Update on the Diagnosis and Management of Acute Colonic Pseudo-obstruction (ACPO).

PURPOSE OF REVIEW: Acute Colonic Pseudo-obstruction (ACPO) is a cause of large intestinal dilation and obstruction without any physical transition point. It remains difficult to diagnose and treat. We review the recent updates on diagnosis and management of ACPO. RECENT FINDINGS: Recent guidelines have posited that conservative management can be tried in most cases of ACPO, but that early decompression and surgery should be considered. Use of neostigmine is still a viable option but there is also promising data on pyridostigmine as well as prucalopride. Resolution of ACPO should be followed by daily use of polyethylene glycol (PEG) to help prevent recurrence. ACPO warrants early and accurate diagnosis with exclusion of alternate causes of large bowel dilation. Conservative management can be attempted for 48-72 h in those with cecal diameters < 12 cm and without signs of peritonitis and perforation. Early escalation of management should be attempted with neostigmine followed by endoscopy and/or surgery as needed, given that longer periods of dilation are associated with worse outcomes. There is promising new evidence for use of pyridostigmine and prucalopride, but further trials are needed prior to incorporating them into regular use. Finally, studies are lacking regarding prevention of ACPO after initial resolution.

Polymer drug conjugates containing memantine, tacrine and cinnamic acid: promising nanotherapeutics for the treatment of Alzheimer's disease.

AIM: To prepare polymer-drug conjugates containing a combination of memantine, tacrine, and E)-N-(3-aminopropyl)cinnamide, promising therapeutics for the treatment of neurodegenerative disorders. METHODS: The conjugates were characterised by 1HNMR, particle size analysis, SEM, LC-MS, TEM/EDX, and XRD, followed by in vitro anti-acetylcholinesterase and drug release studies. RESULTS: 1H NMR analysis revealed successful drug conjugation with drug mass percentages in the range of 1.3-6.0% w/w. The drug release from the conjugates was sustained for 10 h in the range of 20-36%. The conjugates' capability to inhibit acetylcholinesterase (AChE) activity was significant with IC50 values in the range of 13-44.4 µm which was more effective than tacrine (IC50 =1698.8 µm). The docking studies further confirmed that the conjugation of the drugs into the polymer improved their anti-acetylcholinesterase activity. CONCLUSION: The drug release profile, particle sizes, and in vitro studies revealed that the conjugates are promising therapeutics for treating neurodegenerative disorders.

Efficacy of Donepezil in the Treatment of Obstructive Sleep Apnea: A Placebo-Controlled Trial.

Background: The treatments of obstructive sleep apnea (OSA) consist of surgical such as uvulopalatopharyngoplasty and non-surgical approaches such as continuous positive airway pressure (CPAP), weight reduction, dental appliance, and some medications. Cholinergic nerve system has been shown an important role in respiratory regulation and in sleep apnea. Donepezil, a reversible acetylcholine esterase inhibitor, can increase cholinergic nerve activity especially during sleep. There were some studies on the efficacy of donepezil in treatment of OSA patients and found significant improvement in the apneahypopnea index (AHI) and oxygen saturation compared to pretreatment and placebo. Objective: To evaluate the efficacy of donepezil in the treatment of obstructive sleep apnea (OSA). Material and Method: A prospective, randomized study was conducted at HRH Princess Maha Chakri Sirindhorn Medical Center. OSA patients diagnosed by polysomnography and Epworth Sleepiness Scale scores were randomly allocated into study group and control group. The study group received donepezil (5 mg), 1 tablet a day for 4 weeks then increased to 2 tablets a day for the next 4 weeks. The control group received placebo drug in the same doses. The value of apnea-hypopnea index (AHI), minimum oxygen saturation (minimum SpO2) and Epworth Sleepiness Scale scores were used in comparison both before and after the end of the study. Results: At the end of the study, 41 patients were collected of which 21 patients were in study group and 20 patients were in control group. Before treatment, there were no significant difference in age (p = 0.53), body mass index (p = 0.80), sex (p = 0.44), minimum SpO2 (p = 0.36), Epworth sleepiness Scale scores (p = 0.86), and AHI (p = 0.06) between two groups. After treatment, no statistically significant difference in the value of AHI, minimum SpO2 and Epworth Sleepiness Scale scores were identified both in the same group and between two groups (p>0.05). Conclusion: Treatment OSA patients with donepezil did not show better results than placebo.

Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease.

A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC50 values of 0.76 and 0.46 µM, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD.

