Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new mestinon research articles will be listed here shortly after becoming available to us.
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Medical research on mestinon
Chem Biol Interact. 2008 May 3;
Haigh JR, Johnston SR, Peppernay A, Mattern PJ, Garcia GE, Doctor BP, Gordon RK, Aisen PS
As part of a phase Ib clinical trial to determine the tolerability and safety of the highly specific acetylcholinesterase (AChE) inhibitor huperzine A, twelve (12) healthy elderly individuals received an escalating dose regimen of huperzine A (100, 200, 300, and 400mug doses, twice daily for a week at each dose), with three (3) individuals as controls receiving a placebo. Using the WRAIR whole blood cholinesterase assay, red blood cell AChE and plasma butyrylcholinesterase (BChE) were measured in unprocessed whole blood samples from the volunteers following each dose, and then for up to 48h following the final and highest (400mug) dose to monitor the profile of inhibition and recovery of AChE. Significant inhibition of AChE was observed, ranging from 30-40% after 100mug to >50% at 400mug, and peaking 1.5h after the last dose. Gradual recovery of AChE activity then occurs, but even 48h after the last dose red blood cell AChE was about 10% below control (pre-dose) values. Huperzine A levels in plasma peaked 1.5h after the final 400mug dose (5.47+/-2.15ng/mL). Plasma BChE was unaffected by huperzine A treatment (as expected). Aliquots of huperzine A-containing (from three individuals) and placebo blood samples were exposed ex vivo to the irreversible nerve agent soman (GD) for 10min, followed by removal of unbound huperzine and soman from the blood by passing through a small C(18) reverse phase spin column. Eluted blood was diluted in buffer, and aliquots taken at various time intervals for AChE and BChE activity measurement to determine the time taken to achieve full return in activity of the free enzyme (dissociation from the active site of AChE by huperzine A), and thus the proportion of AChE that can be protected from soman exposure. Huperzine A-inhibited red blood cell (RBC) AChE activity was restored almost to the level that was initially inhibited by the drug. The increased doses of huperzine A used were well tolerated by these patients and in this ex vivo study sequestered more red blood cell AChE than has been previously demonstrated for pyridostigmine bromide (PB), indicating the potential improved prophylaxis against organophosphate (OP) poisoning.
Peripheral chemokine receptors, their ligands, cytokines and Alzheimer's disease.
J Alzheimers Dis. 2008 Jun; 14(2): 147-59
Reale M, Iarlori C, Feliciani C, Gambi D
Cerebral inflammation as well as systemic immunological alterations has been reported in Alzheimer's disease (AD). We aimed to determine whether spontaneous and mitogen stimulated production of peripheral blood mononuclear cell (PBMC) cytokines, chemokines and chemokine receptors in clinically diagnosed patients with AD were unregulated. PBMC were purified from AD patients and from healthy controls. Supernatants were analyzed for cytokine levels by ELISA methods. mRNA expression was determined by RT-PCR. Expression of chemokine receptors CCR2 and CCR5 was determined by cytofluorimetric analysis. Both CCR5 and CCR2 expression were increased in AD patients respect to control subjects and the expression of CCR2 and CCR5 was more frequent on CD4;{+} and less frequent on CD8;{+} cells. Levels of Th1-type cytokine IFNgamma and chemokine RANTES were increased and levels of Th2-type cytokine IL-4 and chemokine MCP-1 were reduced in AD patients compared with those of control subjects. Acetylcholinesterase inhibitor pyridostigmine bromide (AChEI)-therapy reduced CCR2, CCR5, RANTES and IFNgamma expression and production in AD patients. CCR5, CCL5/RANTES, CCL2/MCP-1 and IFNgamma expression and production were increased in PBMC treated with amyloid-beta_{1-42}. Addition of AChEI to PBMC suppresses CCL5/RANTES and IFNgamma. The observed patterns of cyto-chemokine involvement strengthen the questions regarding the inflammatory theory in AD, and raise a pathophysiologic role for selective alteration of cyto-chemokine network.
