| 2021 | Prognostic nomogram for the severity of acute organophosphate insecticide self-poisoning: a retrospective observational cohort study. | BMJ Open | To develop a convenient nomogram for the bedside evaluation of patients with acute organophosphorus poisoning (AOPP).This was a retrospective study.Two independent hospitals in northern China, the First Hospital of Jilin University and the Lequn Hospital of the First Hospital of Jilin University.A total of 1657 consecutive patients admitted for the deliberate oral intake of AOPP within 24 hours from exposure and aged >18 years were enrolled between 1 January 2013 and 31 December 2018. The exclusion criteria were: normal range of plasma cholinesterase, exposure to any other type of poisonous drug(s), severe chronic comorbidities including symptomatic heart failure (New York Heart Association III or IV) or any other kidney, liver and pulmonary diseases. Eight hundred and thirty-four patients were included.The existence of severely poisoned cases, defined as patients with any of the following complications: cardiac arrest, respiratory failure requiring ventilator support, hypotension or in-hospital death.440 patients from one hospital were included in the study to develop a nomogram of severe AOPP, whereas 394 patients from the other hospital were used for the validation. Associated risk factors were identified by multivariate logistic regression. The nomogram was validated by the area under the receiver operating characteristic curve (AUC). A nomogram was developed with age, white cells, albumin, cholinesterase, blood pH and lactic acid levels. The AUC was 0.875 (95% CI 0.837 to 0.913) and 0.855 (95% CI 0.81 to 0.9) in the derivation and validation cohorts, respectively. The calibration plot for the probability of severe AOPP showed an optimal agreement between the prediction by nomogram and actual observation in both derivation and validation cohorts.A convenient severity evaluation nomogram for patients with AOPP was developed, which could be used by physicians in making clinical decisions and predicting patients' prognosis. |
| 2021 | Clinical correlates of hypotension in patients with acute organophosphorus poisoning. | World J Emerg Med | The aim of the present study is to describe the clinical correlates of hypotension and its associated outcomes in patients with acute organophosphorus poisoning (AOPP).In this retrospective cohort study, we analyzed data pertaining to 871 patients with AOPP who were treated at two hospitals. Data from hypotensive and non-hypotensive patients were compared to identify clinical correlates of hypotension. We also evaluated the association between clinical parameters (including hypotension) and in-hospital mortality.The incidence of hypotension in AOPP patients was 16.4%. Hypotensive patients showed significantly higher in-hospital mortality (1.1% vs. 39.9%, <0.001). Advanced age (odds ratio [] 1.25, 95% confidence interval [] 1.08-1.44), history of diabetes ( 2.65, 95% 1.14-5.96), and increased white blood cell count ( 1.06, 95% 1.03-1.09), plasma cholinesterase ( 0.91, 95% C 0.84-0.94), plasma albumin ( 0.88, 95% 0.85-0.92), serum amylase ( 1.01, 95% 1.01-1.02), and blood pH ( 0.64, 95% 0.54-0.75) were significantly associated with hypotension. After adjusting for potential confounders, hypotension was associated with increased in-hospital mortality (hazard ratio 8.77-37.06, depending on the controlled variables).Hypotension is a common complication of AOPP and is associated with increased in-hospital mortality. Advanced age, history of diabetes, and changes in laboratory parameters were associated with hypotension in AOPP patients. |
| 2019 | Amitraz Poisoning: The not so (Un)common Poisoning. | Cureus | Amitraz is a widely used insecticide and antiparasitic drug. It can cause poisoning in humans via oral, inhalation, and dermal routes. Clinical features hence produced may mimic organophosphate (OP) poisoning because of several shared features (miosis, bradycardia, hypotension) along with a history of possible insecticide poisoning. But the presence of hyperglycemia, hypothermia, and reduced gastrointestinal motility along with normal serum cholinesterase levels and the absence of fasciculations and a hypersecretory state (salivation, lacrimation, perspiration, and diarrhea) point against OP poisoning. Analysis of the poison container also helps confirm the poison. Management is mostly supportive with a good prognosis. |
| 2019 | [Lewy body dementia: therapeutic propositions according to evidence based medicine and practice]. | Geriatr Psychol Neuropsychiatr Vieil | Lewy body dementia (LBD) may present with two clinical forms: dementia with Lewy bodies (DLB) and Parkinson's disease with dementia. LBD is characterized by a profound deficiency of acetylcholine and a deficiency of dopamine. The cholinergic deficit is implicated in major attention disorders and fluctuations. Acetylcholinesterase inhibitors (donepezil or rivastigmine) were studied in several double-blind placebo-controlled studies. The meta-analyzes show a moderate benefit on the cognitive level and on some psychiatric manifestations including hallucinations. A disabling parkinsonian syndrome can be treated with L-dopa as in Parkinson's disease. However, the results are often limited because the increase in doses is restricted by cognitive and psychobehavioral disorders. Hallucinations may require antipsychotic treatment and the best documented drug is clozapine. Some other antipsychotics were assessed but in few therapeutic trials, and appear less efficacious, and with bad tolerance. Finally, the last of LBD cardinal disorders, REM sleep behavior disorders can be improved by melatonin. Other manifestations of LBD are troublesome. Some therapeutic trials with modafinil were proposed to improve diurnal hypersomnia. Anxiety and depression are often difficult to be treated. For antidepressant drugs, the first choice seems to be selective serotonin receptor inhibitors. Treatment for orthostatic hypotension, constipation, and swallowing dysfunction has also been more or less documented. In each case, non-drug management is considered (cognitive stimulation, physiotherapy, speech therapy, etc.). Finally, a therapeutic strategy is suggested, based on the medical and clinical experience. This strategy underlines the importance to improve cholinergic deficit and sleep disturbances. It also stresses the importance of a careful revision of all drugs administered to the patients with a peculiar attention to the anticholinergic treatment. |
| 2018 | Magnesium sulfate and calcium channel blocking drugs as antidotes for acute organophosphorus insecticide poisoning - a systematic review and meta-analysis. | Clin Toxicol (Phila) | Treatment of acute organophosphorus or carbamate insecticide self-poisoning is often ineffective, with tens of thousands of deaths occurring every year. Researchers have recommended the addition of magnesium sulfate or calcium channel blocking drugs to standard care to reduce acetylcholine release at cholinergic synapses.We aimed to review systematically the evidence from preclinical studies in animals exposed to organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo in reducing mortality or clinical features of poisoning. We also systematically reviewed the evidence from clinical studies in patients self-poisoned with organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo, in addition to standard therapy, in reducing mortality, atropine requirement, need for intubation and ventilation, and intensive care unit and hospital stay.We performed a systematic review for articles on magnesium sulfate and calcium channel blocking drugs in organophosphorus or carbamate insecticide poisoning using PubMed and China Academic Journals Full-text (Medicine/Hygiene Series) databases and keywords: "organophosphorus or organophosphate poisoning", "cholinesterase inhibitor poisoning" OR "carbamate poisoning" AND "magnesium", "calcium channel blocker", or generic names of different calcium channel blocking drugs. Review of titles and abstracts revealed 2262 papers of potential relevance. After review of the full papers, a total of 19 papers relevant to the question were identified: five preclinical studies, nine case reports or small case series, and five clinical studies and trials. We also obtained primary data from three unpublished clinical trials of magnesium sulfate, providing data from a total of eight clinical studies and trials for analysis. All studies were of organophosphorus insecticides; no studies of carbamates were found. No pre-clinical or clinical studies of calcium channel blocking drugs and magnesium sulfate in combination were found. We extracted data on study type, treatment regimens, outcome, and side effects. Pre-clinical studies: Two rodent studies indicated a benefit of calcium channel blocking drugs treatment on mortality if given before or soon after organophosphorus exposure, in addition to atropine and/or oxime. In poisoned minipigs, treatment with magnesium sulfate after organophosphorus insecticide poisoning reduced cholinergic stimulation and hypertension. Of note, magnesium sulfate further suppressed serum butyrylcholinesterase activity in one rat study. Observational clinical studies: Calcium channel blocking drugs and magnesium sulfate have been used to treat cardiac dysrhythmias and hypertonic uterine contractions in organophosphorus poisoned patients. A small neurophysiological study of magnesium sulfate reported reversion of neuromuscular junction effects of organophosphorus insecticide exposure. Comparative clinical studies: Only four of eight studies were randomized controlled trials; all studies were of magnesium sulfate, of small to modest size, and at substantial risk of bias. They included 441 patients, with 239 patients receiving magnesium sulfate and 202 control patients. The pooled odds ratios for magnesium sulfate for mortality and need for intubation and ventilation for all eight studies were 0.55 (95% confidence interval [CI] 0.32-0.94) and 0.52 (95% CI 0.34-0.79), respectively. However, there was heterogeneity in the results of higher quality phase III randomized controlled trials providing more conservative estimates. Although a small dose-escalation study suggested benefit from higher doses of magnesium sulfate, there was no evidence of a dose effect across the studies. Adverse effects were reported rarely, with 11.1% of patients in the randomized controlled trials receiving the highest dose of magnesium sulfate requiring their infusion to be stopped due to hypotension.Both preclinical and clinical data suggest that magnesium sulfate and calcium channel blocking drugs might be promising adjunct treatments for acute organophosphorus insecticide poisoning. However, evidence is currently insufficient to recommend their use. Mechanistic and large multi-center randomized controlled trials testing calcium channel blocking drugs and magnesium sulfate are required to provide the necessary evidence, with careful identification of the insecticides ingested and measurement of surrogate markers of toxicity, including butyrylcholinesterase activity. |
| 2018 | Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives. | Neurol Ther | This article describes the practical considerations in the clinical medical treatment in dementia with Lewy body (DLB) patients. It is illustrated with the voice of a DLB sufferer and his wife. According to our experience, emanating from a 15 year collaboration between a doctor and a nurse at a memory clinic, there are several possible therapeutical entrances. However, the order in which the medication is introduced is of great importance to avoid aggravation of other DLB symptoms. We start the treatment with cholinesterase inhibitor and memantine, and; thereafter, we treat the most disturbing symptom. Thereafter, we consider if orthostatic hypotension is present and treat it. In the treatment of depression and anxiety it is beneficial to use agents affecting both noradrenalin and serotonin. Dysphagia may be lethal but can be improved with carbohydrate drinks. These and other aspects are commented upon from our experience and are also reflected in relation to studies evaluating the existing level of evidence. |
