Oxygen Therapy" OR, "Stem Cell Therapy" OR "Genetic Therapy" and their Mesh Terms. RESULTS: We selected 25 clinical trials investigating the effects of salivary substitutes, chewing gum, malic and citric acids, pilocarpine, cevimeline, bethanechol, acupuncture, hyperbaric oxygen therapy and regenerative therapies on salivary hypofunction. In most studies, the number of participants was low and the follow-up times short. The therapeutic modalities were classified according to the level of evidence on salivary dysfunction. CONCLUSIONS: Pilocarpine and cevimeline had the strongest evidence of beneficial effect on salivary hypofunction. Citric and malic acids increase salivary flow but also increase the risk of erosion and dental caries. There are no controlled clinical trials supporting the efficacy of acupuncture, stem cell therapy and gene therapy on salivary dysfunction, although clinical observations suggest a promising effect. There is no evidence supporting salivary substitutes, chewing gum, bethanechol or hyperbaric oxygen on the treatment of salivary hypofunction.

New technology assessment and current and upcoming therapies for underactive bladder.

BACKGROUND AND AIMS: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder. METHODS: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB. RESULTS: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria. 2) Should residual urine volume be the primary outcome parameter and how often should it be measured? 3) Are there secondary measures that should have a place in UAB trials, such as change in the number of catheterizations, quality of life measures, etc.? 4) Use and format of bladder voiding and catheterization diary for trials. 5) Define role and technique of urodynamics in UAB trials. Are urodynamics required to monitor, and possibly exclude, individuals with high pressure voiding induced by bladder prokinetic therapies? 6) Development and use of UAB questionnaires. DISCUSSION AND CONCLUSION: The UAB regulatory working group recognizes the path forward should include engaging the FDA and other regulatory organizations that may harmonize and formalize guidance for regulatory trial designs for therapeutics for UAB.

Muscarinic and nicotinic acetylcholine receptor agonists: current scenario in Alzheimer's disease therapy.

OBJECTIVES: Alzheimer's disease (AD) has become the primary cause of dementia. It shows a progressive cognitive dysfunction with degenerating neurons. Acetylcholine receptors (AChRs) propagate the cognitive ability and it consists of two primary members namely muscarinic (mAChRs) and nicotinic receptors (nAChRs). Where mAChRs is G-protein coupled receptor, (nAChRs) are ligand-gated ion channels. The conventional therapeutic regimen for AD consists of three acetylcholinestearse inhibitors while a single NMDA receptor antagonist. Researchers around the globe are developing new and modifying the existing AChRs agonists to develop lead candidates with lower risk to benefit ratio where benefits clearly outweigh the adverse events. KEY FINDINGS: We have searched PubMed, MEDLINE, Google scholar, Science Direct and, Web of Science with keywords "Muscarinic/Nicotinic acetylcholine receptor, agonists and, AD". The literature search included articles written in English. Scientific relevance for clinical studies, basic science studies is eligibility criteria for articles referred in this paper. M1 is the primary muscarinic subtype while α7 is the primary nAChR subtype that is responsible for cognition and memory and these two have been the major recent experimental targets for mAChR agonist strategy. SUMMARY: The last cholinergic receptor agonist to enter phase 3 trial was EVP-6124 (Enceniclin) but was withdrawn due to severe gastrointestinal adverse effects. We aim to present an overview of the efforts and achievements in targeting Muscarinic and Nicotinic acetylcholine receptor in the current review for development of better AD therapeutics.

Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature.

As more cancer patients survive their disease, concerns about radiation therapy-induced side effects have increased. The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the therapeutic ratio of radiation therapy by limiting radiation therapy-induced normal tissue injury without compromising its antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated radiation oncologists to target these pathways across different organ systems. These generalized radiation injury mechanisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful framework to organize the multitude of treatments that have been studied. Many commonly available treatments have demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation. These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important method of making radiation therapy safer.

Sjogren's syndrome from the perspective of ophthalmology.