Extended transsternal thymectomy for myasthenia gravis: a report of 19 consecutive cases.
Acta Chir Belg. 2008 Jan-Feb; 108(1): 102-6
Durieux R, Radermecker MA, Dekoster G, Limet R
BACKGROUND: Thymectomy is considered as an effective therapeutic option for patients with myasthenia gravis (MG). This study reports the experience of our centre's investigation into the efficacy and the safety of the procedure and the influence of different pre-operative factors on the surgical outcome. METHODS: A retrospective chart review/interview was made of 19 consecutive patients who underwent extended transsternal thymectomy for MG from 1992 to 2003. The severity of the disease was determined according to the Osserman Classification. Efficacy was measured by determining the change in clinical status, the rate of remission during follow-up, and the reduction in medication requirements after thymectomy. Complete remission (CR) was defined as asymptomatic off medication for 6 months. The CR rate was calculated using the Kaplan-Meyer method. RESULTS: The mean age of the patients at surgery was 34 years (range, 9-63) and 78.9% were female. Mean length of follow up was 86 months (range, 24-163). The overall complication rate was 10.6% (1 episode of atrial fibrillation and a left recurrent laryngeal nerve palsy that resolved after the first postoperative month). There was no operative mortality. The mean hospital stay was 9.4 days (range, 5-23). The crude CR rate was 32% (n = 6). The Kaplan-Meier estimate of CR was 42% at 6 years. Age, gender, duration of symptoms, thymic histology, Osserman stage and the presence of thymoma were not identified as prognostic variables. The average daily dose of Medrol and Mestinon decreased significantly between the pre-operative period and the last follow-up (Medrol, p = 0.0081; Mestinon, p = 0.0013). CONCLUSIONS: Transsternal thymectomy for MG is safe and effective. It benefits patients with MG at all stages. Patients with thymoma are not associated with poorer remission rates. Complete responses are durable, as the CR rate remains stable over time.
[Lambert-Eaton Myasthenic Syndrome associated with vocal cord carcinoma]
Rev Neurol (Paris). 2008 Jan; 164(1): 72-6
Shipley E, Krim E, Deminière C, Lagueny A
INTRODUCTION: Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune channelopathy in which patients produce autoantibodies directed against voltage-gated calcium channels. LEMS is paraneoplastic in 50% of patients, most frequently associated with small cell lung carcinoma. We describe a case of paraneoplastic LEMS associated with a vocal cord carcinoma. OBSERVATION: A 64-year-old man developed in five months muscle weakness affecting gait. Clinical examination showed proximal muscular deficiency, areflexia and dysphonia. Electrophysiologic study showed potentiation greater than 500% after post exercise facilitation and 76 percent increment response at high-rate repetitive nerve stimulation (20Hz). Diagnosis of LEMS was confirmed by electrophysiologic study and anti-voltage gated calcium channel antibodies (90pM, positive value greater or equal to 70pM). Left vocal cord lesion histology showed epidermoid carcinoma. A combination of vocal cord tumor removal by endoscopy and treatment by pyridostigmine, 3-4 diaminopyridine and intravenous human immunoglobulin improved neurological symptoms. CONCLUSION: Paraneoplastic syndromes in association with cancers of the larynx and hypopharynx are unusual. Only two cases are reported with LEMS associated with larynx carcinoma. We describe an unusual case of LEMS associated with a left vocal cord carcinoma.
Acetylcholinesterase inhibitors and Gulf War illnesses.
Proc Natl Acad Sci U S A. 2008 Mar 18; 105(11): 4295-300
Golomb BA
Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose-response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV.