| 2016 | Ocular myasthenia gravis in a person with tetraplegia presenting challenges in diagnosis and management. | Spinal Cord Ser Cases | We report the first case of ocular myasthenia gravis (OMG) in a patient with complete tetraplegia, highlighting diagnostic and management challenges. Spinal multidisciplinary rural clinic and specialised inpatient Spinal Cord Injury Unit, NSW, Australia. A 61-year-old man with established C5 AIS A tetraplegia, presented with sudden onset of diplopia and bilateral ptosis, later diagnosed as OMG, in context of other complex co-morbidities, including a cervical cord syrinx, obstructive sleep apnoea and labile blood pressure. Clinical findings were consistent with fluctuating bilateral partial third and sixth nerve palsies. Acetylcholine receptor antibodies were negative, but electromyography demonstrated muscle fatigue. The ocular signs responded well to pyridostigmine. Medications taken before diagnosis, including solifenacin for neurogenic bladder overactivity, were ceased to avoid attenuating the anti-cholinesterase effect. However, the unopposed anti-cholinesterase activity led to frequent and painful abdominal spasms, associated with uncontrolled detrusor hyperreflexia and worsening autonomic dysreflexia (AD). A trans-vesical phenol block to treat this provided only short-lasting benefit. Pyridostigmine was ceased to avoid provoking his abdominal spasms and his regular medications were recommenced. It was decided that the most appropriate treatment for his distressing diplopia was an eye patch. After discharge home, he continued to experience problems with recurrent urinary tract infections, abdominal spasms, episodic postural hypotension and AD. After 5 months, the patient died from an acute myocardial infarction. This case report contributes new knowledge about the rare presentation of OMG in a person with chronic tetraplegia. |
| 2016 | Evaluating the safety and the effects on colonic compliance of neostigmine during motility testing in patients with chronic constipation. | Neurogastroenterol Motil | Neostigmine, an acetyl cholinesterase inhibitor, stimulates colonic motor activity and may induce vagally mediated cardiovascular effects. Our aim was to evaluate effects of i.v. neostigmine on colonic compliance and its safety in patients with chronic constipation.We retrospectively reviewed medical records of a selected group of 144 outpatients with chronic constipation who were refractory to treatment. These patients had undergone intracolonic motility and compliance measurements with an infinitely compliant balloon linked to a barostat. Data abstracted included barostat balloon mean volumes with increases in pressure (4 mmHg steps from 0 to 44 mmHg) before and after i.v. neostigmine. Vital signs and oxygen saturation before and after neostigmine were recorded.Of the 144 patients, 133 were female, mean age was 41.0 ± 15.4 years (SD), and duration of constipation was 12.9 ± 13.8 years. Among patients who had undergone colonic transit measurement by scintigraphy, the overall colonic transit at 24 h (geometric center, GC24 [n = 115]) was 1.5 ± 0.7 (normal >1.3), and at 48 h (GC48 [n = 75]) it was 2.3 ± 0.9 (normal >1.9). Neostigmine decreased colonic compliance at lower distension pressures (e.g., 12 and 20 mmHg [both p < 0.001]), but not at 40 mmHg. There were expected minor changes in vital signs in response to neostigmine in 144 patients; however, one patient developed unresponsiveness, significant bradycardia, hypotension, and muscular rigidity that responded to 400 mcg i.v. atropine.Neostigmine significantly decreases colonic compliance in patients with refractory chronic constipation. Symptomatic bradycardia in response to neostigmine should be promptly reversed with atropine. |
| 2015 | Amitraz: a mimicker of organophosphate poisoning. | BMJ Case Rep | Amitraz is used as an ectoparasiticide for dogs and cattle. Human poisoning due to amitraz may be misdiagnosed as organophosphate/carbamate (OPC) toxicity, since amitraz poisoning shares several clinical features (miosis, bradycardia and hypotension) encountered with OPC poisoning. A 19-year-old man with an alleged history of suicidal ingestion of a pesticide presented with drowsiness and was found to have constricted pupils, hypotension and bradycardia. He was diagnosed as a case of OPC poisoning and was treated with atropine and pralidoxime prior to presentation to our centre. Absence of a hypersecretory state, and the presence of hyperglycaemia and hypothermia along with a normal serum cholinesterase level suggested an alternate possibility. Retrieval of the poison container confirmed the diagnosis of amitraz poisoning. The patient made a rapid recovery with supportive management. Clinician awareness is key to successful management of this poisoning, which carries a good prognosis. |
| 2016 | Repetitive obidoxime treatment induced increase of red blood cell acetylcholinesterase activity even in a late phase of a severe methamidophos poisoning: A case report. | Toxicol Lett | Accidental self-poisoning or deliberate use in suicidal intent of organophosphorus pesticides (OPP), which are widely used in agriculture, represent a health problem worldwide. Symptoms of poisoning are characterized by acute cholinergic crisis caused by inhibition of acetylcholinesterase. A 75-year-old male patient ingested 20ml of an OPP solution containing 10% methamidophos in suicidal intent. In the course of poisoning typical clinical symptoms of cholinergic crisis (miosis, bradycardia, hypotension, hypersalivation and impairment of neurologic status) were evident. Butyryl (plasma) cholinesterase (BChE) and red blood cell acetylcholinesterase (RBC-AChE) revealed decreased activities, thus specific treatment with the enzyme reactivator obidoxime was started. Inhibitory activity of the patient's plasma indicated significant amounts of persisting methamidophos in the circulation and was still found on day 4 after ingestion. Due to missing spontaneous breathing on day 6, obidoxime was administered again. Afterwards a significant increase of RBC-AChE activity was found. The patient was extubated on day 10 and a restitution ad integrum was achieved. In conclusion, obidoxime is a potent reactivator of OPP-inhibited AChE. A repetitive and prolonged administration of obidoxime should be considered in cases of severe methamidophos poisoning and should be tailored with an advanced analytical biomonitoring. |
| 2015 | Comprehensive treatment of dementia with Lewy bodies. | Alzheimers Res Ther | Dementia with Lewy bodies is an under-recognized disease; it is responsible for up to 20 % of all dementia cases. Accurate diagnosis is essential because the management of dementia with Lewy bodies is more complex than many neurodegenerative diseases. This is because alpha-synuclein, the pathological protein responsible for dementia with Lewy bodies (and Parkinson's disease), produces symptoms in multiple domains. By dividing the symptoms into cognitive, neuropsychiatric, movement, autonomic, and sleep categories, a comprehensive treatment strategy can be achieved. Management decisions are complex, since the treatment of one set of symptoms can cause complications in other symptom domains. Nevertheless, a comprehensive treatment program can greatly improve the patient's quality of life, but does not alter the progression of disease. Cholinesterase inhibitors are effective for cognitive and neuropsychiatric symptoms; rivastigmine has the widest evidence base. Special care needs to be taken to avoid potentially fatal idiopathic reactions to neuroleptic medications; these should be used for short periods only when absolutely necessary and when alternative treatments have failed. Pimavanserin, a selective serotonin 5-HT2A inverse agonist, holds promise as an alternative therapy for synuclein-associated psychosis. Levodopa/carbidopa treatment of parkinsonism is often limited by dopa-induced exacerbations of neuropsychiatric and cognitive symptoms. Autonomic symptoms are under-recognized complications of synucleinopathy. Constipation, urinary symptoms and postural hypotension respond to standard medications. Rapid eye movement sleep behavior disorder is highly specific (98 %) to the synucleinopathies. Nonpharmacological treatments, melatonin and clonazepam are all effective. |
| 2016 | Clonidine as an adjuvant in the management of acute poisoning by anticholinesterase pesticides. | Hum Exp Toxicol | Anticholinesterase pesticides are widely used in agriculture and domestic settings throughout the world, and they are responsible for great morbidity and mortality. In Egypt and other developing countries, there is a pressing need for new affordable antidotes to treat anticholinesterase pesticide poisoning. Hence, this study was conducted to evaluate the safety and effectiveness of moderate doses of clonidine in the management of adult patients with acute anticholinesterase pesticide poisoning.This study was an open-label, phase II pilot clinical trial. Sixty patients with acute anticholinesterase pesticide poisoning gave consent to participate in the study. They were divided into 2 equal groups, with 30 patients in each group. Group I received clonidine plus the routine treatment, while group II received only the routine treatment. Patients were subjected to full history taking, and their vital and clinical data were recorded. Serum cholinesterase levels and routine laboratory investigations were measured. The different outcomes of the patients were assessed.The baseline characteristics of both groups were similar. Thirteen (43.3%) patients developed significant hypotension during clonidine treatment. The clinical outcomes (including mortality, need for assisted ventilation, length of hospital stay, and total doses of atropine) showed no significant differences between the two groups.The use of clonidine in acute anticholinesterase pesticide poisoning may be associated with a high incidence of hypotension requiring intervention. The clinical outcomes may not significantly improve in clonidine-treated patients. |
| 2014 | Severe oral and intravenous insecticide mixture poisoning with diabetic ketoacidosis: a case report. | BMC Res Notes | The widespread use of pesticides in public health protection and agricultural pest control has caused severe environmental pollution and health hazards, especially in developing countries, including cases of severe acute and chronic human poisoning. Diabetic ketoacidosis is an uncommon manifestation of acute pesticide poisoning. Suicidal pesticide poisoning by injection is also an unusual way to take poison. We report a severe pesticide mixture poisoning case with diabetic ketoacidosis in an adult with improved outcome after supportive treatment and large doses of atropine.A 30-year-old unmarried Moroccan Arab male with a previous history of active polysubstance abuse and behavior disorders had ingested and self injected intravenously into his forearm an unknown amount of a mixture of chlorpyrifos and cypermethrin. He developed muscarinic and nicotinic symptoms with hypothermia, inflammation in the site of the pesticide injection without necrosis. Red blood cell cholinesterase and plasma cholinesterase were very low (<10%). By day 3, the patient developed stroke with hypotension (80/50 mmHg) and tachycardia (143 pulses /min). Laboratory tests showed severe hyperglycemia (4.49 g/dL), hypokaliemia (2.4 mEq/L), glycosuria, ketonuria and low bicarbonate levels (12 mEq/L) with improvement after intensive medical treatment and treatment by atropine.Suicidal poisonings with self-injection of insecticide were rarely reported but could be associated with severe local and systemic complications. The oxidative stress caused by pyrethroids and organophosphates poisoning could explain the occurrence of hyperglycemia and ketoacidosis. |
| 2014 | Which rivastigmine formula is better for heart in elderly patients with Alzheimer's disease: oral or patch? | Am J Alzheimers Dis Other Demen | Rivastigmine is commonly used for the treatment of Alzheimer's disease (AD). All cholinesterase inhibitors, including rivastigmine, may cause cardiac side effects. The aim of this study is to compare the electrocardiographic (ECG) and hypotensive effects of formulations of rivastigmine.Eighty-five newly diagnosed patients with AD who were treated with rivastigmine were retrospectively evaluated. The ECG records were reviewed at baseline and at administration of either 12 mg of oral rivastigmine or 10 cm(2) transdermal rivastigmine.When compared with the baseline, there were no changes in any of the ECG parameters in all of the patients (P > .05). Moreover, when compared with the mean change from baseline for each treatment group, there were no changes, except heart rate (P = .035).It was demonstrated that rivastigmine formulations were not associated with increased arrhythmogenic or hypotensive effects in elderly patients with AD and was not superior to each other. |
| Pharmacological treatment of Parkinson disease: a review. | JAMA | Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life.To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea.References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic.Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies.Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established. |
