benzofurans and Peripheral-Nervous-System-Diseases

Topics: Amiodarone; Benzofurans; Chemical and Drug Induced Liver Injury; Eye Diseases; Humans; Hyperthyroidism; Lung Diseases; Peripheral Nervous System Diseases; Pigmentation Disorders; Thyroid Hormones

Topics: Amiodarone; Angina Pectoris; Benzofurans; Cerebrospinal Fluid Proteins; Electromyography; Humans; Inclusion Bodies; Lipid Metabolism; Microscopy, Electron; Movement Disorders; Muscles; Nervous System Diseases; Paresthesia; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Pigments, Biological; Piperidines; Polyradiculoneuropathy; Schwann Cells; Skin; Tremor

The aim of this study was to evaluate the neuroprotective effects of SalB on high glucose (HG)-induced excessive autophagy and apoptosis in vitro.. The proliferation and apoptosis of RSC96 cells were determined using the MTT assay and flow cytometry, respectively. Western blot analysis was performed to examine the expression of autophagy and apoptosis-related proteins. RT-PCR and flow cytometry were manipulated to examine the level of Bcl-2. The signals of autophagy markers were detected using immunofluorescence methods.. We found that HG significantly reduced RSC96 cell's proliferation and induced apoptosis. What's more, HG increased the level of autophagy and apoptosis-related proteins. However, these effects were reversed by SalB. In addition, we also found that 3-MA decreased the expression of LC3A/B and Beclin1, while the JNK inhibitor SP600125 reduced the levels of phosphorylated JNK, LC3A/B and Beclin1.. High glucose not only induced apoptosis but also caused autophagic cell death by activating the JNK pathway. These effects prevented by SalB in an opposite manner.

Topics: Animals; Anthracenes; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Benzofurans; Cell Line; Cell Proliferation; Diabetic Neuropathies; Glucose; MAP Kinase Signaling System; Peripheral Nervous System Diseases; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction

Glucokinase activators (GKAs) are being developed for the treatment of type 2 diabetes. The toxicity of 4 GKAs (PF-04279405, PF-04651887, piragliatin, and PF-04937319) was assessed in mice, rats, dogs, and/or monkeys. GKAs were administered for 2 to 8 weeks. Standard endpoints, glucose, and insulin were assessed. All compounds produced varying degrees of hypoglycemia in all species. Brain neuronal necrosis and/or peripheral neuropathy were observed with most compounds. These findings are consistent with literature reports linking hypoglycemia with nervous system effects. Arteriopathy, mainly of cardiac vessels, was observed at a low frequency in monkey and/or dog. Arteriopathy occurred only at doses that produced severe and prolonged periods of repeated hypoglycemia. Since this lesion occurred in multiple studies with structurally distinct GKAs, these results suggested arteriopathy was related to GKA pharmacology. The morphological characteristics of the arteriopathy were consistent with that produced by experimental catecholamine administration. We hypothesize that the prolonged periods of hypoglycemia resulted in increased local and/or systemic concentrations of catecholamines via a counterregulatory and/or stress-related mechanism. Alternatively, prolonged hypoglycemia may have resulted in endothelial dysfunction leading to arteriopathy. This risk can be managed in human patients in clinical studies by careful glucose monitoring and intervention to avoid prolonged episodes of hypoglycemia.

Topics: Animals; Azetidines; Benzeneacetamides; Benzofurans; Chromatography, High Pressure Liquid; Dogs; Drug Evaluation, Preclinical; Female; Hypoglycemia; Hypoglycemic Agents; Insulin; Macaca fascicularis; Male; Mice; Mice, Inbred ICR; Necrosis; Neurons; Peripheral Nervous System Diseases; Pyrimidines; Rats; Rats, Sprague-Dawley

Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB(2)) receptors are expressed in the microglia in neurodegenerative disease models.. To explore the potential of CB(2) agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB(2)-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB(2)(+/+) and CB(2)(-/-) mice. We hypothesized that the CB(2) receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways.. We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB(2)(-/-) mice and was blocked by CB(2) antagonists, suggesting that MDA7's action directly involves CB(2) receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB(2) expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models.. Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae.