A case of Lambert-Eaton myasthenic syndrome with possible myasthenia gravis.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission (NMJ) that shares many clinical features with myasthenia gravis (MG). We report a 73 year-old lady who presented 10 years previously with stiffness of both calves, dry mouth, fatigue, proximal weakness and areflexia in lower limbs. Neurophysiological studies were consistent with LEMS. Her work up for an underlying neoplasm was negative. She recently developed unilateral ptosis and diplopia which dramatically improved with pyridostigmine suggesting concomitant MG.

Systematic development of lectin conjugated microspheres for nose-to-brain delivery of rivastigmine for the treatment of Alzheimer's disease.

The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be - 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p < 0.001) between the plain (29%) and lectin functionalized microspheres (64%). In vivo behavioral and biochemical studies in the rats treated with lectin functionalized microspheres showed markedly better memory-retention vis-à-vis test and pure drug solution treated rats (p < 0.001). In a nutshell, the present studies showed successful development of nasal microspheres for enhanced brain delivery of rivastigmine for Alzheimer's treatment.

Treatment of Alzheimer's disease with a cholinesterase inhibitor combined with antioxidants.

A formula (formula F) was prepared to counteract oxidative stress (OS) in the brain. The formula contained the most common antioxidants and was intended to: (a) protect proteins, lipids, DNA and proteoglycans from oxidation (carnosine, coenzyme Q(10), vitamin E, vitamin C, beta-carotene, selenium, L-cysteine and ginkgo biloba); (b) reduce homocysteine (HCy) blood levels (vitamins B(6), B(9) and B(12)), and (c) sustain the pentose phosphate cycle in circulating cells (vitamins B(1), B(2) and B(3)). Formula F contained low doses of each antioxidant component and was administered in a two-phase ampoule. A cohort of 52 patients (21 males and 31 females) affected with moderate probable AD (according to NINCDS-ARDA and NINCS-AIREN criteria) already being treated with donepezil (5 mg/day for at least two months) was randomly divided into two groups, and followed for 6 months. A double-blind design was used in which 26 cases were treated once a day with formula F plus donepezil, and the other 26 with placebo plus donepezil. The level of OS was measured on the basis of a d-ROMs test (which measures plasma hydroperoxides), plasma HCy and glutathione, and percentage of sickle erythrocytes. The two patient groups were comparable for all variables (age, sex, concomitant diseases, ApoE epsilon4, MMSE II score, OS, antioxidant reserve and sickle erythrocytes). Forty-eight subjects completed the trial. Significant decreases in OS and HCy were only observed when there was an increase in glutathione (in erythrocytes) and a decrease in sickle erythrocytes in patients treated with formula F. The MMSE II score remained almost the same in the group treated with donepezil and placebo, whereas some significant improvements were found in the group treated with donepezil plus formula F.

The cholinesterase inhibitor physostigmine for the local treatment of dry mouth: a randomized study.

Application of physostigmine to the oromucosal surface with the aim of stimulating underlying mucin-producing glands while reducing cholinergic systemic effects might be a strategy for treating dry mouth. Subjects suffering from dry mouth and with hyposalivation participated in a crossover, double-blind, randomized study. A gel containing physostigmine (0.9, 1.8, 3.6, and 7.2 mg) or placebo was applied to the inside of the lips and distributed with the tongue. The feeling of dryness was assessed using a visual analogue scale (VAS) (where a score of 100 = extremely dry) and systemic effects were registered. Based on assessments of efficacy and safety, the dose of 1.8 mg of physostigmine was selected for use in the second part of the study to make objective measurements of saliva volumes. Physostigmine (1.8 mg) produced long-lasting (120 min) relief (evident as a score reduction of 25 on the VAS) in the feeling of dryness. Judging from AUC values related to baseline over 180 min, the improvement for both mouth and lips in response to physostigmine was six times greater than that to placebo. At higher doses of physostigmine, gastrointestinal discomfort predominantly occurred. The volume of saliva collected in response to physostigmine was five times higher over 180 min than that collected in response to placebo. Physostigmine, applied locally, therefore appears to be a promising modality for dry-mouth treatment.

Datura and Brugmansia plants related antimuscarinic toxicity: an analysis of poisoning cases reported to the Taiwan poison control center.