| 2014 | Antihypertensive treatment in people with dementia. | J Am Med Dir Assoc | The range and magnitude of potential benefits and harms of antihypertensive treatment in people with dementia has not been previously established.A scoping review to identify potential domains of benefits and harms of antihypertensive therapy in people with dementia was undertaken. Systematic reviews of these domains were undertaken to examine the magnitude of the benefits or harms.Potential outcome domains identified in the 155 papers in the scoping review were cardiovascular events, falls, fractures and syncope, depression, orthostatic hypotension, behavioral disturbances, polypharmacy risks, kidney problems, sleep problems, interactions with cholinesterase inhibitors, and pain. The systematic reviews across these domains identified relatively few studies done in people with dementia, and no convincing evidence of safety, benefit, or harm across any of them.Given the lack of firm evidence of benefits or harm from antihypertensive therapy in people with dementia and the weak evidence for benefits in people over 80 years of age, the current presumption that the favorable evidence drawn from the treatment of nondemented people should be extrapolated to those with dementia is contentious. There is sufficient evidence to warrant particular caution and further research into treatment in this group of patients. |
| Clinical and autonomic profile of patients with Alzheimer's disease and mixed dementia patients. | Rev Assoc Med Bras (1992) | To analyze the clinical and autonomical profile of patients with Alzheimer's disease or mixed dementia (MD).Fifty-four patients with indication for cholinesterase inhibitors use were evaluated through clinical examination, rest electrocardiogram, and spectral analysis of heart rate (HR) variability through digital Holter system recordings.Overall, 61.1% of patients were female and were, on average, 77.1 years of age, 3.3 years of schooling and scored 16.4 points on the Mini Mental State Examination. The gap between symptom onset and diagnosis was 26.2 months. Almost all patients (90.7%) presented at least one clinical comorbidity, and each patient took, on average, 3.7 drugs to control them. Thirty-one patients had some alteration on the electrocardiogram and nine (16.6%) had orthostatic hypotension (OH). The latter was associated with the diagnosis of MD (p=0.001), with lower values of low (LF) and high (HF) frequency components of the spectral analysis in the supine position (p=0.000 and p=0.017, respectively) and with lower values of LF in the orthostatic position (p=0.006). Diagnosis of MD was associated with lower values of LF in both positions (p=0.003 and p=0.007).This sample of patients had frequent comorbidities, which resulted in the prescription of multiple drugs. Signs of autonomic dysfunction resulting in OH were found mainly in those with MD. |
| 2013 | Cholinesterase inhibitors modulate autonomic function in patients with Alzheimer´s disease and mixed dementia. | Curr Alzheimer Res | Cholinesterase inhibitors (ChEIs), the mainstay treatment for dementia, have systemic actions that can affect cardiovascular and autonomic nervous system (ANS). Thirty-nine patients with Alzheimer´s disease or mixed dementia underwent a comprehensive clinical evaluation, prior to and during ChEIs therapy, including orthostatic challenge, electrocardiogram (EKG) and heart rate variability (HRV) spectral analysis through Holter recordings. ChEIs therapy determined a decrease in supine diastolic blood pressure (BP) and in both diastolic and systolic BP in orthostatic position (79.8 ± 9.0 vs. 76.4 ± 9.3 mmHg, p=0.012; 79.9 ± 11.6 vs. 75.3 ± 9.9, p=0.005 and 144.6 ± 25.8 vs. 137.6 ± 21.1, p=0.020, respectively). Spectral analysis revealed no difference on static HRV components, but, during orthostatic challenge, an increase in LF/HF ratio (2.2±2.4 vs. 4.6±5.9, p=0.011) and a reduction in HF component emerged (1604.3 ± 5610.1 vs. 266.1 ± 525.5, p=0.010). ChEIs showed no influence on EKG parameters or on the occurrence of orthostatic hypotension. Treatment with ChEIs was associated with functional improvement of the ANS behavior and to a decrease in supine DBP and in both orthostatic SBP and DBP. |
| 2011 | Treatment of Parkinson's disease. Psychological disorders: striking a balance in order to optimise antiparkinsonian treatment. | Prescrire Int | Parkinson's disease is frequently associated with psychological disorders, especially depression, psychotic disorders, and dementia. We examined the management of psychological disorders in Parkinson's disease, including the use of psychotropic drugs, by reviewing the literature using the standard Prescrire methodology. About one-third of patients with Parkinson's disease experience visual hallucinations. Other hallucinations and delusions can also occur. Dose reduction or withdrawal of certain antiparkinsonian drugs sometimes improves psychotic disorders, providing an acceptable level of symptom control. Clozapine is effective and does not worsen parkinsonian symptoms, but it carries a risk of severe adverse effects, including agranulocytosis. Other neuroleptics are ineffective or worsen motor status. Mood disorders and depression are frequent during the course of Parkinson's disease. Pramipexole, an antiparkinsonian dopamine agonist, improved depressive symptoms in patients with Parkinson's disease in one trial. Its main adverse effects are ocular disorders. Several trials have shown that some tricyclic antidepressants improve depression in Parkinson's patients, but these drugs can worsen cognitive status and cause postural hypotension. Data on selective serotonin reuptake inhibitor antidepressants (SSRIs) are unconvincing. A meta-analysis of three trials showed that treatment withdrawals due to adverse events were similarly frequent with tricyclics and SSRIs. Dementia is frequent in end-stage Parkinson's disease. When severe cognitive disorders occur, it is advisable to withdraw any drugs capable of worsening the situation, especially drugs with antimuscarinic effects and benzodiazepines. Cholinesterase inhibitors have a negative harm-benefit balance in this setting. When a Parkinson's patient presents with a psychological disorder, the first step is to optimise antiparkinsonian treatment by striking a balance between motor control and psychological adverse effects. In the few situations in which drug treatment is likely to be beneficial, it should be remembered that psychotropic drugs are at best only moderately effective and should be used with care, monitoring patients for adverse effects. |
| 2011 | Dementia in Parkinson's disease. | Curr Treat Options Neurol | Dementia in Parkinson's disease encompasses a spectrum relating to motor, psychiatric, and cognitive symptoms that are classified as either Dementia with Lewy Bodies (DLB) (initial cognitive symptoms) or Parkinson's Disease Dementia (PDD) (initial motor signs preceding cognitive symptoms by at least a year). Anticholinergic and antipsychotic drugs have a high risk of adverse cognitive and/or motor effects, so their use should be minimized or avoided. Neuroleptic sensitivity is a severe psychomotor adverse reaction that is particularly associated with potent dopamine-blocking agents such as haloperidol. It occurs in up to 50% of individuals with PDD or DLB. Mild psychotic symptoms should first be addressed by reducing anticholinergic and/or dopaminergic agents, if possible. Patients with psychotic symptoms that threaten the safety of the patient or caregiver may benefit from treatment with quetiapine or, in refractory cases, clozapine. Cholinesterase inhibitors as a drug class have been shown to have beneficial effects on cognition in DLB and PDD, and may help to alleviate some psychiatric symptoms, such as apathy, anxiety, hallucinations, and delusions. Memantine may help to moderate cognitive symptoms in DLB and PDD, although current data suggest a more variable response, particularly in PDD. Parkinsonian motor signs that are accompanied by clinically significant cognitive impairment should be treated with carbidopa/levodopa only, as dopamine agonists and other antiparkinsonian medications generally carry a higher risk of provoking or exacerbating psychotic symptoms. Excessive daytime sleepiness and REM sleep behavior disorder are common associated features of PDD and DLB. Minimizing sedating medications during the day and promoting nocturnal sleep may help the daytime sleepiness; melatonin, clonazepam, gabapentin, and possibly memantine may be useful in treating REM sleep behavior disorder. Orthostatic hypotension can be managed with various nonpharmacologic interventions, and if needed, fludrocortisone and pyridostigmine. Midodrine should be used cautiously, if at all. |
| 2011 | Amitraz poisoning in South Africa: a two year survey (2008-2009). | Clin Toxicol (Phila) | Analysis of the annual pesticide poisoning statistics of the Tygerberg Poison Information Centre (TPIC) for the period 2005-2007 showed an increase in the number of amitraz poisonings. This prompted a 2-year survey (2008-2009) to establish the extent of amitraz poisoning in South Africa. Amitraz is a pesticide used as a tick dip. It acts as an α(2)-adrenoceptor agonist and the principal clinical effects of amitraz poisoning are related to its stimulation of these receptors;Data from amitraz poisoning cases in humans were evaluated for 2 years and analyzed for: demographic data, type of exposure, type of formulation, and clinical details. Serious cases were followed up;4.6% of the pesticide poisoning cases were amitraz-related which comprised 0.8% of all TPIC poisoning consultations. Ingestion of amitraz formulations accounted for the majority of the cases (94%). Forty-one percent of cases were children (n = 28) and all were accidental exposures. Of the adult cases (59%), 88% were intentional ingestions. The majority of the cases were from the predominantly rural province of KwaZulu Natal (44.9%). CNS depression was the most common clinical sign (76.8%) followed by bradycardia 34.8%, respiratory depression 27.5%, miosis 27.5%, and hypotension 23.1%. Mechanical ventilation was required in 15.9% of cases. Other commonly reported clinical signs were hypothermia 15.9%, mydriasis 10.1%, and hyperglycaemia 7.2%. Supportive and symptomatic care was shown to be adequate treatment. Amitraz poisoning was misdiagnosed as cholinesterase inhibitor poisoning in 17.4% of cases;This is the first report of amitraz poisoning in humans in Africa. The data suggest a different demographic pattern in South Africa to that currently reported in the literature. The study identified a very high incidence of intentional poisoning in adults. The misuse of amitraz for deliberate self-harm emphasizes the necessity for continued toxicovigilance. |
| 2010 | Cortical oxygen supply during postural hypotension is further decreased in Alzheimer's disease, but unrelated to cholinesterase-inhibitor use. | J Alzheimers Dis | Cerebrovascular function and structure of the cortical cerebral microvessels are profoundly altered in patients with Alzheimer's disease (AD). The functional hemodynamic consequences of such changes, however, remain essentially unknown. Cholinesterase inhibitors (ChEIs) potentially affect brain perfusion through either augmentation or inhibition of cerebral vasodilatation. This study investigated the cerebrovascular regulation during postural changes in AD before and after treatment with the ChEI galantamine. In 21 AD patients and 20 controls, blood pressure (BP--Finapres), frontal cortical oxygenation (near-infrared-spectroscopy), and cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography) were measured following a hypotensive challenge induced by postural change. In AD, measurements were repeated after 10 (SD 4) weeks of galantamine. Baseline cerebrovascular resistance was higher in AD (AD 2.83 (0.87) mmHg/cm/s, control 2.24 (1.3) mmHg/cm/s, p=0.010). 13 AD patients and 17 controls had a sufficiently large postural drop in BP (> 10 mmHg). AD patients had a larger postural decline in the frontal cortical concentration of total hemoglobin (Delta [tHb] AD=1.03 (0.70) micromol/l, control =0.30 (0.90) micromol/l, p=0.015). Moreover, the reduction in oxygenated hemoglobin was 57% larger in AD (p=0.085). Unexpectedly, the postural changes in BP were smaller in AD. Galantamine treatment affected neither orthostatic BP nor the decrease in [tHb]. In conclusion, even for moderate orthostatic hypotension during commonly occurring postural changes, cerebral cortical tissue perfusion declined more in AD, suggesting increased ischemic vulnerability of the brain. Galantamine neither improved nor impaired cerebrovascular regulation. |