Topics: Animals; Antineoplastic Agents, Phytogenic; Astrocytes; Benzofurans; Blotting, Western; CD11b Antigen; Cricetinae; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Profiling; Glial Fibrillary Acidic Protein; Humans; Hyperalgesia; Image Processing, Computer-Assisted; Immunohistochemistry; Lipopolysaccharides; Male; Mice; Mice, Knockout; Microscopy, Confocal; Neuroglia; Neuroprotective Agents; Paclitaxel; Peripheral Nervous System Diseases; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Cannabinoid, CB2; Spinal Cord; Toll-Like Receptor 2

The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.

Topics: Acetates; Amines; Animals; Benzofurans; Carbamates; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Male; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Piperidines; Rats; Rats, Sprague-Dawley

Topics: Amiodarone; Benzofurans; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Peripheral Nervous System Diseases

Three patients developed peripheral neuropathy after taking amiodarone for more than 18 months. All had high serum concentrations of amiodarone and its desethyl metabolite; in one patient concentrations in a sural nerve biopsy were 80 times higher than in serum. Peripheral neuropathy is a complication of large doses of amiodarone taken over long periods.

Topics: Aged; Amiodarone; Benzofurans; Female; Humans; Male; Middle Aged; Peripheral Nervous System Diseases

Sural nerve changes are described in 2 cases of amiodarone neuropathy. Clinically, 1 patient developed a sensorimotor neuropathy, whereas in the other it was predominantly motor. Examination of sural nerves showed demyelination with only mild axonal loss. Cytoplasmic changes developed in Schwann cells of myelinated and unmyelinated axons, and involved loss of most recognizable organelles. These changes were associated with, and possibly preceded, myelin sheath breakdown. Inclusions, mainly of a lamellated type, were found in all cell types in the nerves. These inclusions, known to be lysosomal in origin, are a characteristic finding in amiodarone-induced neuropathy. The pathogenesis of the neuropathy is discussed, with particular reference to the findings in a parallel experimental study.

Topics: Adult; Aged; Amiodarone; Benzofurans; Humans; Male; Peripheral Nervous System Diseases

Rats and mice were given amiodarone by mouth at doses of 50 mg/kg/day. The drug induced accumulations of lipids within lysosomes, leading to the formation of cytoplasmic bodies. These were found in many tissues, both nervous and nonnervous, but were excluded from regions with blood-brain or blood-nerve barriers. Of nervous system regions lying outside a vascular barrier, autonomic ganglia were the most affected, with large accumulations of lysosomal bodies in nerve cells and processes, and evidence of degenerative changes. the myenteric plexus was also involved. No significant changes were seen in peripheral nerves. A limited period of increased permeability caused by nerve crush, or due to immaturity of the blood-nerve barrier resulted in the short-lived appearance of drug-induced inclusions. The rate of regeneration of axons following nerve crush was not affected, although there were small defects in myelination.

Topics: Amiodarone; Animals; Benzofurans; Mice; Mice, Inbred BALB C; Nervous System Diseases; Neurotoxins; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Child; Drug Interactions; Eye Diseases; Female; Humans; Lung Diseases; Male; Peripheral Nervous System Diseases; Skin Diseases; Thyroid Diseases; Time Factors

Topics: Amiodarone; Benzofurans; Humans; Male; Middle Aged; Paresthesia; Peripheral Nervous System Diseases; Time Factors

Topics: Aged; Amiodarone; Benzofurans; Electromyography; Female; Humans; Male; Middle Aged; Motor Neurons; Muscles; Nerve Degeneration; Neural Conduction; Peripheral Nervous System Diseases

Topics: Amiodarone; Benzofurans; Half-Life; Humans; Male; Middle Aged; Peripheral Nervous System Diseases; Tachycardia

Four cases of amiodarone neuropathy are reported. Patients presented a sensorimotor neuropathy with distal predominance. Improvement occurred after drug discontinuation. Nerve conduction velocities were significantly decreased. Other secondary effects of amiodarone were noted in two cases. In one case serum levels of amiodarone and N-monodesethylamiodarone were evaluated during and after treatment. Pathological study of nerve with morphometric evaluation was performed. Axonal degeneration changes were predominant in 3 cases. Aspects of segmental demyelination and remyelination were noted in one case and related to secondary demyelination. Numerous lysosomal inclusions were present in Schwann cells, fibroblasts, capillary endothelial and perithelial cells and in perineural cells. Similar inclusions have been observed in other drug-induced lipidosis. The factors responsible for this neuropathy are unknown. In one case, amiodarone-induced hepatic failure might explain the persisting high serum levels of the drug.