INTRODUCTION: Datura and Brugmansia plants, especially Datura species, have been used for their hallucinogenic effects in the United States and Europe; whereas Datura plants have been used as a traditional medicine in many Asian countries. This study was conducted to better understand the pattern and outcome of Datura/Brugmansia plant related poisoning in Taiwan. METHODS: This is a retrospective case series study of all cases with Datura/Brugmansia exposure reported to the Taiwan Poison Control Center between 1986 and 2015. Data for patients with relevant poisoning were reviewed and abstracted. Logistic regression analysis was used to identify potential predictors of the severity of poisoning; bivariate analysis was employed to assess the effectiveness of physostigmine in the treatment of Datura/Brugmansia poisoning. RESULTS: A total of 203 cases involving 114 Datura exposures and 89 Brugmansia suaveolens exposures were eligible for analysis. Using Datura/Brugmansia for a medicinal purpose by the patients without consulting Chinese medicine practitioners was the most common reason of poisoning (81.2%); whereas only 2% of the patients were poisoned after medicinal use associated with the prescription from Chinese medicine practitioners. None of the 203 patients had used Datura/Brugmansia plant for recreational purpose. Most frequently observed clinical effect was mydriasis (53.2%), followed by confusion (40%), tachycardia (35.5%), dry mouth (35.5%), dizziness (34%), dry skin (32.5%), and delirium (31%). Seventy-three cases (36%) had severe effects; none of them died. Misidentification of the plants and ingestion of plant parts other than flowers were positively associated with the severity of poisoning. Forty patients (19.7%) received physostigmine therapy and patients receiving physostigmine had an earlier resolution of central nervous system toxicity than those who did not. CONCLUSIONS: Medicinal use without consulting Chinese medicine practitioners is the main reason for Datura/Brugmansia poisoning in Taiwan. Consumption of parts other than flowers and misidentification of the plants predicted the severity of poisoning in this study. Patients who received physostigmine appear to have earlier improvement in the central nervous system effects. No adverse events were reported from physostigmine administration.

Advancements in nanotherapeutics for Alzheimer's disease: current perspectives.

Objectives Considerable progress has been made in the treatment of Alzheimer's disease (AD), but all available strategies focus on alleviating symptoms rather than curing, which means that AD is viewed as an unresolvable neurodegenerative disease. Nanotechnological applications offer an alternative platform for the treatment of neurodegenerative diseases. This review aims to summarize the recent nanomedicine and nanotechnology developments for the treatment of AD.  Key findings A plethora of nanocarriers and nanoparticle prodrugs have been reported to have negligible cytotoxicity in animal models, and these developments have revealed new opportunities for development of new classes of potent drug formulations for AD. Different nanotechnology-based approaches such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes and metal-based carriers have been developed over the past decade, and they have been focusing on both neuroprotective and neurogenerative techniques to treat AD. Studies also reveal that nanotechnological approaches can aid in early diagnosis of AD and enhance therapeutic efficacy and bioavailability.  Summary  Notably, the drugs used conventionally to target the central nervous system have limitations that include an inability to cross the 'blood-brain barrier' or the 'blood-cerebrospinal fluid barrier' effectively and high drug efflux due to the activity of P-glycoprotein, but these limitations can be successfully overcome when nanocarriers are used for targeted drug delivery in AD.

Effect of pyridostigmine on in vivo and in vitro respiratory muscle of mdx mice.

The current work was conducted to verify the contribution of neuromuscular transmission defects at the neuromuscular junction to Duchenne Muscular Dystrophy disease progression and respiratory dysfunction. We tested pyridostigmine and pyridostigmine encapsulated in liposomes (liposomal PYR), an acetylcholinesterase inhibitor to improve muscular contraction on respiratory muscle function in mdx mice at different ages. We evaluated in vivo with the whole-body plethysmography, the ventilatory response to hypercapnia, and measured in vitro diaphragm strength in each group. Compared to C57BL10 mice, only 17 and 22 month-old mdx presented blunted ventilatory response, under normocapnia and hypercapnia. Free pyridostigmine (1mg/kg) was toxic to mdx mice, unlike liposomal PYR, which did not show any side effect, confirming that the encapsulation in liposomes is effective in reducing the toxic effects of this drug. Treatment with liposomal PYR, either acute or chronic, did not show any beneficial effect on respiratory function of this DMD experimental model. The encapsulation in liposomes is effective to abolish toxic effects of drugs.

Preparation and in vitro and in vivo release studies of Huperzine A loaded microspheres for the treatment of Alzheimer's disease.