| 2007 | Drug interactions with cholinesterase inhibitors: an analysis of the French pharmacovigilance database and a comparison of two national drug formularies (Vidal, British National Formulary). | Drug Saf | Cholinesterase inhibitors (ChEIs) could be involved in several drug-drug interactions (DDIs) because of their complex pharmacodynamic and/or pharmacokinetic properties.To identify spontaneous reports in the French Pharmacovigilance Database containing DDIs with the three ChEIs marketed in France (donepezil, galantamine or rivastigmine) and to compare the informativity of two national drug references, the French national formulary (Vidal) and the British National Formulary (BNF), for their ability to identify ChEI-related DDIs.Spontaneous reports submitted to the French Pharmacovigilance Database concerning donepezil, galantamine or rivastigmine were reviewed by two clinical pharmacologists from Toulouse Regional Pharmacovigilance Centre. Spontaneous reports containing DDIs were identified according to Vidal, BNF or their own judgement (and with use of the interaction supplement of the French independent drug information bulletin La Revue Prescrire). Then, the potential of DDIs to result in adverse drug reactions (ADRs) was evaluated. Finally, the presentations of the different ChEIs in the two references (Vidal, BNF) were compared for their DDI informativity.A total of 1058 spontaneous reports were identified that involved ChEIs in the French Pharmacovigilance Database up to 31 March 2006; of these 376 (35.5%) contained at least one DDI according to experts' judgement. In total, 118 DDIs (31.4%) were the cause of ADRs. Most of the DDIs were due to pharmacodynamic interactions (247 cases, 65.7%). The most frequently encountered drugs involved in DDIs were bradycardic (205 cases, 54.5%) and anticholinergic (118 cases, 31.4%) drugs. DDIs were found in 309 spontaneous reports (29.2%) according to Vidal and in 127 (12.0%) according to BNF. In total, 88 'serious' ADRs were related to DDIs (including seven deaths, mainly due to cardiovascular ADRs). The most frequently observed ADRs due to DDIs were cardiovascular (67 cases, mainly bradycardia, atrioventricular block and arterial hypotension) and neurological (33 cases, mainly mental confusion). Comparison of the different presentations of summary of product characteristics (SPC) showed that Vidal was more informative than BNF for all the ChEIs, and that galantamine had the most complete data in the two references.DDIs were present in more than one-third of spontaneous reports including ChEIs registered in the French Pharmacovigilance Database. Approximately, one-third of these DDIs were the cause of ADRs. The informativity of European drug dictionaries differs substantially and Vidal was found to be more informative than BNF for all the ChEIs. |
| 2007 | Prevalence of positive carotid sinus massage and related risk of syncope in patients with Alzheimer's disease. | Europace | The prevalence of positive carotid sinus massage (CSM) in asymptomatic elderly persons and related risk of syncope are poorly known.We examined the ability of CSM to predict the risk of profound bradycardia or syncope in 30 patients with Alzheimer's disease (AD) and no history of syncope, before treatment with cholinesterase inhibitors. Carotid sinus massage was repeated at 1, 2 and 8 months after onset of cholinergic therapy. The long-term incidence of syncope was observed over a 20-month follow-up. Among the study patients (mean age = 80 +/- 6 years, 83% women), 10 had positive CSM, with prolonged ventricular standstill in two of them (6.7%). The response to CSM was not predictive of an increased risk in bradycardia-mediated syncope, though syncope occurred in three patients during long-term follow-up, related to orthostatic hypotension in one and to undetermined causes in the others. Cholinergic therapy in all patients, or drugs that slow cardiac conduction, administered to 40% of the responders to CSM and 45% of the non-responders, or the presence of a bundle branch block did not affect the response to CSM or incidence of syncope.A positive CSM was (i) observed in 30% of elderly persons with AD and no history of syncope, and (ii) not predictive of an increased risk of bradycardia-mediated syncope. |
| 2006 | Prognostic value of human erythrocyte acetyl cholinesterase in acute organophosphate poisoning. | Am J Emerg Med | Acute organophosphate poisoning (OPP) such as dichlorvos may be monitored by the measurement of the erythrocyte acetyl cholinesterase (EAChE) and the serum cholinesterase (SChE) activities. The aim of this study was to look at correlation between the severity of the OPP judged by certain parameters such as coma, hemodynamic disturbances, respiratory failure, and the decrease of cholinesterases enzymes including EAChE and SChE at admission. Cholinesterase activity was determined upon admission and then on days 3 and 15 in the morning. Clinical effects, EAChE, and SChE activities data were investigated in 42 patients with OPP aged of 29.6 +/- 11.8 years with acute cholinergic crisis in all cases. They were comatose in 29% of cases, presenting both hypotension or shock and hypoxemia in 17% of cases. Fifteen of them (36%) required mechanical ventilation. The mean EAChE activity at admission was 24.3 +/- 11.6 micromol/mL per hour at 37 degrees C; it was 1260 +/- 2204 IU/L for SChE. There were no correlations between the EAChE and the SChE activities. The EAChE was decreased only in comatose patients and those presenting hypotension, hypoxemia, and bradycardia with a cutoff of 23.5 micromol/mL per hour at 37 degrees C. Death was observed in 2 patients with a deep decrease of the EAChE at 5 micromol/mL per hour at 37 degrees C in 1 case and 9 micromol/mL per hour at 37 degrees C in another. The kinetics of improvement of the EAChE activity below the cutoff showed the absence of statistical improvement of the EAChE activity on day 3 (16.6 +/- 9 vs 19.5 +/- 5.7 micromol/mL per hour at 37 degrees C); this improvement was remarkable on day 15 (16.6 +/- 9 vs 27.5 +/- 6.5micromol/mL per hour at 37 degrees C, P = .0004). In summary, the marked decrease of EAChE activity appears in this study as prognostic factor in acute OPP, and coma, respiratory failure, hemodynamic disturbances, and death are associated with a decrease of the EAChE of less than 23.5 micromol/mL per hour at 37 degrees C. |
| 2006 | The use of neuraxial adjuvant drugs (neostigmine, clonidine) in obstetrics. | Curr Opin Anaesthesiol | Neuraxial adjuvant drugs are used to improve analgesia and to decrease complications associated with a high dose of a single drug. Opioids are used in routinely, but alpha2-agonists, such as clonidine or cholinesterase inhibitors (neostigmine), have also been used for labour analgesia or to relieve pain following caesarean section. Both drugs possess a common mechanism of action that can be beneficial.Small doses of intrathecal clonidine (30 microg), combined with local anaesthetics and opioids, prolong labour analgesia. Hypotension can occur and must be promptly treated by ephedrine to avoid fetal side effects. Epidural clonidine (60 to 75 microg) produces prolonged analgesia from local anaesthetics and opioids and allows a ropivacaine sparing effect. Intrathecal neostigmine has analgesic properties, but its gastro-intestinal side effects contraindicate its clinical use. Epidural neostigmine, combined with sufentanil or clonidine, initiates labour analgesia (minimum 6 to 7 microg/kg; 500 microg) without side effects, however, and allows a 'mobile epidural'. Epidural and spinal clonidine can be used to improve postcaesarean section analgesia. Epidural neostigmine at the doses studied produces modest analgesia following caesarean section.Co-administration of neuraxial drugs may enhance analgesia and reduce the side effects of each drug. Clonidine and neostigmine may be used in obstetrics, under some conditions. |
| 2006 | Atypical neuroleptics as a treatment of agitation and anxiety in Alzheimer's disease: risks or benefits. | Expert Rev Neurother | Behavioral problems produce excess disability that can be potentially devastating in cognitively impaired patients. These behavioral symptoms can be a major cause of stress, anxiety and concern for caregivers. While psychotropic drugs are frequently used to control these symptoms, they have the potential for significant side effects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonism and akathisias. On examination of the consequences of adverse events, somnolence, as well as postural instability and postural hypotension, have been noted. All patients with Alzheimer's disease (AD) and other progressive dementias will advance through stages of moderate-to-severe AD unless effective treatments suspend transition from mild deterioration to dementia, or competitive mortality truncates survival. Treatment trials suggest that these patients respond to both disease-modifying (such as inhibitors of cholinesterase and butirrylcholinesterase) and symptomatic (such as neuroleptics) agents. Relatively few studies have been conducted in this patient population, and more information regarding the type of behavioral disturbances exhibited, how best to measure them in this disabled population and their optimum treatment are urgently needed. |
| 2006 | Cardiovascular effects and risk of syncope related to donepezil in patients with Alzheimer's disease. | CNS Drugs | When otherwise unexplained, syncope in patients with Alzheimer's disease may be attributed to bradycardia caused by cholinesterase inhibitors. We studied prospectively the clinical events and cardiovascular changes occurring during treatment with donepezil in patients with Alzheimer's disease.Consecutive patients presenting with mild-to-moderate Alzheimer's disease were included in the study. Their clinical characteristics, blood pressure, heart rate and electrocardiogram were recorded before (baseline) and during treatment with donepezil. The drug was administered at a dosage of 5 mg/day for 1 month and 10 mg/day for the following 7 months, as tolerated. We compared the baseline observations with those made at 1, 2 and 8 months of donepezil treatment. We also examined the effects of negatively chronotropic or dromotropic drugs concomitantly administered with donepezil.Thirty patients were included in the study, of whom 43% were taking negatively chronotropic or dromotropic drugs. The first month of therapy (donepezil 5 mg/day) was completed by 26 patients. During the 7-month high-dosage phase (10 mg/day), four patients dropped out of the study; thus, 22 patients completed the full 8 months of the study. The mean heart rate was 66 +/- 8 beats/min at baseline in the overall study population. This decreased significantly to 62 +/- 9, 61 +/- 7 and 62 +/- 8 beats/min at the 1, 2 and 8 month timepoints, respectively (all p = 0.002 vs baseline). Among patients not receiving negatively chronotropic or dromotropic drugs, heart rate decreased significantly over the course of the study (from 67 +/- 8 beats/min at baseline to 62 +/- 8 beats/min at 1 month, 62 +/- 7 beats/min at 2 months and 62 +/- 8 beats/min at 8 months [all p = 0.005 vs baseline]). There was no significant change in heart rate in patients who were receiving negatively chronotropic or dromotropic drugs. The PR interval increased over the course of the study in all patient groups, but these changes were only statistically significant in the group of patients who were not taking negatively chronotropic or dromotropic drugs (155 +/- 23ms at baseline vs 158 +/- 21, 160 +/- 22 and 163 +/- 24ms at the 1, 2 and 8 month timepoints; all p = 0.02 vs baseline). One patient developed syncope due to orthostatic hypotension; there were no cases of bradycardia-induced syncope. Gastrointestinal manifestations were reported in ten of the study patients. Abdominal pain and vomiting were the reasons for study termination in five of the eight patients who did not complete the trial.A donepezil-induced decrease in heart rate and increase in PR interval were observed only in patients with Alzheimer's disease who were not treated with negatively chronotropic or dromotropic drugs. These changes were not associated with bradycardia-induced syncope. |