Sjogren's syndrome (SS) is an autoimmune disease affecting the lacrimal glands resulting in dry eye disease (DED). Ophthalmologists may be the first line of detection of Sjogren's syndrome given the frequency of DED in SS and that dry eye is often the presenting symptom. Numerous symptom questionnaires and tests have been developed to help diagnose DED, but as of yet, there is no "gold standard." Minimally invasive objective metrics are needed for a reliable diagnosis of DED. Currently there is no single test to diagnose SS-associated DED. Although there are several approaches to treatment, none are specific for DED in SS, and, generally, several methods need to be tried to find what works best for a specific patient. Treatment for DED continues to be an unmet medical need, especially given that DED in SS is typically on the severe end of the spectrum.

Discovering the Relative Efficacy of Inhaled Medications for Chronic Obstructive Pulmonary Disease: Multiple Treatment Comparisons.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is managed by three major classes of inhaled medications: inhaled corticosteroids (ICS), long-acting Beta 2-agonist (LABA), long-acting muscarinic antagonist (LAMA). Single inhaled medication is usually replaced by combined inhaled medications for efficacy enhancement. However, this practice should be supported by clinical evidence for large-scale implementations. METHODS: The relative efficacy of inhaled medications is determined by three endpoints: changes in the trough forced expiratory volume in 1 second (tFEV1), changes in the St George's Respiratory Questionnaire (SGRQ) score and the proportion of SGRQ responders which represents a reduction in SGRQ total score at week 24 of ≥4.0. A total of 76 eligible studies were identified in PubMed and Embase. Relevant data were extracted for the purpose of evidence synthesis. Then, raw mean differences (MD) and odds ratios (ORs) were produced by using the network meta-analysis. RESULTS: Patients with ICS + LABA, ICS + LABA + LAMA, LABA, LABA + LAMA, LAMA exhibited significant increases in the tFEV1 compared to those with placebo (P < 0.05). Moreover, patients with ICS + LABA + LAMA exhibited the largest increase in the average tFEV1 and the largest decrease in the average SGRQ scores compared to those with placebo. COPD patients with ICS + LABA + LAMA were far more likely to achieve a significant reduction in the SGRQ scores compared to those with placebo or other inhaled medications (OR > 1). CONCLUSIONS: The combined inhaled medication of ICS + LABA + LAMA may be more efficacious than other inhaled medications for COPD patients.

Salivary gland function after sialendoscopy for treatment of chronic radioiodine-induced sialadenitis.

BACKGROUND: The purpose of this study was to determine whether sialendoscopy could ameliorate radioactive iodine-induced obstructive sialadenitis and restore the salivary gland dysfunction in recalcitrant radioactive iodine sialadenitis. METHODS: Ten patients with 15 parotid glands of chronic radioactive iodine sialadenitis who did not respond to medical treatment were enrolled in this prospective study. We assessed subjective symptom scores and evaluated the objective salivary gland functions before and 3 months after sialendoscopy. RESULTS: The post-sialendoscopic obstructive symptoms were significantly improved relative to pre-sialendoscopy (p = .009). Xerostomia-related symptom scores post-sialendoscopy did not differ significantly from the pre-sialendoscopy scores. Stimulated salivary flow rate post-sialendoscopy tended to increase relative to pre-sialendoscopy. No pre-sialendoscopic parameters associated with salivary uptake and secretion by salivary gland scintigraphy were significantly improved post-sialendoscopy. CONCLUSION: These results show that sialendoscopy can improve obstructive symptoms; however, it seems to have some limitations for relief of xerostomia and improvement of salivary gland dysfunctions in recalcitrant chronic radioactive iodine sialadenitis.