Topics: Adult; Aged; Amiodarone; Axons; Benzofurans; Heart Diseases; Humans; Inclusion Bodies; Male; Microscopy, Electron; Middle Aged; Nerve Fibers, Myelinated; Neural Conduction; Peripheral Nervous System Diseases; Schwann Cells; Sensation; Sural Nerve

Muscle weakness, neuropathy, and transient rises in hepatic enzyme activity have been reported with the use of the antiarrhythmic agent amiodarone. A 68 year old teetotaller with normal liver function was given amiodarone for resistant supraventricular arrhythmias. He presented 19 months later with vomiting, muscle weakness and wasting, sensory neuropathy, and hepatomegaly. Liver biopsy showed fibrosis and the presence of hyaline. The amiodarone was withdrawn. Three months later he developed ascites. Oesophageal varices were found and he later died. The liver showed micronodular cirrhosis. The large volume of distribution and long half life of amiodarone may explain the persistence of toxicity, which may have been aggravated by simultaneously administered doxepin in this case. Amiodarone should be withdrawn if abnormal liver function or neuropathy develops.

Topics: Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Chemical and Drug Induced Liver Injury; Humans; Liver Cirrhosis; Male; Peripheral Nervous System Diseases

Topics: Amiodarone; Benzofurans; Humans; Peripheral Nervous System Diseases

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Corneal Diseases; Dose-Response Relationship, Drug; Female; Heart Conduction System; Humans; Liver; Male; Middle Aged; Peripheral Nervous System Diseases; Photosensitivity Disorders; Pigmentation Disorders; Pulmonary Fibrosis; Thyroid Diseases; Time Factors

Amiodarone, a drug used to treat refractory cardiac arrhythmias, produced a peripheral neuropathy in 5 of 50 cases (10%). Although the neuropathy may be severe, it tends to improve with lowering of the dosage or discontinuation of the medication.

Topics: Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Female; Humans; Male; Middle Aged; Nervous System Diseases; Paresthesia; Peripheral Nervous System Diseases; Tremor

A 54-year-old woman, with no previously documented thyroid disease, treated with amiodarone (200 mg/day, five days a week for 33 months) for paroxysmal tachyarrhythmia complicating mitral stenosis, suddenly developed extremely severe thyrotoxicosis. After therapeutic failures with carbimazole and propylthyrouracil (PTU) associated with beta-blockers, she was transferred to intensive care for plasma exchange (PE). Two PE were performed, temporarily aggravating the cardiovascular status of the patient, with no secondary improvement. The quantity of T3 removed was very small, about 1,000 ng per exchange. On the 14th day PTU had to be discontinued (toxic thrombopenia) and only symptomatic treatment was maintained (assisted ventilation, digitalis, hyperalimentation). In the 4th month, while the patient had a high total serum iodine, hypothyroidism developed due to partial block of the organification of the iodine with high TSH and fixation; this state also lasted 4 months. Spontaneous recovery was observed after 8 months. In addition a severe peripheral neuropathy was observed during the hyperthyroid phase confirmed by electromyography, distinct from the signs of thyrotoxic myopathy. This gradually regressed over 7 months and may be attributed to amiodarone therapy. The association of these two successive types of thyroid disorder due to amiodarone is an exceptionally rare phenomenon. Severe thyrotoxicosis generally requires long-term symptomatic therapy, its natural course being towards spontaneous regression. PE are ineffective on the circulating hormonal levels and were dangerous because of the underlying cardiac disease. The development of hypothyroidism at the 4th month is explained by the persistent iodine overload, and therefore prolonged surveillance after withdrawal of therapy is advised. The neurological complication of amiodarone was quite distinct from the hyperthyroid myopathy.