Toxicology. 2008 Apr 18; 246(2-3): 188-92
Herkert NM, Eckert S, Eyer P, Bumm R, Weber G, Thiermann H, Worek F
The efficacy of oxime treatment in soman poisoning is limited due to rapid aging of inhibited acetylcholinesterase (AChE). Pre-treatment with carbamates was shown to improve antidotal treatment substantially. Recently, by using a dynamically working in vitro model with real-time determination of membrane-bound AChE activity, we were able to demonstrate that pre-inhibition of human erythrocyte AChE with pyridostigmine or physostigmine resulted in a markedly higher residual AChE activity after inhibition by soman or paraoxon than in the absence of reversible inhibitors. The purpose of the present study was to compare the effect of carbamate pre-treatment and soman challenge with human erythrocyte and muscle homogenate AChE. Both enzyme sources were immobilized on particle filters which were perfused with acetylthiocholine, Ellman's reagent and phosphate buffer. AChE activity was continuously analyzed in a flow-through detector. Pre-inhibition of AChE with pyridostigmine or physostigmine resulted in a concentration-dependent increase in carbamylation, residual activity after soman inhibition and fraction of decarbamylation AChE after discontinuation of the inhibitors without differences between human erythrocyte and muscle AChE. This data support the view that human erythrocyte AChE is an adequate surrogate marker for synaptic AChE in OP poisoning.
Surg Endosc. 2008 Feb 23;
Bachmann K, Burkhardt D, Schreiter I, Kaifi J, Busch C, Thayssen G, Izbicki JR, Strate T
BACKGROUND: Myasthenia gravis is an autoimmune disease with a great impact on quality of life. Besides conservative treatment with mestinon and immunosuppressive medication, thymectomy is an established intervention that offers substantial improvements of the disease. Since the past decade, minimally invasive procedures have been performed. This study aimed to report on the long-term results for all the patients who underwent thymectomy for myasthenia gravis, paying special attention to postoperative disease-related outcome, quality of life, and differences regarding the operative approach. METHODS: This report describes a series of 131 patients with generalized myasthenia gravis who underwent thymectomy between 1980 and 2005. The clinical course data during the hospitalization and consultation in our outpatient clinic were reviewed, and survival data were generated. The patients were seen in the outpatient clinic, where a modified Osserman and quality-of-life score was evaluated at the end of the follow-up period for all surviving patients. RESULTS: A total of 106 patients with myasthenia gravis were followed up after thymectomy for a median time of 8 years (range, 1-27 years). Eight patients died during this period. The perioperative mortality rate was 0%, and the morbidity rate was 19.8%. The patients with thymoma and a high preoperative Osserman score had a significantly shorter survival. With minimally invasive procedures, the hospital stay was significantly shorter, and the rate for improvement of myasthenia gravis-associated symptoms was significantly higher. The rate of perioperative complications and myasthenia-related complications during the follow-up period showed no significant differences. CONCLUSIONS: Transsternal and minimally invasive thymectomy contribute to an improvement in myasthenia gravis symptoms for all subgroups. Surgery can be performed with low individual risks. In our trial, minimally invasive surgery was found to be superior in terms of improvement in myasthenia gravis-associated symptoms. Additionally, the hospital stay was shorter, and the patients felt less disturbed by direct effects of the operation. Therefore, minimally invasive thymectomy can be regarded as the treatment of choice for patients undergoing surgery for myasthenia gravis.
Xenobiotica. 2008 Mar; 38(3): 294-313
Abu-Qare AW, Abou-Donia MB
1. The in vitro human plasma activity and liver microsomal metabolism of pyridostigmine bromide (PB), a prophylactic treatment against organophosphate nerve agent attack, N,N-diethyl-m-toluamide (DEET), an insect repellent, and permethrin, a pyrethroid insecticide, either alone or in combination were investigated. 2. The three chemicals disappeared from plasma in the following order: permethrin > PB > DEET. The combined incubation of DEET with either permethrin or PB had no effect on permethrin or PB. Binary incubation with permethrin decreased the metabolism of PB and its disappearance from plasma and binary incubation with PB decreased the metabolism of permethrin and its clearance from plasma. Incubation with PB and/or permethrin shortened the DEET terminal half-life in plasma. These agents behaved similarly when studied in liver microsomal assays. The combined incubation of DEET with PB or permethrin (alone or in combination) diminished DEET metabolism in microsomal systems. 3. The present study evidences that PB and permethrin are metabolized by both human plasma and liver microsomal enzymes and that DEET is mainly metabolized by liver oxidase enzymes. Combined exposure to test chemicals increases their neurotoxicity by impeding the body's ability to eliminate them because of the competition for detoxifying enzymes.