The treatment of gastroparesis, constipation and small intestinal bacterial overgrowth syndrome in patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) affects the nerves of the entire gastrointestinal (GI) tract and may result in profound gastrointestinal (GI) dysfunction leading to poor patient outcomes. Common GI disturbances in patients with PD include gastroparesis (GP), constipation and small intestinal bacterial overgrowth syndrome (SIBO). In particular, GP is difficult to treat due to the limited options available and precautions, contraindications and adverse effects associated with the approved treatments. Moreover, some commonly used medications can worsen pre-existing PD. AREAS COVERED: Our review will focus on treatment options for GP and SIBO with motilin agonists, dopamine receptor antagonists, Ghrelin agonists muscarinic agonists, 5-HT4 receptor agonists, antibiotics, probiotics and herbal formulation such as iberogast. Constipation occurs in the majority of patients with PD and fortunately many treatments are now available. Our review is based on original papers or reviews selected from PUBMED search and Cochrane reviews. EXPERT OPINION: Motility disorders of the GI tract are found frequently in patients with PD and treating the underlying GI disorders caused by PD with various prokinetics and laxatives is paramount in achieving improvements in patient's motor function. Various prokinetics and laxatives are now available to provide some relief of the GI morbidity caused by PD leading even to better absorption of even the PD treatments.

Effects of Salivary Secretion Stimulation on the Treatment of Chronic Radioactive Iodine-Induced Sialadenitis.

BACKGROUND: The aim of this prospective study was to investigate the effect of salivary stimulation therapy using pilocarpine (a cholinergic agent) on chronic radioactive iodine (RAI)-induced sialadenitis. METHODS: Sixty-one patients with a diagnosis of chronic RAI-induced sialadenitis after thyroidectomy and RAI therapy were enrolled in this prospective study. Patients received salivary stimulation therapy with pilocarpine (5 mg, 3 times daily) over a 3-month period. Subjective symptom scores were assessed using self-reported questionnaires. Salivary flow rates (SFRs) were measured and salivary gland scintigraphy (SGS) was performed to evaluate objective salivary gland functions. RESULTS: After salivary stimulation therapy, subjective symptom scores were significantly improved (p=0.002), but posttreatment unstimulated and stimulated SFRs did not differ significantly from pretreatment values. SGS parameters, that is, uptake ratio (UR), maximum accumulation (MA), Tmin, and maximum secretion (MS) of parotid and submandibular glands were nonsignificantly different after salivary stimulation therapy. CONCLUSION: The study shows that salivary stimulation therapy may reduce the subjective symptoms of RAI-induced chronic sialadenitis but does not significantly induce functional restoration.

Advanced therapeutic directions to treat the underactive bladder.

Muscarinic agonists are the most commonly used agents for treating the underactive bladder (UAB). However, because of the absence of pharmacologic specificity for bladder-only effects and possibly as a result of degenerative and other post-synaptic changes involving detrusor smooth muscle cells, they are simply not effective and side effects are common. If safe and effective therapy for UAB is made available, then most experts agree that the potential market would exceed industry expectations, just as antimuscarinic agents for overactive bladder did in the late 1990 s. The pharmaceutical and biotechnology industries that have a pipeline to urology and women's health should consider UAB as a potential target condition. A rational approach to treating the pathology of UAB is presented with a discussion of potential targets that may allow the development of safe and effective agents for the treatment of UAB.

Voiding dysfunction due to detrusor underactivity: an overview.

Detrusor underactivity (DUA) is defined as a voiding contraction of reduced strength and/or duration, which prolongs urination and/or prevents complete emptying of the bladder within a 'normal' period of time. This issue is associated with voiding and postmicturition urinary symptoms, and can predispose to urinary infections and acute urinary retention. The aetiology of DUA is influenced by multiple factors, including ageing, bladder outlet obstruction, neurological disease, and autonomic denervation. The true prevalence of this condition remains unknown, as most data come from referral populations. Urodynamic testing is used to diagnose the condition, either by assessing the relationship between bladder pressures and urinary flow, or by interrupting voiding to measure detrusor pressure change under isovolumetric conditions. Current treatments for DUA have poor efficacy and tolerability, and often fail to improve quality of life; muscarinic receptor agonists, in particular, have limited efficacy and frequent adverse effects. Bladder emptying might be achieved through Valsalva straining, and intermittent or indwelling catheterization, although sacral nerve stimulation can reduce dependency on catheterization. Novel stem-cell-based therapies have been attempted; however, new drugs that increase contractility are currently largely conceptual, and the complex pathophysiology of DUA, difficulty achieving organ specificity of treatment, the limited availability of animal models, and the subjective nature of current outcome measures must be addressed to facilitate the development of such agents.