| 2006 | Organophosphate poisonings with parathion and dimethoate. | Intensive Care Med | Organophosphate toxicity is the leading cause of morbidity and death in poisoning by insecticides. The clinical symptoms of pesticide toxicity range from the classic cholinergic syndrome to flaccid paralysis and intractable seizures. The mainstays of therapy are atropine, oximes, benzodiazepines and supportive care. The toxicokinetics vary not only with the extent of exposure, but also with the chemical structure of the agent.We report two cases of poisoning with parathion-ethyl and dimethoate. The patients developed a cholinergic syndrome immediately, accompanied by bradycardia and hypotension.The patients were admitted to the intensive care unit (ICU) a few hours after ingestion. Atropine was administered according to the cholinergic symptoms. The patients recovered in the ICU after 10-12 days and were discharged after 3 and 4 weeks.Organophosphate blood and urine levels were determined on admission and during hospitalisation. The pesticides were rapidly distributed and slow elimination rate of the poisons was documented. In the case of parathion-ethyl the distribution half-life estimated was t(1/2alpha) = 3.1h while the terminal half-life was t(1/2beta) = 17.9 h. Using a one-compartment model for dimethoate the elimination half-life was t(1/2beta) = 30.4 h in plasma and 23.8 h in urine. The serum pseudo-cholinesterase activity was below the limit of detection at admission and recovered during the following 3weeks. |
| 2005 | Management of neurodegenerative disorders: Parkinson's disease and Alzheimer's disease. | J Indian Med Assoc | Neurodegenerative disorders result from premature progressive degeneration of specific neurons, and manifest as diseases or syndromes with varied combinations of cognitive, motor, sensory and autonomic dysfunctions. The management involves pharmacotherapy as well as non-pharmacological measures and also to lessen the burden of the care-givers. The medications available for medical treatment are: Levodopa, dopamine agonists, amantadine, anticholinergics, enzyme inhibitors, etc. Advanced Parkinson's disease is concerned with management of motor complications and non-motor complications. Recently surgical treatment is a great option for managing motor complication. Orthostatic hypotension, gait distiurbances, emotional and psychiatric problems, sleep disturbances can be managed and had been discussed in brief. Currently there is no medication available for the cure of Alzheimer's disease. The specific medications claimed to improve patient's well being and cognition include cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonist, anti-oxidants, and anti-amyloid therapy. While medical and surgical treatments for Parkinson's disease have revolutionised the management, still drug therapy for Alzheimer's disease is dismal. |
| 2005 | Causes of syncope in patients with Alzheimer's disease treated with donepezil. | Drugs Aging | Treatment of Alzheimer's disease (AD) with cholinesterase inhibitors carries a theoretical risk of precipitating bradycardia. Though syncope occurs in patients with AD, its aetiology is unclear. The aim of this study was to determine the causes of syncope in patients with AD who were treated with donepezil and hospitalised for evaluation of syncope.We studied 16 consecutive patients (12 women, 4 men) with AD aged 80 +/- 4 years who were hospitalised for evaluation of syncope. All patients underwent staged evaluation, ranging from physical examination to electrophysiological testing.The mean dose of donepezil administered was 7.8 mg/day, and the mean duration of donepezil treatment at the time of syncope was 12 +/- 8 months. A cause of syncope was identified in 69% of patients. Carotid sinus syndrome was observed in three patients, complete atrioventricular block in two patients, sinus node dysfunction in two patients, severe orthostatic hypotension in two patients and paroxysmal atrial fibrillation in one patient. A brain tumour was discovered in one patient. No cause of syncope was found in 31% of patients despite comprehensive investigation. Repetition of the investigations after discontinuation of donepezil was noncontributory.In patients with AD treated with donepezil, a noninvasive evaluation identified a probable cause of syncope in over two-thirds of patients. Cardiovascular abnormalities were predominant. Noninvasive evaluation is recommended before discontinuing treatment with cholinesterase inhibitors in patients with AD and unexplained syncope. |
| 2004 | Most common intoxication in nephrology ward organophosphate poisoning. | Ren Fail | In Taiwan, the widespread use of organophosphates (OPs) in agricultural and household environments results in numerous OP poisoning. To better understand the clinical significance of associated parameters on respiratory failure and patient outcome, we evaluate patients admitted to the Nephrology ward in our hospital with OP intoxication.Over a period of 2 years, a total of 42 consecutive patients with OP poisoning admitted to the nephrology ward or the Intensive Care Unit of Chang-Gung Memorial Hospital were the subjects in the study. The diagnosis of poisoning was based on history of ingestion and characteristic clinical features of anticholinesterase agent poisoning. Prior to treatment, all symptoms recorded at emergency room and blood samples for blood chemistry including plasma amylase and plasma acetyl-cholinesterase were collected from each patient immediately after the admission.As clinical manifestations of OP show, nausea and vomiting and salivation were the leading manifestations, 45.2% and 33.3%, respectively. Patients who developed respiratory failure were older than those who did not (54.3+/-6.9 vs. 43.1+/-5.6, p<0.05). The dosage of atropine administered for treatment was significantly higher in the patient group with respiratory failure compared to those without respiratory failure (29.7+/-14.5 vs. 9.1+/-10.2, p<0.05). Plasma amylase level of the patient group with respiratory failure was significantly higher than those without respiratory failure (436.1+/-87.1 vs. 181.3+/-29.6, p<0.01). Of course, mean days of hospitalization in the respiratory failure group are significantly longer than the other group (12.1+/-2.1 vs. 5.4+/-1.9, p<0.05). Based on univariant analysis, bradycardia, hypotension, fasciculation and coma were significant factors associated with respiratory failure. The dose of atropine administered for treatment was significantly higher in the oral exposure group compared to nonoral exposure group (23.6+/-12.6 vs. 10.6+/-6.4, p<0.05). The same is true for the pralidoxime treatment (9.6+/-1.9 vs. 5.3+/-1.4, p<0.05). As for mean days of hospitalization (11.6+/-3.9 vs. 6.4+/-2.1, p<0.05) and fatality (2 vs. 0, p<0.05), those of oral exposure patients were significantly longer and higher than those with nonoral exposure.We demonstrate that elevated plasma amylase concentration was related to the development of respiratory failure in OP intoxication. It also provided us various important risk factors to identify those patients with OP poisoning who would ultimately require ventilatory support. |
| 2004 | Depression of mitochondrial respiratory enzyme activity in rostral ventrolateral medulla during acute mevinphos intoxication in the rat. | Shock | We investigated possible changes in bioenergetics at the rostral ventrolateral medulla (RVLM), a medullary site where sympathetic vasomotor tone originates and where the organophosphate poison mevinphos (Mev) acts to elicit cardiovascular intoxication. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection bilaterally of Mev (10 nmol) into the RVLM induced progressive hypotension that was accompanied by an early augmentation (80-100 min post-Mev; Phase I), followed by a decrease (>100 min post-Mev; Phase II) in the power density of the vasomotor components (0-0.8 Hz) in systemic arterial pressure (SAP) signals. Enzyme assay revealed that local application of Mev into the RVLM also significantly and progressively depressed the activity of NADH cytochrome c reductase (marker for Complexes I and III) and cytochrome c oxidase (marker for Complex IV) in the mitochondrial respiratory chain of the RVLM, but not the heart. On the other hand, the activity of succinate cytochrome c reductase (marker for Complexes II and III) remained unaltered. Both the cardiovascular consequences and depression of mitochondrial respiratory chain enzymes elicited by Mev were significantly antagonized on comicroinjection of atropine (3.5 or 7 nmol) bilaterally into the RVLM. We conclude that Mev adversely effects cardiovascular control by acting as a cholinesterase inhibitor in the RVLM, whose neuronal activity is intimately related to the death process. The resulting accumulation of acetylcholine and prolonged activation of muscarinic receptors in the RVLM is manifested by a selective dysfunction of respiratory enzyme Complexes I and IV in the mitochondrial respiratory chain that underlies cardiovascular toxicity associated with organophosphate poisons such as Mev. |
| 2003 | Treatment of psychosis in Parkinson's disease: safety considerations. | Drug Saf | Psychosis only rarely occurs in patients with untreated Parkinson's disease. Much more commonly, psychosis is induced by drug therapy for Parkinson's disease and is the strongest known risk factor for nursing home placement. Delusions are less frequent than hallucinations, but are more concerning as they are often paranoid in nature. Treatment begins with a search for correctable infectious, toxic, and metabolic aetiologies. If symptoms persist, anti-Parkinson's disease medications are slowly reduced. However, withdrawal of these drugs usually worsens parkinsonism and is often not tolerated. Certain atypical antipsychotics can be used to treat psychosis without compromising motor function. The choice of atypical antipsychotic is largely based on ease of use and adverse effect profile as most have comparable efficacy in improving psychosis. Currently, there are five marketed atypical drugs - clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Ziprasidone is the only agent whose adverse effect profile has not been reported in Parkinson's disease. The most common adverse effects of clozapine in Parkinson's disease are sedation, orthostatic hypotension and sialorrhoea. Sedation is generally helpful since these patients are frequently awake at night and tend to have worse behavioural problems then. Clozapine does not induce deterioration of motor function, but it has the potential to cause agranulocytosis, which is idiosyncratic and not dose-related. In risperidone-treated Parkinson's disease patients, reported adverse effects include somnolence, sialorrhoea, dizziness, palpitations, constipation, delirium, fatigue, leg cramps, depression, urinary incontinence and hypotension. Although in some Parkinson's disease studies, risperidone has been well tolerated, others have shown that many patients are unable to tolerate the drug due to deterioration of motor function. While an initial study of olanzapine in Parkinson's disease psychosis showed the drug to be effective without deterioration of motor function, succeeding reports demonstrated a deleterious effect of the drug on motor functioning. The most common adverse effects of quetiapine in Parkinson's disease patients are sedation and orthostatic hypotension. There is a lack of double-blind trials; however, cumulative reports involving >200 Parkinson's disease patients strongly suggest that quetiapine is well tolerated and effective. Unlike clozapine, it does not improve tremor and may induce mild deterioration of motor function. Recently, cholinesterase inhibitors have been reported to alleviate psychosis in Parkinson's disease. Although ondansetron, an antiemetic with antiserotonergic properties, has been reported to relieve psychosis in Parkinson's disease, its prohibitive cost has prevented further study in this population. Electroconvulsive treatment is generally reserved for the patient with psychotic depression who is unable to tolerate any pharmacological therapy. |
| 2002 | The use of remifentanil for bloodless surgical field during vertebral disc resection. | Minerva Anestesiol | A short hospital stay is nowadays desirable and affordable for a wide range of surgical pathology, respecting safety of care and home discharge. In the present study, the Authors investigated the use of TIVA with propofol/remifentanil during microsurgical vertebral disc resection to maintain a controlled vascular hypotension for bloodless surgical field aiming to reduce the operating time and consequently recovery room length of stay and morbility related to anaesthesia.The study took place in a 300 bed Orthopaedics hospital over a period of 3 months and 50 ASA I-II patients were enrolled in this trial; further data are presented for comparison of 50 ASA I-II patients homogeneous for age and sex to the studied population, operated under a standard TIVA with propofol and boluses of fentanyl. Duration of anaesthesia and surgery, time for awakening after cessation of TIVA, incidence of postoperative nausea and vomiting (PONV), amount and quality of postoperative analgesia, length of stay in the recovery room are reported in statistical presentation.Time of surgery and anaesthesia were reduced in the remifentanil group compared with the fentanyl group, thanks to an easily reachable and durable state of controlled hypotension in the first group without the use of any other drug. The recovery profile was shorter in the remifentanil group the drug being rapidly metabolised by plasma cholinesterase.No difference occurred between the two groups regarding quality and amount of postoperative analgesia, while PONV presented more in the fentanyl group and shivering more in the remifentanil group. |
