Gene/Protein Disease Symptom Drug Enzyme Compound
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 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.
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PMID:Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology. 988 90

Alzheimer's disease is, in part, characterised by the loss of neurones in the basal forebrain cholinergic cells that project to the cerebral cortex and hippocampus. These impairments have correlated with the memory loss noted in dementia of the Alzheimer's type. This 'cholinergic hypothesis' has led to the rational design of drugs to enhance or stimulate acetylcholine-mediated neurotransmission. Early acetylcholinesterase inhibitors, such as tacrine and physostigmine, are poorly tolerated and have a short duration of action. Rivastigmine is a centrally-selective acetylcholinesterase inhibitor with a relatively long duration of action and is a 'pseudo-irreversible' cholinesterase inhibitor due to slow dissociation of a carbamoyl derivative from the esteratic site of acetylcholinesterase. Preclinical studies confirmed the central selectivity of the drug and its distribution into the cerebrospinal fluid (CSF). Early studies demonstrated that rivastigmine improved cognition and was relatively well-tolerated at moderate doses. Clinical investigations of rivastigmine administered at doses of 6 - 12 mg/day significantly improved cognition, as measured by the ADAS-Cog score, and activities of daily living, as measured by the Progressive Deterioration Scale. Significant global improvements were also noted as measured by the Clinician's Interview Based Impression of Change that required the use of caregiver information. The most frequent adverse effects noted in clinical trials were consistent with peripheral cholinergic stimulation and included nausea, vomiting, abdominal pain, dizziness and diarrhoea. These effects were dose-related and minimised by slow dose-escalation upon initiation of therapy. Rivastigmine undergoes minimal metabolism by the cytochrome P450 system. As a result, it has few drug interactions. The drug is currently marketed widely in over 60 countries worldwide. In the United States, the drug received 'approvable' status subsequent to the NDA filing, and should be available later this year.
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PMID:Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. 1113 19

We aimed to determine whether the cholinesterase inhibitor rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), would improve quality of life and cognitive function in 16 clinically stable subjects affected by schizophrenia in the residual phase. Study subjects began rivastigmine treatment at a dose of 1.5 mg bid. This dose was escalated at monthly intervals in increments of 1.5 mg bid to a maximum of 6 mg bid. All subjects were followed for 12 months. Quality of life was assessed using the Satisfaction with Life Domains Scale (SLDS, a self-report scale containing 10 "satisfaction" items); cognitive function, attentional function, and aspects of learning and memory were evaluated using common neuropsychological tests. Psychopathology was evaluated by means of the Brief Psychiatric Rating Scale (BPRS). Rivastigmine treatment resulted in significant improvements in quality of life, which were paralleled by significant improvements in cognitive function, learning and memory, and trends for improvement in attention. The BPRS factor "anergia" showed significant improvement, while low baseline scores in other psychotic factors did not permit further improvements. There were no reports of nausea or vomiting. In conclusion, rivastigmine significantly improved quality of life in subjects with schizophrenia. These benefits may relate to the drug's effects on cognitive deficits and negative symptoms associated with the condition.
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PMID:Effects of rivastigmine on cognitive function and quality of life in patients with schizophrenia. 1464 12