Promising future therapies for asthma.

Asthma affects 300 million people worldwide and that number has been increasing especially in developed countries. The current standard of care for asthma treatment is based on 2 key pathological features of asthma, airway inflammation and airway obstruction. Improving bronchodilation can be accomplished with ultra-long acting beta2 agonists or long-acting muscarinic agonists used in combination with inhaled corticosteroids. These combinations have already been used effectively for the treatment of COPD. An inhaled phosphodiesterase inhibitor has been shown to improve bronchodilation and decrease airway inflammation. Directly altering the airway smooth muscle with bronchial thermoplasty in select patients has demonstrated long-term benefits but must be measured with immediate post procedure complications. The development of monoclonal antibodies to directly target specific cytokines has had mixed results. In eosinophilic asthma blocking IL-4, IL-5 and IL-13 have improved asthma outcomes. The promise of more directed therapy for asthma appears closer than ever with increased options available for the clinician in the near future.

New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors.

The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer' and Sjogren's diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer's disease drugs.

Visante optical coherence tomography and tear function test evaluation of cholinergic treatment response in patients with sjögren syndrome.

PURPOSE: To evaluate tear meniscus changes in patients with Sjögren syndrome (SS) receiving oral pilocarpine with Visante optical coherence tomography (OCT). METHODS: Eight patients with primary SS were recruited in this prospective interventional case series study. Patients received pilocarpine tablets twice a day for 3 months. Visual analog scale assessment for dry eye and dry mouth symptoms was carried out. Patients underwent OCT and slit-lamp microscopy graticule scale tear meniscus height (TMH) measurements, strip meniscometry testing, tear film breakup time measurement, fluorescein and Rose Bengal staining, and the Schirmer 1 test. The data were analyzed 1 week, 1 month, and 3 months after treatment. Mann-Whitney test was performed. RESULTS: Visual analog scale assessment showed a significant time-wise improvement (P < 0.05). OCT and graticule scale TMH measurements significantly improved after 1 week (P < 0.05), 1 month, and 3 months of treatment (P < 0.001). Strip meniscometry, mean tear film stability, and fluorescein and Rose Bengal scores remained improved 3 months after treatment (P < 0.001), whereas Schirmer 1 test values tended to improve without statistical significance. CONCLUSIONS: Visante OCT was effective in monitoring tear meniscus changes during the course of treatment noninvasively and quickly. Oral pilocarpine seemed to be effective in improving TMH, and the signs and symptoms of dryness in patients with SS.

Malakoplakia in a healthy young female patient

Malakoplakia is a rare granulomatous disease that occurs commonly in the urinary tract and secondarily in the gastrointestinal tract. Most reported cases of malakoplakia are associated with immunosuppressive diseases or chronic prolonged illness. Here, we report a rare case of malakoplakia in a young healthy adolescent without any underlying disease. A 19-year-old female was referred to our hospital following the discovery of multiple rectal polyps with sigmoidoscopy. She had no specific past medical history but complained of recurrent abdominal pain and diarrhea for 3 months. A colonoscopy revealed diverse mucosal lesions including plaques, polyps, nodules, and mass-like lesions. Histological examination revealed a sheet of histiocytes with pathognomonic Michaelis-Gutmann bodies. We treated the patient with ciprofloxacin, the cholinergic agonist bethanechol, and a multivitamin for 6 months. A follow-up colonoscopy revealed that her condition was resolved with this course of treatment.