| 2002 | [Delirium in old age can be prevented and treated]. | Tidsskr Nor Laegeforen | Delirium is a common neuropsychiatric syndrome characterized by disturbance of attention and consciousness developing over a short period of time. Symptoms tend to fluctuate during the course of the day. Delirium is by definition a direct physiological consequence of a general medical condition and is probably the most common presenting symptom of disease in old age.Literature review based on search on PubMed and Medline up to 31 December 2001 and a summary of several doctoral theses and our own clinical experience.Several recent intervention studies have clearly shown that delirium can be prevented and treated. Successful intervention programmes have been multifactorial and interdisciplinary, including assessment and treatment of underlying causes as well as prevention and treatment of factors endangering cerebral metabolism. In particular, cerebral hypoxemia caused by i.e. sleep-apnoea syndrome, anaemia, hypotension, pulmonary diseases, and heart failure is often easily prevented and treated. Excellent nursing care seems to be a prerequisite for successful prevention and treatment of delirium. Acceptable scientific evidence for pharmacological treatment is still lacking; it is sometimes necessary but should be used with caution. If sedation is acceptable, clomethiazole is the drug of choice but if the delirium is complicated by frightening hallucinations and agitation, haloperidol or risperidone can be used but only for short periods. Cholinesterase inhibitors are probably a better choice, though randomised treatment studies are still lacking. |
| 2002 | [Poisoning with organophosphate compounds]. | Ned Tijdschr Geneeskd | A 50-year-old man swallowed 200 ml of an insecticide containing the organophosphates dimethoate and phenitrotion in an attempted suicide. On admission, signs of a cholinergic syndrome were observed: miosis, rhinorrhoea, and fasciculations. This was followed by bradycardia with hypotension and vomiting. The patient was treated with the antidotes atropine and obidoxime. Decreasing consciousness necessitated intubation, mechanical ventilation and other supportive measures. Although the serum concentrations of both organophosphate compounds rapidly decreased, the activity of cholinesterase showed a prolonged inhibition. The clinical course was complicated by hypotension, acute respiratory distress syndrome, nosocomial pneumonia, and an epileptic seizure. A period with muscle weakness and a persisting depressive disorder then followed. This case is characteristic for acute intoxications with irreversible acetylcholinesterase inhibitors, such as organophosphate compounds. The treatment of these potentially severe intoxications includes rapid decontamination and the administration of high doses of atropine followed by obidoxime. Mechanical ventilation and circulatory support are also indicated. |
| Engagement of inducible nitric oxide synthase at the rostral ventrolateral medulla during mevinphos intoxication in the rat. | J Biomed Sci | We evaluated the relationship between the toxicity induced by the organophosphate mevinphos (Mev) and inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasomotor tone. Adult Sprague-Dawley rats that were anesthetized and maintained with propofol were used. Laser scanning confocal microscopic analysis revealed colocalization of the M2 subtype of muscarinic receptors (M(2)R) and iNOS immunoreactivity in RVLM neurons. Comicroinjection bilaterally of Mev (10 nmol) and artificial cerebrospinal fluid (aCSF) into the RVLM elicited a progressive decline in systemic arterial pressure (SAP) and heart rate. This was accompanied during phase 1 Mev intoxication by an increase in the power density of the very high-frequency (VHF; 5-9 Hz), high-frequency (HF; 0.8-2.4 Hz), low-frequency (LF; 0.25- 0.8 Hz) and very low-frequency (VLF; 0-0.25 Hz) components of SAP signals. Phase 2 exhibited a reversal of the VHF and VLF power to control levels and a further reduction in the power density of both HF and LF components to below baseline. Hypotension and bradycardia promoted by Mev were significantly blunted on coadministration into the RVLM of the selective iNOS inhibitors S-methylisothiourea (250 pmol) or aminoguanidine (250 pmol). Not only was the augmented power density of HF and LF components during phase 1 Mev intoxication further enhanced, the reduced power of these two spectral components during phase 2 was appreciably antagonized. On the other hand, the temporal changes in VHF and VLF power were essentially the same as with coadministration of Mev and aCSF. We conclude that, as a cholinesterase inhibitor, Mev may induce toxicity via nitric oxide produced by iNOS on activation of the M(2)R by the accumulated acetylcholine in the RVLM. |
| 2001 | [Clinical analysis of patients with community-acquired pneumonia requiring hospitalization classified by age group]. | Kansenshogaku Zasshi | We classified 1017 patients with community-acquired pneumonia requiring hospitalization experienced in Kawasaki Medical School Kawasaki Hospital during the past 15 years into five age groups (< or = 54 years old, 55-64 years old, 65-74 years old, 75-84 years old, > or = 85 years old). With particular emphasis on the elderly patients, we then compared the clinical and microbiological findings in the five groups. The results were as follows; (1) Half of patients in the over 85 years old group were bed-ridden. (2) The proportion receiving antibiotics before hospitalization decreased with age. (3) There were striking atypical pneumonic symptoms, such as dyspnea and consciousness disturbance in the two age groups over 75 years old. (4) Hypotension (shock) increased with age. (5) Markers of nutritional conditions, such as serum protein, albumin, cholinesterase, and hypoxia remarkably increased in the two age groups over 75 years old. (6) There were no significant differences in the isolation rate of etiological microorganisms. (7) The number of polymicrobial agents in the < or = 54 years old group was lower than that in the other age groups. (8) Mycoplasma pneumoniae was most significantly higher in < or = 54 years old group, Haemophilus influenzae in patients 55-64 years old, and Streptococcus pneumoniae in both 65-74 and 75-84 years old groups. (9) The isolation rate of MSSA, gram-negative bacilli such as Klebsiella pneumoniae, Pseudomonas aeruginosa, respiratory viruses increased with age. (10) The amount of sepsis increased with age. (11) The prognosis was poor in the two groups over 75 years old because the mortality rate (over 10%) was higher that for the other age groups. |
| 2001 | Spectral changes in systemic arterial pressure signals during acute mevinphos intoxication in the rat. | Shock | We investigated the cardiovascular consequences of acute intoxication by the organophosphate poison, mevinphos (Mev), and delineated the underlying mechanism. Based on on-line power spectral analysis of systemic arterial pressure (SAP) signals in rats anesthetized and maintained by propofol, we identified two distinct phases after intravenous administration of Mev (160 or 320 microg/kg). Phase I was characterized by transient hypertension and mild tachycardia, concurrent with an increase in the very high-frequency (BVHF; 5-9 Hz), high-frequency (BHF; 0.8-2.4 Hz), low-frequency (BLF; 0.25-0.8 Hz),and very low-frequency (BVLF; 0-0.25 Hz) components of SAP signals. Phase II exhibited significant hypotension, a reversal of the BVHF and BVLF power to control levels, and further reduction in the power density of both BHF and BLF components to below baseline. Microinjection of Mev (2 microg) into the bilateral nucleus reticularis ventrolateralis (NRVL), the medullary origin of sympathetic neurogenic vasomotor tone, essentially duplicated those phasic cardiovascular changes. Similarly, sympathoexcitatory NRVL neurons exhibited respectively an elevation and a decline in their spontaneous activities during Phase I and Phase II Mev intoxication. We conclude that the progressive accumulation of acetylcholine over time induced by a direct inhibition of Mev on cholinesterase in the NRVL may be responsible for the phasic changes in cardiovascular events over the course of acute Mev intoxication. Whereas the initial amount of acetylcholine is excitatory to NRVL neurons, overstimulation by the amassed acetylcholine results instead of an inhibitory action. |
| 2000 | Experience in the treatment of myasthenia gravis with double filtration plasmapheresis. | Chang Gung Med J | Myasthenia gravis (MG) is an autoimmune disease characterized by production of autoantibodies directly against acetylcholine receptors on postjunctional membranes. The treatment modalities of myasthenia gravis include cholinesterase inhibitors, surgical thymectomy, immunosuppressive treatment, and short-term immunotherapies, including plasmapheresis and intravenous immune globulin. Double filtration plasmapheresis (DFP) is a new technique of plasmapheresis. The aim of our study is to evaluate the effectiveness and complications of DFP in the treatment of MG.From December, 1993 to August, 1998, a total of 33 patients with MG received 68 courses (total of 299 sessions) of DFP in our hospital. Plasmapheresis volume, drainage volume, treatment duration, heparin dose, and complications were recorded. In addition, clinical responses after DFP were also evaluated.Only 4 courses (5.88%) of treatment were ineffective. Sixty-four courses (94.12%) of treatment lessened disease activity. The complications of DFP included 15 episodes of hypotension (5.01%), 2 of bradycardia (0.67%), 3 of chest pain (1.00%), 7 of dizziness (2.34%), 58 of high transmembranous pressure of plasma separator (19.40%), 3 of high secondary pressure of plasma fractionator (1.00%), 12 of hemolysis (4.01%), 2 of plasma separator clot (0.67%), 2 of plasma fractionator clot (0.67%), 3 of blood leakage (1.00%), and 1 of air embolism (0.33%). There was no mortality associated with the DFP procedure.DFP is a safe, convenient, and time-saving therapy with rare severe complications in the treatment of MG. Our experience confirms its effectiveness when used in combination with drug therapy and thymectomy. |
| 1999 | Effects of mercury on the arterial blood pressure of anesthetized rats. | Braz J Med Biol Res | The available data suggests that hypotension caused by Hg2+ administration may be produced by a reduction of cardiac contractility or by cholinergic mechanisms. The hemodynamic effects of an intravenous injection of HgCl2 (5 mg/kg) were studied in anesthetized rats (N = 12) by monitoring left and right ventricular (LV and RV) systolic and diastolic pressures for 120 min. After HgCl2 administration the LV systolic pressure decreased only after 40 min (99 +/- 3.3 to 85 +/- 8.8 mmHg at 80 min). However, RV systolic pressure increased, initially slowly but faster after 30 min (25 +/- 1.8 to 42 +/- 1.6 mmHg at 80 min). Both right and left diastolic pressures increased after HgCl2 treatment, suggesting the development of diastolic ventricular dysfunction. Since HgCl2 could be increasing pulmonary vascular resistance, isolated lungs (N = 10) were perfused for 80 min with Krebs solution (continuous flow of 10 ml/min) containing or not 5 microM HgCl2. A continuous increase in pulmonary vascular resistance was observed, suggesting the direct effect of Hg2+ on the pulmonary vessels (12 +/- 0.4 to 29 +/- 3.2 mmHg at 30 min). To examine the interactions of Hg2+ and changes in cholinergic activity we analyzed the effects of acetylcholine (Ach) on mean arterial blood pressure (ABP) in anesthetized rats (N = 9) before and after Hg2+ treatment (5 mg/kg). Using the same amount and route used to study the hemodynamic effects we also examined the effects of Hg2+ administration on heart and plasma cholinesterase activity (N = 10). The in vivo hypotensive response to Ach (0.035 to 10.5 microg) was reduced after Hg2+ treatment. Cholinesterase activity (microM h-1 mg protein-1) increased in heart and plasma (32 and 65%, respectively) after Hg2+ treatment. In conclusion, the reduction in ABP produced by Hg2+ is not dependent on a putative increase in cholinergic activity. HgCl2 mainly affects cardiac function. The increased pulmonary vascular resistance and cardiac failure due to diastolic dysfunction of both ventricles are factors that might contribute to the reduction of cardiac output and the fall in arterial pressure. |
