Effect of treatment with Fufang Huangqi decoction on dose reductions and discontinuation of pyridostigmine bromide tablets, prednisone, and tacrolimus in patients with type I or II myasthenia gravis.

OBJECTIVE: To investigate the clinical efficacy of Fufang Huangqi decoction in combination with pyridostigmine bromide tablets, prednisone, and tacrolimus in the treatment of type I and II myasthenia gravis (MG) through changes in the clinical symptom scores of 100 patients with type I and II MG. This study also aimed to examine dose reductions and dis-continuation of these 3 Western medicines after administration of Fufang Huangqi decoction. METHODS: The clinical data on 100 patients with type I or II MG who were treated in the outpatient department of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China, between June 2017 and June 2020 were collected. The patients were divided into 4 groups based on whether they had taken pyridostigmine bromide tablets, prednisone, and/or tacrolimus at the time of their hospital visit: the Fufang Huangqi decoction group (group A), the pyridostigmine bromide tablets + Fufang Huangqi decoction group (group B), the pyridostigmine bromide tablets + prednisone + Fufang Huangqi decoction group (group C), and the pyridostigmine bromide tablets + tacrolimus + Fufang Huangqi decoction group (group D). The average treatment time was (15.6 ± 11.5) months (range: 0.5-55 months). Changes in the clinical symptom scores of the 4 groups of patients after medication administration and dose reductions and discontinuation of the 3 Western medicines were analyzed. RESULTS: An overall effectiveness rate of 86.00% was achieved in the 100 patients after treatment for (15.6 ± 11.5) months (range 0.5-55 months). The effectiveness rates were 85.71% in group A, 88.24% in group B, 76.92% in group C, and 80.00% in group D. The dosage of pyridostigmine bromide was reduced for 69.12% of the patients in group B for the first time after (4.2 ± 4.1) months, and 45.59% of the patients in group B discontinued pyridostigmine bromide after (8.8 ± 6.1) months. The dosage of pyridostigmine bromide was reduced for 46.15% of the patients in group C for the first time after (5.3 ± 3.4) months, and 23.08% of the patients in group C discontinued pyridostigmine bromide after (19.8 ± 11.0) months; 76.92% reduced hormone dosage after (2.8 ± 1.9) months, and 23.08% discontinued hormone treatment after (6.7 ± 2.9) months. The dosage of pyridostigmine bromide was reduced for 1 patient in group D after 1 month; this patient discontinued pyridostigmine bromide after 3 months and reduced tacrolimus dosage after 5 months. One patient in group D discontinued pyridostigmine bromide and tacrolimus on his own initiative at 0.5 months and took Fufang Huangqi decoction for 2 months without discontinuing Western medicine. CONCLUSION: Fufang Huangqi decoction is effective for the treatment of type I and II MG and improves the associated clinical symptoms. Moreover, this agent is conducive to dose reductions and discontinuation of basic Western medicines, thereby reducing the side effects experienced by patients.

Flaccid paralysis in an infant associated with a dirty wound and application of honey.

An infant, who was born preterm at 36 weeks, presented with fever and ulcer at umbilical region which progressed to necrotising fasciitis of anterior abdominal wall. He was treated with intravenous penicillin, intravenous cloxacillin and local application of medicated honey. Subsequently, he required wound debridement. Postoperatively, he required prolonged invasive ventilation due to poor respiratory effort which was associated with hypotonia and areflexia. Nerve conduction study revealed absent responses. The diagnosis of infant botulism was made based on the clinical presentation, nerve conduction study and his clinical progress. Botulinum immunoglobulin was not available. He was treated with intravenous immunoglobulin and oral pyridostigmine. He was successfully extubated after 37 days, and currently the patient is doing well.

Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques.

Galantamine hydrobromide and (-)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID50) was 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3-16 days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile.

Improving vagal activity ameliorates cardiac fibrosis induced by angiotensin II: in vivo and in vitro.