The purpose of this study was to prepare microspheres containing Huperzine A, which is used for patients suffering from Alzheimer's disease because of its potent anticholineestase activity, and to clarify in vitro and in vivo release characteristics of them. The preparation and in vitro and in vivo release studies of Huperzine A loaded microspheres were described. By spray drying method, Huperzine A was encapsulated successfully in the microspheres which were spherical with a non-porous and smooth surface. In vitro studies showed that the release of Huperzine A from microspheres was depended on the properties of polymers and the release medium. Counter-ionic interaction between the primary amine group of Huperzine A and the carboxylic terminal group of PLG polymers improves the encapsulation of Huperzine A, reducing the initial burst and extending the sustained release. High molecular weight of PLG polymer leads to a negative influence on sustained release of Huperzine A due to less carboxylic terminal groups. Acidic medium also reduces the initial burst and sustained the release due to decreased swelling of the polymeric matrix. In vivo experiment showed, after intramuscular injection, that the plasma concentration of Huperzine A reached the max. at 2 h, then fell rapidly to a stable and near constant level of 0.5 to 2.5 ng/ml within 2 weeks, until the drug was exhausted from the microspheres. It indicates the potential of a 2-week sustained release system of Huperzine A.

[Physostigmine for the immediate treatment of a patient with the central anticholinergic syndrome induced by cocaine cut with atropine]. / Fysostigmine als acute behandeling van een patiënt met het centraal anticholinerg syndroom na gebruik van cocaïne versneden met atropine

A 34-year-old man was admitted in a coma after a nightlong abuse of cocaine and alcohol, whereupon he fell and convulsed at home. There was a fracture of the nose, hyperpyrexia, tachycardia and hypertension. Dry mouth and mydriasis were suggestive of anticholinergic poisoning. Physostigmine 3 mg were slowly administered intravenously, followed by complete neurological recovery and normalisation of the body temperature. There was no brain damage. Cocaine and atropine were found in the patient's urine. Several users of cocaine in various European countries have recently developed a central anticholinergic syndrome due to adulteration of cocaine with atropine. In the presence of indications for such an intoxication, physostigmine is the antidote of first choice.

Donepezil for psychotropic-induced memory loss.

BACKGROUND: Donepezil is an acetylcholinesterase inhibitor marketed for treatment of memory loss and behavioral deterioration associated with the acetylcholine deficit of Alzheimer's disease. We investigated the utility and tolerability of donepezil in nongeriatric affective illness for treatment of psychotropic-induced memory loss, dry mouth, and constipation. METHOD: Nondemented outpatients with stabilized DSM-IV affective illness took 5 mg/day of donepezil for 3 weeks and then increased to 10 mg/day in open trials. Self-rating scales of target symptoms were completed by patients before and 3 to 4 weeks after starting each dose condition. Patients who chose to continue donepezil therapy returned for clinical monitoring every 4 to 8 weeks. RESULTS: Eleven women and 11 men (mean +/- SD age = 45.4+/-8.5 years) completed donepezil trials. Nineteen patients with memory loss rated improvement while taking 5 mg/day of donepezil (p<.001); subsequently, 6 rated further improvement with 10 mg/day (p = .057). Donepezil, 5 mg/day, also reduced ratings of dry mouth (N = 16; p<.001) and constipation (N = 11; p<.05). Side effects included insomnia, nausea, vomiting, and diarrhea; surprisingly, 2 bipolar patients became manic within hours of starting donepezil. Sixteen patients (72%) continued donepezil for an average of 7 months. Consideration of family histories suggested that donepezil response in affective illness may be an early indicator of vulnerability to dementia of the Alzheimer's type. CONCLUSION: (1) Donepezil can reduce memory loss, dry mouth, and constipation in nongeriatric affective patients, but may trigger mania; and (2) long-term follow-up will reveal the predictive value for dementia of donepezil's memory restoration in nongeriatric subjects.

Association of a salivary acetylcholinesterase with Alzheimer's disease and response to cholinesterase inhibitors.

OBJECTIVES: A decrease in cholinergic activity is a key event in the biochemistry of Alzheimer's disease (AD). The aim of the study was to investigate the expression levels of markers of cholinergic function in saliva, which is a readily accessible body fluid that can be obtained from subjects with minimal distress. DESIGN AND METHODS: Salivary samples were obtained from people with NINCDS-ARDRA "probable" Alzheimer's disease and age- and sex-matched controls. Salivary acetylcholinesterase enzyme (AChE) activity was determined colorometrically. RESULTS: Robust AChE catalytic activity was detected in the saliva samples that was stable for up to 6 h at room temperature following the provision of the salivary sample. The activity of the enzyme was significantly lower in people with AD than in age-matched controls. In addition, there were significant differences in activity between those who responded to acetylcholinesterase inhibitor (AChE-I) therapy and those who did not. CONCLUSIONS: Salivary enzyme activity may therefore prove to be a useful marker of central cholinergic activity.

Huperzine A, a nootropic agent, inhibits fast transient potassium current in rat dissociated hippocampal neurons.