| 1998 | Adverse effects and drug interactions associated with local and regional anaesthesia. | Drug Saf | Systemic and localised adverse effects of local anaesthetic drugs usually occur because of excessive dosage, rapid absorption or inadvertent intravascular injection. Small children are more prone than adults to methaemoglobinaemia, and the combination of sulfonamides and prilocaine, even when correctly administered, should be avoided in this age group. The incidence of true allergy to local anaesthetics is rare. All local anaesthetics can cause CNS toxicity and cardiovascular toxicity if their plasma concentrations are increased by accidental intravenous injection or an absolute overdose. Excitation of the CNS may be manifested by numbness of the tongue and perioral area, and restlessness, which may progress to seizures, respiratory failure and coma. Bupivacaine is the local anaesthetic most frequently associated with seizures. Treatment of CNS toxicity includes maintaining adequate ventilation and oxygenation, and controlling seizures with the administration of thiopental sodium or benzodiazepines. Cardiovascular toxicity generally begins after signs of CNS toxicity have occurred. Bupivacaine and etidocaine appear to be more cardiotoxic than most other commonly used local anaesthetics. Sudden onset of profound bradycardia and asystole during neuraxial blockade is of great concern and the mechanism(s) remains largely unknown. Treatment of cardiovascular toxicity depends on the severity of effects. Cardiac arrest caused by local anaesthetics should be treated with cardiopulmonary resuscitation procedures, but bupivacaine-induced dysrhythmias may be refractory to treatment. Many recent reports of permanent neurological complications involved patients who had received continuous spinal anaesthesia through a microcatheter. Injection of local anaesthetic through microcatheters and possibly small-gauge spinal needles results in poor CSF mixing and accumulation of high concentrations of local anaesthetic in the areas of the lumbosacral nerve roots. In contrast to bupivacaine, the hyperbaric lidocaine (lignocaine) formulation carries a substantial risk of neurotoxicity when given intrathecally. Drugs altering plasma cholinesterase activity have the potential to decrease hydrolysis of ester-type local anaesthetics. Drugs inhibiting hepatic microsomal enzymes, such as cimetidine, may allow the accumulation of unexpectedly high (possibly toxic) blood concentrations of lidocaine. Reduction of hepatic blood flow by drugs or hypotension will decrease the hepatic clearance of amide local anaesthetics. Special caution must be exercised in patients taking digoxin, calcium antagonists and/or beta-blockers. |
| 1997 | SB 202026: a novel muscarinic partial agonist with functional selectivity for M1 receptors. | J Pharmacol Exp Ther | The finding that ascending cholinergic systems are severely degenerated in Alzheimer's disease has driven the search for a cholinomimetic therapy. Adverse effects observed with cholinesterase inhibitors and high-efficacy muscarinic agonists led us to design compounds with an improved profile. SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes. In functional models in vitro, SB 202026 caused maximal depolarization of the rat superior cervical ganglion at low concentrations (300 nM) (M1-mediated effect), while producing a lower maximal effect than the high-efficacy agonists oxotremorine-M and carbachol on M2-mediated release of ACh and M3-mediated smooth muscle contraction (guinea pig ileum), respectively. The functional selectivity and partial agonist profile seen in vitro were reflected in vivo through potent cognition-related activity (M1-induced increase in hippocampal EEG power) combined with low efficacy, compared with arecoline or oxotremorine, on induction of bradycardia (M2-mediated response), hypotension (via M3-mediated vasorelaxation) and tremor (thought to be mediated by M3 receptors). The foregoing profile of SB 202026 predicted that cognition-enhancing activity would be achieved at doses below those that initiate undesirable side effects, and this has subsequently been demonstrated in rodents, marmosets and humans. |
| 1994 | [Evaluation of the total hepatic function after treatment with fosinopril in hypertensive patients with liver cirrhosis]. | Clin Ter | Fosinopril is distinguished from other ACE inhibitors by a pharmacokinetic pecularity in the sense that is can be metabolized either by liver or kidney. This was the rationale of the present research the aim of which was to verify if administered to patients with liver cirrhosis the drug was liable to alter global liver function and ability to metabolize drugs. Eight cirrhotic males, mean age 56 years, also suffering from high blood pressure, were studied. In these patients, liver and kidney function tests (BUN, creatinine blood level, serum and urinary electrolytes, creatinine clearance, calcium and phosphor blood level, transaminases, alkaline phosphatase prothrombin time, cholinesterase, gamma-glutamyl-transpeptidase) were carried out at baseline and after 30 days' fosinopril treatment (1 capsule every morning in the fasting state); in addition total functioning liver mass was assessed by the galactose test, and drug-metabolizing capacity by the antipyrine test. Treatment resulted in a significant improvement of pressure values in all patients (p < 0.01) and did not alter liver and kidney function parameters. Besides, no side effects were registered, especially no case of orthostatic hypotension. The antipyrine test was not influenced by fosinopril treatment. Therefore, short-term treatment with this ACE-inhibitor can be concluded to be effective and not to cause additional alterations of liver function in patients with liver cirrhosis. |
| 1994 | Intrathecal cholinergic agonists lessen bupivacaine spinal-block-induced hypotension in rats. | Anesth Analg | Hypotension is an important side effect of spinal anesthesia. Intrathecal (IT) cholinergic agonists, including neostigmine (NEO), increase arterial blood pressure by stimulating spinal sympathetic neurons. Therefore, we tested the ability of IT cholinergic agonists to prevent the hypotensive effect of IT bupivacaine (BUP) (430 nmol) in rats instrumented with IT and arterial catheters. The mean arterial pressure (MAP) decreased 35 +/- 4 mm Hg (n = 10) after IT-BUP alone. In contrast, MAP did not significantly change after IT-BUP + IT-NEO (12.5 and 25 nmol; n = 5 for each dose). Intramuscular (IM) NEO was not effective, and MAP decreased 38 +/- 4 mm Hg after IT-BUP + IM-NEO (25 nmol; n = 5). Three additional cholinesterase inhibitors, physostigmine, edrophonium, and ambenonium, as well as the direct-acting cholinergic agonists carbachol, oxotremorine, and arecoline, each lessened the hypotension seen after IT-BUP. Furthermore, the nonselective muscarinic antagonist, atropine, as well as the M2 receptor selective antagonist, methoctramine, prevented the vasopressor effect of IT-NEO in our model. Finally, the nicotinic antagonist, mecamylamine, and the M1 selective antagonist, pirenzepine, did not affect the pressor effects of NEO in our model. In conclusion, IT cholinergic agonists lessen BUP spinal-block-induced hypotension in rats by a muscarinic dependent pathway. |
| 1994 | Organophosphate poisoning: peripheral vascular resistance--a measure of adequate atropinization. | J Toxicol Clin Toxicol | We report severe organophosphate poisoning complicated by hypotension and ischemic sequelae in two patients with pre-existing vascular disease. Both patients had a low total peripheral resistance and high cardiac output that were significantly reversed by doses of atropine in excess of those required to control other muscarinic symptoms. Cerebral infarcts and gangrene requiring a below knee amputation were complications of the poisonings. It is proposed that the ischemic complications are due to paradoxical vasoconstriction by acetylcholine at sites of endothelial injury. One patient, who had taken fenthion, also had a significantly delayed peak and prolonged, 2-3 week, systemic toxicity. We propose that stability of the plasma cholinesterase at 6 to 8 h after temporarily suspending oxime provides a rapid guide to the duration of therapy, especially in patients whose complications make clinical assessment difficult. |
| 1993 | Pregnancy decreases the threshold for cocaine-induced convulsions in the rat. | J Lab Clin Med | The objective of this study was to test our hypothesis that pregnancy modifies the central nervous and cardiovascular toxicity of cocaine. Ten chronically catheterized term pregnant rats and 13 chronically catheterized nonpregnant female rats were infused with cocaine (2 mg/kg/min) intravenously to observe the sequential toxic manifestation of cocaine from mild central nervous stimulation (hyper-locomotor activities) to fatal cardiovascular collapse. Arterial blood samples were withdrawn at the onset of major toxic signs or symptoms--namely convulsion, hypotension, and circulatory collapse--for determination of cocaine concentrations and plasma cholinesterase activity. The dosage and plasma concentrations of cocaine associated with the onset of convulsions and cardiovascular depression were significantly lower in pregnant rats when compared with the nonpregnant animals. The mean time required to develop convulsions in the pregnant rat was significantly shorter (21 minutes) than that in the nonpregnant animal (33 minutes). However, once convulsive activity had developed, the time interval to achieve circulatory collapse was similar in both groups. Although the baseline plasma cholinesterase activity was higher in the pregnant rats than in the nonpregnant ones, the values in the samples obtained from the pregnant group at the onset of circulatory collapse were similar to the baseline values for the nonpregnant group. These findings suggest that a higher enzyme activity does not protect the development of toxic manifestations in the pregnant rat as compared to the nonpregnant animal when cocaine was administered at the same infusion rate. |
| 1993 | Inhibitory effect of fenthion and diazinon on the contraction of rat aorta, and its contribution to lethality. | J Vet Med Sci | Fenthion and diazinon, P = S type organothiophosphates which are precursors of cholinesterase inhibitors, cause remarkable atropine-insensitive hypotension in rats when administered intravenously in lethal doses. We investigated their effects on isolated rat aorta and atria to reveal the site of action. Fenthion and diazinon inhibited both types of contractions induced by high K+ solution and norepinephrine in aortic preparations from which the endothelium was removed. IC50 values (under [Ca2+] = 1.5 mM) were 2 x 10(-5) M and 7 x 10(-5) M, respectively. However, the atrial preparations were relatively resistant, since fenthion showed no effect up to 10(-3) M and diazinon at 10(-4) M exhibited a slight inhibition which was antagonized by atropine. The hypotensive effect of fenthion or diazinon was therefore attributable to the direct inhibiting action on the arterial muscle tone, which may be independent of the activation of muscarinic receptors. The results suggested that fenthion and diazinon affect movement and/or utilization of calcium in the aortic muscle cells, since an increase in the calcium concentration in the bathing solution antagonized their inhibitory effect. |