Cardiac remodeling is characterized by overactivity of the renin-angiotensin system (RAS) and withdrawal of vagal activity. We hypothesized that improving vagal activity could attenuate cardiac fibrosis induced by angiotensin II (Ang II) in vivo and in vitro. Rats were subjected to abdominal aorta constriction (AAC) with or without pyridostigmine (PYR) (31 mg/kg/d). After 8 weeks, PYR significantly decreased Ang II level, AT1 protein expression, and collagen deposition in cardiac tissue and improved heart rate variability, baroreflex sensitivity and cardiac function, which were abolished by atropine. In vitro, treatment of cardiac fibroblasts (CFs) with Ang II (10(-7) M) increased cell proliferation, migration, transformation, and secretory properties, which were significantly diminished by acetylcholine (ACh, 10(-6) M). Subsequently, Ang II significantly increased collagen type I expression as well as metalloproteinase (MMP)-2 expression and activity. Transforming growth factor (TGF)-ß1 expression and Smad3 phosphorylation presented a similar trend. Notably, the knockdown of the acetylcholine M2 receptor by siRNA could abolish ACh anti-fibrotic action. These data implicated cholinesterase inhibitor can increase vagal activity and reduce local Ang II level, and ACh inhibit Ang II pro-fibrotic effects. Our findings suggested that the parasympathetic nervous system can serve as a promising target for cardiac remodeling treatment.

Acetylcholinesterase Inhibition Attenuates the Development of Hypertension and Inflammation in Spontaneously Hypertensive Rats.

BACKGROUND: It is hypothesized that chronic increase of availability of acetylcholine, resulting from the effect of antiacetylcholinesterases, may prevent autonomic imbalance and reduce inflammation yielding benefic effects for cardiovascular disorders in hypertension. The effect of long-term administration of antiacetylcholinesterase agents with central and/or peripheral action, i.e., donepezil and pyridostigmine, were investigated on arterial pressure (AP), sympathovagal balance, plasma cytokine levels, and cardiac remodeling in spontaneously hypertensive rats (SHR). METHODS: Chronic treatment with donepezil or pyridostigmine started before the onset of hypertension. AP was measured by plethysmography every 4 weeks. At the end of 16 weeks of treatment, methylatropine was used to evaluate the cardiac vagal tone; AP and pulse interval (PI) variability were also evaluated followed by plasma and heart collection for analysis. RESULTS: Pyridostigmine, which does not cross the blood-brain barrier, increased cardiac vagal tone, and reduced cardiomyocyte diameter and collagen density, but did not affect the AP and plasma cytokine levels. Donepezil, which crosses the blood-brain barrier, attenuated the development of hypertension, increased cardiac vagal tone, and improved AP and PI variability. Likewise, donepezil reduced the plasma levels of tumor necrosis factor-α, interleukin 6, and interferon γ, besides reducing cardiomyocyte diameter and collagen density. CONCLUSIONS: Donepezil attenuated the development of hypertension in SHR probably involving antiinflammatory effects, indicating that acetylcholinesterase inhibition yields benefic effects for antihypertensive therapy.

[+]-Huperzine A protects against soman toxicity in guinea pigs.

The chemical warfare nerve agent (CWNA) soman irreversibly inhibits acetylcholinesterase (AChE) causing seizure, neuropathology and neurobehavioral deficits. Pyridostigmine bromide (PB), the currently approved pretreatment for soman, is a reversible AChE inhibitor that does not cross the blood-brain barrier (BBB) to protect against central nervous system damage. [-]-Huperzine A, a natural reversible AChE inhibitor, rapidly passes through the BBB and has numerous neuroprotective properties that are beneficial for protection against soman. However, [-]-Huperzine A is toxic at higher doses due to potent AChE inhibition which limits the utilization of its neuroprotective properties. [+]-Huperzine A, a synthetic stereoisomer of [-]-Huperzine A and a weak inhibitor of AChE, is non-toxic. In this study, we evaluated the efficacy of [+]-Huperzine A for protection against soman toxicity in guinea pigs. Pretreatments with [+]-Huperzine A, i.m., significantly increased the survival rate in a dose-dependent manner against 1.2× LD(50) soman exposures. Behavioral signs of soman toxicity were significantly reduced in 20 and 40 mg/kg [+]-Huperzine A treated animals at 4 and 24 h compared to vehicle and PB controls. Electroencephalogram (EEG) power spectral analysis showed that [+]-Huperzine A significantly reduces soman-induced seizure compared to PB. [+]-Huperzine A (40 mg/kg) preserved higher blood and brain AChE activity compared to PB in soman exposed animals. These data suggest that [+]-Huperzine A protects against soman toxicity stronger than PB and warrant further development as a potent medical countermeasure against CWNA poisoning.

Reversal of rocuronium-induced neuromuscular blockade by pyridostigmine in patients with Duchenne muscular dystrophy.