Zhongguo Zhen Jiu. 2007 Dec; 27(12): 901-3
Wang SH, Cui X, Feng J
OBJECTIVE: To observe the therapeutic effect of electroacupuncture (EA) warming therapy on myasthenia gravis (MG) and effect on IL-4 in the patient. METHODS: Sixty patients with MG were randomly divided into two groups, 30 patients in each group. The observation group were treated with EA warming therapy with Tanzhong (CV 17), Shimen (CV 5), Guanyuan (CV 4), Zhongwan (CV 12), Yanglingquan (GB 34) selected as main points, and oral administration of Pyridostigmine (90 - 240 mg each day) and Prednisone (30 - 60 mg each day). The control group were treated with oral administration of Pyridostigmine (240-480 mg each day) and Prednisone (60-100 mg each day). Clinical therapeutic effects and serum Interleukin-4 (IL-4) levels before and after treatment were observed. RESULTS: The total effective rate was 93.3% in the observation group, which was better than 70.0% in the control group (P < 0.01); after treatment, the serum IL-4 levels in the two groups significantly decreased (P < 0.01), the decrease of IL-4 in the observation group being significantly better than the control group (P < 0.05). CONCLUSION: EA warming therapy combined with western medicine has a significant therapeutic effect on myasthenia gravis. One of the mechanisms possibly is to restrain specific immune reaction by regulating the level of IL-4.
Arthritis Rheum. 2008 Feb; 58(2): 612-22
Jones KD, Burckhardt CS, Deodhar AA, Perrin NA, Hanson GC, Bennett RM
OBJECTIVE: A subset of fibromyalgia (FM) patients have a dysfunctional hypothalamic-pituitary-insulin-like growth factor 1 (IGF-1) axis, as evidenced by low serum levels of IGF-1 and a reduced growth hormone (GH) response to physiologic stimuli. There is evidence that pyridostigmine (PYD) improves the acute response of GH to exercise in FM patients. The purpose of this study was to evaluate the clinical effectiveness of 6 months of PYD and group exercise on FM symptoms. METHODS: FM patients were randomized to 1 of the following 4 groups: PYD plus exercise, PYD plus diet recall but no exercise, placebo plus exercise, and placebo plus diet recall but no exercise. The primary outcome measures were the visual analog scale (VAS) score for pain, tender point count, and total myalgic score. Secondary outcome measures were the total score on the Fibromyalgia Impact Questionnaire (FIQ) and FIQ VAS scores for individual symptoms (fatigue, poor sleep, stiffness, and anxiety), as well as quality of life (QOL) and physical fitness (lower body strength/endurance, upper and lower body flexibility, balance, and time on the treadmill). RESULTS: A total of 165 FM patients completed baseline measurements; 154 (93.3%) completed the study. The combination of PYD and exercise did not improve pain scores. PYD groups showed a significant improvement in sleep and anxiety in those who completed the study and in QOL in those who complied with the therapeutic regimen as compared with the placebo groups. Compared with the nonexercise groups, the 2 exercise groups demonstrated improvement in fatigue and fitness. PYD was generally well tolerated. CONCLUSION: Neither the combination of PYD plus supervised exercise nor either treatment alone yielded improvement in most FM symptoms. However, PYD did improve anxiety and sleep, and exercise improved fatigue and fitness. We speculate that PYD may have improved vagal tone, thus benefiting sleep and anxiety; this notion warrants further study.