| Clinical pharmacology of mivacurium chloride: a review. | J Clin Anesth | Mivacurium chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovery) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The ED95 in adults under narcotic-based anesthesia is 0.07-0.08 mg/kg. At twice the ED95 (0.15 mg/kg) onset time is about 2 to 3 minutes, duration to 25% recovery is 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 micrograms/kg/min (range 2-15) with a 5-95% recovery time of 14 minutes. Enflurane and isoflurane require a 20-30% decrease in dosage; halothane, enflurane, and isoflurane prolong the duration of mivacurium 25-30%. The ED95 in children 2 to 12 years of age is slightly higher (0.09-0.11 mg/kg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mg/kg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When administered rapidly at doses of 0.2 mg/kg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mg/kg or higher are not recommended by the manufacturer. Mivacurium is metabolized by plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal plasma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mg/kg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic transplant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Adverse reactions and interactions of the neuromuscular blocking drugs. | Med Toxicol Adverse Drug Exp | The adverse reactions seen following administration of neuromuscular blocking agents are mainly cardiovascular. Due to the lack of specificity for the nicotinic receptor at the neuromuscular junction, these agents may interact with receptors in autonomic ganglia and muscarinic receptors in the heart. Furthermore, muscle relaxants may have histamine-releasing properties. The cardiovascular effects vary with potency and specificity of the drug, depending mainly on the chemical structure. Pancuronium, fazadinium and especially gallamonium block cardiac muscarinic receptors, and tachycardia may be seen. Atracurium, metocurine and in particular d-tubocurarine have histamine-releasing properties and may cause flushing, hypotension and tachycardia. Vecuronium has no effect on the cardiovascular system. The effect of succinylcholine on heart rate differs between children, where bradycardia is seen, and adults in whom tachycardia may follow. However, bradycardia may occur in adults following a single dose. Succinylcholine increases plasma potassium, especially in patients with nerve damage, and arrhythmias may be observed. The neuromuscular adverse effects of succinylcholine, such as fasciculations and increased gastric and intraocular pressure, may be prevented by precurarisation. Many drugs interact with neuromuscular blocking agents and there is often a potentiation of the neuromuscular effect. This is of clinical importance in the case of antibiotics, inhalational anaesthetics, lithium and cyclosporin. Difficulty in reversing the block may occur with calcium channel blockers and polymyxin. However, some drugs, such as phenytoin, carbamazepine and lithium, may cause resistance to neuromuscular blocking agents. Furthermore, clinically important interactions exist between individual neuromuscular blocking drugs. Precurarisation with a non-depolarising drug prolongs the onset of succinylcholine, and conversely a prolonged effect of non-depolarising drugs is seen following succinylcholine. The effect of succinylcholine is markedly prolonged if the drug is administered during recovery from pancuronium blockade or following neostigmine for reversal. Succinylcholine is hydrolysed by plasma cholinesterase, and drugs which decrease the activity of this enzyme may produce a prolonged block, i.e. contraceptive pills, cyclophosphamide, echothiopate and organophosphate. |
| 1988 | Cardiorespiratory effects produced by activation of cholinergic muscarinic receptors on the ventral surface of the medulla. | J Pharmacol Exp Ther | Our purpose was to examine the influence of inhibition of cholinesterase at the ventral surface of the medulla on cardiorespiratory activity in the chloralose-anesthetized cat. Administration of the anticholinesterase agent, diisopropylfluorophosphate (DFP) to areas responding to acetylcholine (i.e., rostral and caudal chemosensitive areas of the ventral surface of the medulla) in doses ranging from 12.5 to 50 micrograms bilaterally had minimal effects on cardiorespiratory activity. However, similar doses applied to the intermediate area of the ventral surface of the medulla produced an increase in tidal volume and hypotension. For example, a dose of 12.5 micrograms increased tidal volume by 14 +/- 3 ml (P greater than .05). Similar responses were seen with higher doses of DFP; in addition, respiratory depression (apnea) also occurred. This depression was characterized by a slowing in respiratory rate. The organophosphate compound, soman, in doses of 0.25 and 0.5 micrograms produced effects similar to those seen with DFP with the exception that an increase in respiratory rate was observed before the decrease in respiratory rate occurred. In addition, a greater degree of hypotension was observed with soman as compared to DFP. Findings comparable to those obtained with DFP were produced by the muscarinic receptor agonist, oxotremorine (0.077-10 micrograms). The effects of DFP, soman and oxotremorine were counteracted by locally applied atropine. In addition, measurements of acetylcholinesterase activity taken from the rostral, intermediate and caudal areas indicate a relatively low activity at the rostral area but a relatively high activity at the intermediate area.(ABSTRACT TRUNCATED AT 250 WORDS) |
| 1987 | Aminoglycoside antibiotics: interaction with trimethaphan at the neuromuscular junctions. | Drugs Exp Clin Res | Trimethaphan, a ganglionic blocking agent which is administered by intravenous drip to produce controlled hypotension during surgery, produces a complete neuromuscular blockade at the isolated phrenic nerve-hemidiaphragm preparation of the rat at a concentration of 0.3 mmol X l-1. This blockade is not reversed by neostigmine, a cholinesterase inhibitor, nor by calcium chloride, and this action is attributed to the local anaesthetic activity of the drug. Trimethaphan (1.5 X 10(-2) mmol X l-1) interacts with the following aminoglycoside antibiotics: gentamicin (0.04), streptomycin (0.05), netilmicin (0.06), amikacin (0.11), sisomicin (0.14), kanamycin (0.17), tobramycin (0.18) and dibekacin (0.21 mmol X l-1) to produce a complete neuromuscular blockade. These pharmacodynamic interactions of trimethaphan and aminoglycoside antibiotics occur at significantly reduced concentrations of the interacting drugs which are very close to the ones obtained after administration of therapeutic doses. When trimethaphan or aminoglycoside antibiotics are used alone at the above reduced concentrations they do not exert any neuromuscular blocking activity. The neuromuscular blockade which is obtained after the interaction of trimethaphan with aminoglycoside antibiotics is not reversed by either neostigmine or calcium chloride, although the neuromuscular blockade which is produced by aminoglycoside antibiotics alone is reversed by calcium chloride. It is concluded that the local anaesthetic effect of trimethaphan is the predominant factor of the mechanism of the above interactions. These interactions may produce severe respiratory disturbances (respiratory depression or apnoea) to the patients, during the perioperative period, which can be reversed only with artificial ventilation. |
| 1984 | Enzymatic and nonenzymatic hydrolysis of D,L-dipivefrin. | Arch Ophthalmol | D,L-dipivefrin hydrochloride was administered bilaterally to rabbit eyes five or 150 minutes after unilateral application of a cholinesterase inhibitor. Aqueous humor levels of D,L-epinephrine, measured 30 minutes later by high-performance liquid chromatography, were not significantly different in the two eyes. Nonenzymatic conversion of D,L-dipivefrin to D,L-epinephrine was measured in tissue-free (pH 7.4) solutions; after three hours less than 1% of D,L-dipivefrin became D,L-epinephrine. Homogenates of corneal epithelium were 16 times more effective in converting D,L-dipivefrin to D,L-epinephrine than after heat-inactivation. The ocular hypotension produced by 0.25% D,L-dipivefrin eyedrops was unaffected by prior administration of 0.25% echothiophate iodide eyedrops provided the D,L-dipivefrin was administered after the echothiophate-induced ocular hypertensive phase. It was concluded that D,L-dipivefrin was converted to D,L-epinephrine in vivo primarily by enzymatic hydrolysis and that cholinesterase inhibitors did not affect this conversion. |
| 1981 | Central cardiovascular effects of physostigmine in the cat; possible cholinergic aspects of blood pressure regulation. | Arch Int Pharmacodyn Ther | The cental actions of the lipophilic cholinesterase inhibitor physostigmine were investigated by infusing very low doses (0.8 micrograms up to 18 micrograms per kg) into the left vertebral artery of the anaesthetized cat. A dose as low as 2.7 micrograms per kg reduced blood pressure by about 35%. High doses caused bradycardia. Occlusion of the right vertebral artery shifted the dose-response curve to the left. It seems likely that the hypotension was due to stimulation of muscarinic receptors in the pontomedullary region, since pretreatment with dexetimide administered via the vertebral artery strongly reduced the effect. Mecamylamine and the adrenergic blocking agents metoprolol and piperoxan, infused into the vertebral artery, could not reduce the depressor response and the bradycardic action. Both bilateral cervical vagatomy and peripherally applied N-methylatropine did not change the hypotensive action of physostigmine. This observation points towards a reduction of sympathetic outflow as the possible cause of the depressor effect. Atenolol, given intravenously, diminished the bradycardia to a great extent, whereas N-methylatropine did not significantly alter the negative chronotropic action of physostigmine. These results suggest a dominant role for the sympathetic system in reducing cardiac frequency. After intravenous administration, only doses higher than 28 micrograms per kg evoked hypotension, which could not be blocked by intravenously administered N-methylatropine. However, centrally infused dexetimide considerably antagonized this effect, indicating that the hypotension was brought about by a central action and not evoked peripherally. Application of the drug via the external carotid arteries resulted in hypotension after considerably higher doses than those following administration via the vertebral artery, indicating the pontomedullary region as the main site of action. It is concluded that the present experimental data obtained with physostigmine support the hypothesis that ACh might have a transmitter role in the central haemodynamic control. |
| 1980 | comparison of the efficacy of HS-6 versus HI-6 when combined with atropine, pyridostigmine and clonazepam for soman poisoning in the monkey. | Arch Int Pharmacodyn Ther | Monkeys were exposed to varying doses of soman and given therapy. Therapy consisted of pyridostigmine, clonazepam, atropine and HS-6 or HI-6. Cerebral electrical activity, heart rate, respiration, systemic blood pressure and cholinesterase activity were recorded thoughtout the experiment. The animals in the HS-6 series were divided into 4 groups depending upon the dose of soman; one group received 30 microgram/kg of soman, the second group received 40 microgran/kg. All animals in the HI06 series survived while only one of three monkeys in the fourth group survived. Administration of therapy immediately suppressed all seizure activity and convulsions and the animals appeared awake throughout the experiment. All animals exhibited bradycardia and hypotension following the adminstration of therapy. The cholinesterase activity was depressed after administration of HS-6 therapy. Three of the four monkey that received therapy consisting of HI-6 at a dose of 15 mg/kg survived, while one of two that received HI-6 at a dose of 30 mg/kg survived. The animals that received HI-6 at a dose of 15 mg/kg did not exhibit as severe a decrease in blood pressure as the animals in either the HS-6 series or the monkeys that received HI-6 at 30 mg/kg. In addition, these monkeys were awake and appeared alert throughout the experiment and were up within 4-6 hr post-exposure to soman. The animals that received 30 mg/kg exhibited severe hypotension and did poorly. |
| 1979 | Pharmacological activities of acetal derivatives of hemicholinium no. 3. | Eur J Pharmacol | Acetal derivatives of hemicholinium no. 3 (HC-3) were synthesized and their chemical structures were confirmed by spectrophotometric evidence and elemental analysis. The acetals elicited a biphasic pattern of neuromuscular inhibition in the cat: (a) an immediate inhibition (early phase block) was judged to be curare-like as responses to acetylcholine (close i.a.) were abolished by acetal administration and reversal of inhibition was effected by neostigmine (25 micrograms/kg); (b) a slow, progressive inhibition of transmission (late phase block) was considered HC-3-like as it occurred only during high frequency stimulation and was antagonized by small doses of choline (1--3 mg/kg). In comparison to HC-3, significanlty greater curare-like activity was noted following acetal administration in vivo and in vitro. Mouse toxicity and cat nerve--muscle studies revealed the acetals to be HC-3-like but 1/2 to 1/3 as active as the parent compound. Cholinesterase inhibition by HC-3 and the acetals was low (I50 greater than 0.1 mM) and did not account for differences in activities. Acetal-elicited hypotension in the cat was attributed to postsynaptic ganglionic blockade and histamine release. Studies employing the 14C-(N-methyl) acetals furnished no evidence of the bioactivation (O-dealkylation) of the acetals to HC-3 in the cat in vivo or in cat liver in vitro. Chromatographic analysis afforded no evidence of molecular modifications of 14C-HC-3 or of the 14C-acetals in these systems. |
| 1963 | [REACTIVATION, BY MEANS OF PRALIDOXIME SULFOMETHYLATE, OF CHOLINESTERASES BLOCKED BY METHYLATED OR ETHYLATED DERIVATIVES OF HYPOPHOSPHORIC ACID. II. TRIAL ON THE ARTERIAL PRESSURE OF CHLORALOSE-TREATED DOGS]. | Med Exp Int J Exp Med | |