BACKGROUND: The aim of this study was to investigate the effect and safety of pyridostigmine for the reversal of a neuromuscular block (NMB) in patients with Duchenne muscular dystrophy (DMD). In patients with DMD recovery from a rocuronium-induced NMB is markedly delayed. METHODS: Fourteen DMD patients (aged between 11 and 19 years) scheduled for elective scoliosis repair were studied. Following tracheal intubation without muscle relaxant, all patients received a single dose of rocuronium 0.6 mg.kg(-1). NMB was monitored by acceleromyography at the adductor pollicis muscle. When the first twitch height (T1) of the train-of-four (TOF) had recovered to 25% seven patients received either pyridostigmine 0.1 mg.kg(-1) (the anticholinergic drug with a long duration of action) or saline in a blinded manner. The times to attain TOF ratio of 0.9 were recorded. For comparison the Mann-Whitney U-test was used. RESULTS: Recovery to TOF ratio of 0.9 was significantly (P < 0.05) accelerated by pyridostigmine [84 (median), 57-141(range)] compared with controls (148, 84-243 min). The recovery time (time between T1 of 25% and TOF of 90%) was also significantly (P < 0.01) shortened by pyridostigmine (15, 8-49 vs 76, 43-144 min, respectively). Time to recovery of T(1) to 90% was not different between the groups (108, 63-134 vs 169. 61-208 min, respectively). CONCLUSIONS: Pyridostigmine 0.1 mg.kg(-1) effectively reversed a rocuronium-induced NMB in DMD patients.

Extrapolating from animal studies to the efficacy in humans of a pretreatment combination against organophosphate poisoning.

The extrapolation from animal data to therapeutic effects in humans, a basic pharmacological issue, is especially critical in studies aimed to estimate the protective efficacy of drugs against nerve agent poisoning. Such efficacy can only be predicted by extrapolation of data from animal studies to humans. In pretreatment therapy against nerve agents, careful dose determination is even more crucial than in antidotal therapy, since excessive doses may lead to adverse effects or performance decrements. The common method of comparing dose per body weight, still used in some studies, may lead to erroneous extrapolation. A different approach is based on the comparison of plasma concentrations at steady state required to obtain a given pharmacodynamic endpoint. In the present study, this approach was applied to predict the prophylactic efficacy of the anticholinergic drug caramiphen in combination with pyridostigmine in man based on animal data. In two species of large animals, dogs and monkeys, similar plasma concentrations of caramiphen (in the range of 60-100 ng/ml) conferred adequate protection against exposure to a lethal-dose of sarin (1.6-1.8 LD(50)). Pharmacokinetic studies at steady state were required to achieve the correlation between caramiphen plasma concentrations and therapeutic effects. Evaluation of total plasma clearance values was instrumental in establishing desirable plasma concentrations and minimizing the number of animals used in the study. Previous data in the literature for plasma levels of caramiphen that do not lead to overt side effects in humans (70-100 ng/ml) enabled extrapolation to expected human protection. The method can be applied to other drugs and other clinical situations, in which human studies are impossible due to ethical considerations. When similar dose response curves are obtained in at least two animal models, the extrapolation to expected therapeutic effects in humans might be considered more reliable.

Autoimmune gastrointestinal dysmotility treated successfully with pyridostigmine.

BACKGROUND & AIMS: Autoimmune gastrointestinal dysmotility (AGID) is a limited form of autoimmune autonomic neuropathy occurring idiopathically or in a paraneoplastic context. This disorder is considered rare, but is underrecognized as a cause for GI dysmotilities of varying anatomic extent, severity, and duration. We describe the diagnosis and management of an instructive case. METHODS: A 60-year-old (nondiabetic) woman presented with a 15-year history of severe isolated gastroparesis. Paraneoplastic autoantibody evaluation aided the diagnosis of AGID. This included indirect immunofluorescence (neuronal nuclear and cytoplasmic antibodies), radioimmunoprecipitation assays (neuronal and muscle plasma membrane cation channel antibodies), and enzyme-linked immunosorbent assay (muscle striational antibodies). RESULTS: Serologic testing revealed both ganglionic neuronal acetylcholine receptor and N-type voltage-gated calcium channel autoantibodies. This profile was consistent with AGID and, despite the long history, raised the possibility of lung, breast, or ovarian carcinoma or thymoma. An underlying neoplasm was excluded by appropriate investigations. In a 1-month trial of oral pyridostigmine therapy, the patient's GI symptoms improved and her weight stabilized. Pyridostigmine was continued at a low dose, and was supplemented by tegaserod. CONCLUSIONS: Autoimmune serology is a valuable adjunct to the diagnosis and guide to management of patients with AGID. The favorable response to acetylcholinesterase inhibitors, despite a 15-year history, suggests an immunopharmacologic rather than an inflammatory cytotoxic pathology. Immunomodulatory therapy may not always be required. Of numerous autoantibodies currently recognized as biomarkers of AGID, the ganglionic acetylcholine receptor autoantibody is the only proven pathophysiologic effector. Certain neuronal nuclear and cytoplasmic autoantibodies are highly predictive of an underlying malignancy.