Some experimental models suggest that the use of pralidoxime in carbamate toxicity is deleterious. Although pretreatment with atropine minimizes the adverse effect of pralidoxime reported in these models, concerns over the risks of pralidoxime in humans with carbamate poisoning continue. We present a unique case of carbamate toxicity treated successfully with pralidoxime alone. An 80-year-old woman with Alzheimer's dementia presented to the emergency department with 3-4 days of lightheadedness, vomiting, diarrhea, and bilateral lower extremity muscle pain. Extensive review of systems was otherwise negative. Her vital signs were BP, 207/85 mmHg; pulse, 101 beats/min; rectal temperature, 36.6( degrees )C; respirations, 18/min; and SpO(2), 95% breathing room air. Her bedside glucose measurement was 6.7 mmol/L. Physical examination revealed a confused, diaphoretic, ill-appearing woman with miosis and fasciculations of the tongue, eyelids, gastrocnemius and quadriceps bilaterally. The heart, lung, abdominal and head, eyes, ears, nose and throat examinations were otherwise unremarkable. Nine 5-cm(2) rivastigmine patches (9.5 mg/24-hour) were found adherent to her torso and lower extremities. The patches were immediately removed and underlying skin cleansed with soap and water. Laboratory values including complete blood count, basic metabolic panel, calcium, magnesium, phosphorus, troponin, coagulation studies and urinalysis were unremarkable. Due to the absence of pulmonary muscarinic findings, no atropine was administered. However, 1 g of pralidoxime was administered intravenously over 30 min to treat fasciculations. Within 30 min of this treatment, there was significant improvement in symptoms and resolution of fasciculations. She was admitted to the hospital, required no further pralidoxime therapy and was discharged after 3 days. Rivastigmine is a reversible (carbamate) cholinesterase inhibitor used to treat dementia. In overdose, cholinergic crisis is expected and in this case was precipitated by patch overuse. We believe there was a causal relationship between pralidoxime administration and the prompt resolution of symptoms and fasciculations. This case of apparently safe and effective pralidoxime use without concomitant atropine administration in a patient with carbamate toxicity reinforces recent data demonstrating the potential safety of pralidoxime in carbamate toxicity.
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PMID:Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity. 1975 37

Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M1 muscarinic receptor in the brain. However, their side effects such as nausea, vomiting, dizziness, insomnia, loss of appetite and altered heart rate are related to non-specific activation of M2-M5 muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M1 receptor selectivity. Unfortunately, this is limited due to a high degree of orthosteric site homology among the receptor subtypes. In contrast, their allosteric sites are unique and, therefore, allow selective targeting using positive allosteric modulators (PAMs). PAMs of M1 receptors are devoid of agonist activity, however, when bound they enhance the binding affinity of orthosteric ligand, ACh. The major limitation of these PAMs is their bioavailability in the brain. In the current hypothesis, we propose surface modified nano-lipid drug conjugates (LDC-NPs) of PAMs of M1 receptors to improve their bioavailability in brain. When co-administered with AChE inhibitors they are expected to increase their efficacy and reduce their therapeutic dose and side effects.
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PMID:Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer's disease. 2835 83

Rivastigmine is a non-competitive reversible inhibitor of acetylcholinesterase which is approved as one of the fi rst-line treatment options for Alzheimer's disease. We present the case of a 33-year-old woman with acute cholinergic syndrome secondary to deliberate rivastigmine poisoning. The patient presented at the emergency department (ED) with drowsy consciousness, dizziness, vomiting, diarrhea, sweating, and hypertension (171/103 mmHg). At the scene, an empty bottle of Rivast 120 mL/Bot, containing rivastigmine 2 mg/mL, was found beside the patient. Two hours later, we noted bronchorrhea and persistent salivation along with drowsiness, agitation, fatigue, incontinence, and limbs paralysis. A notably low serum cholinesterase level (651 U/l) was identified. Acute cholinergic syndrome secondary to rivastigmine intoxication was diagnosed. Endotracheal intubation with ventilator support was required due to respiratory failure. Atropine (0.5 mg intravenous injection) was administered. She was subsequently admitted to the intensive care unit for further care. Extubation was performed on the third day. The patient insisted on being discharged on the second day after extubation, and after administration of a total of 11 mg of atropine, no signs of either intermediate syndrome or delayed polyneuropathywere noted. rivastigmine, an acetylcholinesterase inhibitor, can precipitate an acute cholinergic crisis in cases of intoxication. Typical clinical features of cholinergic excess include increased secretions in the airway and oral cavity, miosis, diarrhea, anxiety, twitching, bronchoconstriction, convulsions, confusion, and gastrointestinal and muscular cramps. The treatment for acute cholinergic crisis is administration of atropine alone or in combination with an antidote to the cholinesterase inhibitor (such as pralidoxime). Patients often recover well with atropine supplements and optimal supportive care.
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PMID:Successful Resuscitation of a Young Girl Who Drank Rivastigmine With Respiratory Failure. 3299 49