Topics: Amiodarone; Benzofurans; Female; Humans; Hyperthyroidism; Hypothyroidism; Middle Aged; Peripheral Nervous System Diseases; Plasma Exchange; Time Factors

Topics: Amiodarone; Benzofurans; Female; Humans; Hypothyroidism; Middle Aged; Peripheral Nervous System Diseases; Thyroid Neoplasms

Topics: Amiodarone; Benzofurans; Humans; Male; Middle Aged; Peripheral Nervous System Diseases; Time Factors

Topics: Amiodarone; Benzofurans; Central Nervous System Diseases; Drug Administration Schedule; Eye Diseases; Gastrointestinal Diseases; Heart Conduction System; Humans; Liver; Peripheral Nervous System Diseases; Pulmonary Fibrosis; Skin Diseases; Thyroid Diseases

We evaluated the electrophysiologic effects of amiodarone and its ability to control ventricular arrhythmia in a selected group of 51 patients with refractory sustained ventricular arrhythmia. Amiodarone in doses of 400 to 800 mg/day prolonged refractoriness in the atria, atrioventricular (AV) node, and ventricle as well as conduction through the AV node and His-Purkinje system. Although it had no effect on measurements of sinus nodal function (sinus nodal recovery time and sinoatrial conduction time), it prolonged the sinus cycle length and 2 patients required a permanent pacemaker for symptomatic sinus bradycardia. Amiodarone did not alter the ease of inducibility in any consistent manner, and only 5 of 43 patients (12%) who had inducible ventricular tachycardia before amiodarone therapy had none induced during amiodarone treatment. The clinical effectiveness of amiodarone could be evaluated in 46 patients followed up for 8.6 +/- 6 months (range 0.5 to 22). It provided effective therapy in 23 patients (50%), partly effective therapy in 13 (28%), and was ineffective in 10 (22%). Adverse effects were noted in 28 of 51 patients (55%), and in 11 of these (22%) the drug had to be discontinued because of adverse effects. We conclude that amiodarone is a useful agent for the treatment of refractory sustained ventricular arrhythmia. Its use should be reserved for patients with life-threatening sustained arrhythmia because of the significant incidence of adverse effects. Furthermore, good clinical response can be observed in patients receiving amiodarone in spite of continued inducibility.

Topics: Adolescent; Adult; Aged; Amiodarone; Benzofurans; Cardiac Pacing, Artificial; Chemical and Drug Induced Liver Injury; Corneal Diseases; Electrophysiology; Female; Heart Conduction System; Heart Failure; Humans; Male; Middle Aged; Myocardial Contraction; Peripheral Nervous System Diseases; Photosensitivity Disorders; Pulmonary Fibrosis; Stroke Volume; Tachycardia; Ventricular Fibrillation

Topics: Aged; Amiodarone; Benzofurans; Female; Humans; Lipidoses; Peripheral Nervous System Diseases

Clinical, electrophysiological, and the nerve and muscle biopsy findings from a case treated with amiodarone are reported. Marked distal motor and sensory impairment and distal muscular atrophy were observed clinically. The electrophysiological examination revealed normal motor and sensory conduction velocities in the median nerve; the sensory action potentials were polyphasic and reduced in amplitude. Electromyography revealed denervation potentials and severe loss of motor units in the M. extensor digitorum brevis and in the M. tibialis anterior. The light and electronmicroscopical study of a N. suralis biopsy displayed total loss of large myelinated fibers and an almost total reduction of small myelinated fibers. The number of unmyelinated axons was markedly reduced. Fibrocytes and degenerative axons polymorphous inclusion bodies were present in Schwann cells. The muscle biopsy revealed both neurogenic and myopathic changes. Lipid storage was also present in the muscle fibers. Physical and chemical analysis of the nerve and muscle biopsy revealed the content of iodine to be more than 40 times increased. The findings indicate damage of axons, schwann cells and muscle fibers. It is suggested that the lipid storage in nerve and muscle tissue might be related to the accumulation of the drug or its metabolites.

Topics: Aged; Amiodarone; Benzofurans; Humans; Iodine; Male; Microscopy, Electron; Muscles; Neuromuscular Diseases; Peripheral Nerves; Peripheral Nervous System Diseases

Topics: Aged; Amiodarone; Benzofurans; Humans; Lipidoses; Male; Peripheral Nervous System Diseases

Topics: Amiodarone; Benzofurans; Peripheral Nervous System Diseases

Topics: Aged; Amiodarone; Benzofurans; Female; Humans; Male; Middle Aged; Peripheral Nervous System Diseases