Efficacy of huperzine in preventing soman-induced seizures, neuropathological changes and lethality.

Huperzine A (HUP) is a potent reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. Its ability to prevent seizures and subsequent hippocampal neuropathological changes induced by the organophosphate soman was studied in guinea pigs. Results were compared to guinea pigs treated with pyridostigmine (PYR, 0.2 mg/kg, subcutaneously). HUP pretreatment at 0.5 mg/kg, intraperitoneally, totally prevented seizures and ensured the survival of all animals for 24 h after intoxication. Hippocampal tissue was then free of any neuronal damage. Comparatively, all animals pretreated with PYR exhibited epileptic activity after soman poisoning and five of six animals died. Examination of the hippocampus of the only surviving guinea pig pretreated with PYR showed extensive neuropathological changes. Although HUP or PYR induced similar inhibitions of blood AChE activity, only HUP pretreatment led to a decrease in central AChE activity. In binding studies on guinea-pig brain homogenates, HUP had no affinity for muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and gamma-aminobutyric acid (GABA)A receptors and only a very low one for N-methyl-D-aspartate (NMDA) receptors. In conclusion, HUP, unlike PYR, protects against soman-induced convulsions and neuropathological changes in the hippocampus. This efficacy seems to be related to a protection by HUP of both peripheral and central stores of AChE.

Exacerbation of a case of myasthenia gravis during therapeutic electric stimulation.

In patients with myasthenia gravis, vigorous exercise and electric stimulation produce weakness that is usually reversed by rest. We describe a case of persistent weakness in a 31-year-old woman with myasthenia gravis following therapeutic electric stimulation. She was injured in an automobile accident, with cervical and lumbar muscle strain diagnosed by a local emergency room physician. She consulted a chiropractor two days later because her symptoms had not abated. The chiropractic treatment of short-wave diathermy, high-voltage electric stimulation and spinal manipulation continued thrice weekly for six weeks. She then presented to her neurologist, complaining of persistent fatigue, weakness, increased diplopia, cervical and occipital pain, and disrupted sleep. Neck weakness had developed since her last visit. She was admitted to the hospital for evaluation. Neurologic exam showed no other abnormality of strength, sensation, or reflexes. The exacerbation of myasthenia responded to prednisone and increased pyridostigmine. After two months she required only her preinjury dose of pyridostigmine (60 mg q.d. p.r.n.) to prevent diplopia or fatigue, and her strength was normal. Repeated electrically induced muscle contraction is suspected of causing this exacerbation of myasthenia gravis.

Dose-response curves for edrophonium, neostigmine, and pyridostigmine after pancuronium and d-tubocurarine.

To determine the potencies of neostigmine, pyridostigmine, and edrophonium in reversing pancuronium and d-tubocurarine blockade, dose-response curves were established for first twitch height recovery and train-of-four ratio. One hundred and twenty ASA physical status I or II patients scheduled for elective surgery received either 0.06 mg/kg pancuronium or 0.36 mg/kg d-tubocurarine during a thiopental-nitrous oxide-enflurane anesthetic. Train-of-four stimulation was applied every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When first twitch height had recovered spontaneously to 10% of its initial value, neostigmine (0.005, 0.01, 0.02 or 0.05 mg/kg), pyridostigmine (0.02, 0.04, 0.1, or 0.2 mg/kg), or edrophonium (0.1, 0.2, 0.4 or 1 mg/kg) was injected by random allocation. Recovery was measured 10 min after the injection of the antagonist. First twitch ED50's were 0.013, 0.085, and 0.17 mg/kg after pancuronium, and 0.017, 0.11, and 0.27 mg/kg after d-tubocurarine, for neostigmine, pyridostigmine, and edrophonium, respectively. The ED50 for pyridostigmine and edrophonium obtained after d-tubocurarine was significantly larger (P less than 0.05) than that after pancuronium. The train-of-four dose-response curves were significantly flatter for edrophonium than for the other two agents, indicating a greater ability of edrophonium to antagonize fade at low doses. It is concluded that the potency of reversal agents may be different for different relaxants, and that potency ratios might depend upon the end-point chosen as full neuromuscular recovery.