The actions of huperzine A (HupA), a novel cholinesterase inhibitor, on the fast transient potassium current (IA) were investigated in CA1 pyramidal neurons acutely dissociated from rat hippocampus. HupA reversibly inhibited IA (IC(50) = 914 +/- 1 microM). The effect was voltage-independent and insensitive to atropine. Tacrine was eight times more potent than HupA (IC(50) = 115 +/- 2 M), whereas huperzine B had little effect. HupA slowed down the decay of IA and its recovery from inactivation. HupA had no effect on the steady-state inactivation, but hyperpolarized the activation curve of IA by 6 mV. The results suggest that HupA may act as a blocker at the external mouth of the A channel. The potential relevance of the inhibitory effect of HupA on IA to the treatment of Alzheimer's disease has been discussed.

Controlled release tacrine delivery system for the treatment of Alzheimer's disease.

Alzheimer's disease is a neurodegenerative condition that affects approximately 5 million people and is the fourth leading cause of death in America. Tacrine is one of the three drugs approved by the FDA for the treatment of Alzheimer's disease. However, the drug has a short biologic half-life of 2-3 hr and gastrointestinal, cholinergic, and hepatic adverse reactions that are associated with high doses of the drug. The aim of our study was to formulate a controlled release delivery system of tacrine that could be used to minimize the side effects associated with the drug. Microparticles of tacrine were formulated using poly(D,L-lactide-co-glycolide) (PLG). PLG and tacrine were dissolved in mixed organic solvents and added to a polyvinyl alcohol solution that was stirred at a constant rate. The organic solvent was evaporated overnight and the formed microparticles were collected by filtration, dried, and sieve-sized. The effects of such formulation variables, as molecular weight of polymer, stir speed during preparation, and drug loading on encapsulation efficiency (EEF), and in vitro release profiles of tacrine were investigated. An increase in the molecular weight of polymer from 8,000 to 59,000 and 155,000 resulted in approximately 10-fold increase in EEF, but the rate of release decreased with increasing molecular weight. Stir speed during preparation had an effect on the EEF but not on the rate of release. Drug loading did not have a significant effect on the EEF but had an effect on the rate of tacrine release. The results suggest that tacrine could be delivered at controlled levels for weeks for the treatment of Alzheimer's disease.

Providing dental care for patients diagnosed with Alzheimer's disease.

Alzheimer's disease is the most common dementing illness affecting over 4 million Americans. As the population ages, dentists and other health care providers will be faced with the daunting task of managing an increasing number of people with this disease. Currently, there are no definitive medications to treat this disease, although there are a number of recent drugs which may help to alleviate some symptoms. This article reviews the current medical treatment and the dental concerns which face the dentist, patient, and family. Suggestions for dental management are given along with practical recommendations for caregivers.

Lambert-Eaton myasthenic syndrome.

The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterised by proximal muscle weakness initially affecting gait, autonomic symptoms (dry mouth, constipation, erectile failure), augmentation of strength during initial voluntary activation, and depressed tendon reflexes with post-tetanic potentiation. The disorder is paraneoplastic (small cell lung cancer) in about 60p. cent (P-LEMS); no cancer is associated in the remainder (NP-LEMS). LEMS affects all races. NP-LEMS can occur in childhood as well as adult life; P-LEMS is unusual at<30 Years. The weakness results from a reduction in the quantal release of acetylcholine from motor nerve terminals, caused by autoantibodies to P/Q-type voltage-gated calcium channels (VGCCs) that are provoked by tumour VGCCs in P-LEMS; the stimulus in NP-LEMS is not known. These antibodies may be implicated in the rarely associated cerebellar degeneration. The diagnosis can be confirmed by detecting the specific antibody in a radioimmunoprecipitation assay, and by finding a reduced compound muscle action potential amplitude that increases by>100p. cent following maximum voluntary activation. Most patients benefit from 3,4-diaminopyridine; pyridostigmine is less effective. Specific tumour therapy in P-LEMS will often ameliorate the neurological disorder. In those with severe weakness, IVIg or plasmapheresis confers short-term benefits. Prednisone alone or combined with azathioprine or cyclosporin can achieve long-term control of the disorder.

Myasthenia gravis and masticatory muscle myositis in a dog.

A 21-month-old, castrated male Vizsla was presented for pelvic limb weakness, difficulty opening his mouth, ptyalism, voice change, and urinary incontinence. Myasthenia gravis and masticatory myositis were diagnosed. The unusual clinical findings, diagnosis, treatment, and case outcome are described, followed by a brief discussion of myasthenia gravis and masticatory myositis.