Neuropharmacology of amyotrophic lateral sclerosis.
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Amyotrophic Lateral Sclerosis↗
Biomedical subjects
H Askmark
Publications and source records attributed to H Askmark.
Epidemiology of adverse reactions to carbamazepine as seen in a spontaneous reporting system.
A survey was made of 505 reports on 713 adverse reactions to carbamazepine submitted to the Swedish Adverse Drug Reactions Advisory Committee from 1965-1987. For the period after 1972, the relation between the reports and sales statistics could be investigated. The total incidence of reported adverse reactions to carbamazepine was 4.5 per million defined daily doses (DDD), corresponding to 2.7 per million prescribed daily doses (PDD). Most often reported were skin reactions (48%), but reports on haematological (12%) and hepatic disorders (10%) were also frequent. Virtually all hepatic disorders and severe skin reactions, as well as the majority (60%) of the haematological reactions, occurred within the first 2 months of treatment. In view of the very low incidence of reported serious blood dyscrasias, such as pancytopenia (0.04/million PDD) and agranulocytosis (0.06/million PDD), continuous haematological monitoring seems to be of little value. The elderly appear to be at increased risk of developing blood dyscrasias and liver reactions, and alcohol abusers seem to represent a high-risk group for developing serious skin reactions.
Age Factors↗
Functional and pharmacokinetic studies of tetrahydroaminoacridine in patients with amyotrophic lateral sclerosis.
Assuming the presence of clinically significant cholinergic hypofunction in amyotrophic lateral scleroses (ALS), seven patients with ALS were treated with 100-200 mg tetrahydroaminoacridine (THA) together with 11 g lecithin daily for up to 7 weeks. In a separate experiment pharmacokinetics and effects on muscle strength and neurophysiological parameters were studied following the injection of 30 mg THA intravenously. Following the injection of THA an increase in muscle strength was observed in two patients. There were no consistent pharmacokinetic differences that could explain the effect on intravenous THA on muscle strength in these two patients. The plasma clearance of THA was high and the oral bioavailability low with large interindividual differences (6-36%). No beneficial effect was seen during oral medication and side-effects were common. There were no conclusive changes observed regarding neurophysiological parameters after drug administration. THA has probably no place in the treatment of ALS.
Administration, Oral↗
Spinal cholinergic mechanisms.
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Acetylcholine↗
Lactation headache--a new form of headache?
The case of a 26-year-old woman suffering from brief attacks of headache occurring on every occasion of nursing is described. Pulse rate and blood pressure are normal during the attacks and serum prolactin responds normally to nursing. Plasma vasopressin increases before each headache attack. Propranolol does not prevent the headache, which disappears only after lactation has ceased. Possible pathophysiological mechanisms related to suckling are discussed.
Adult↗
Drug-related headache.
A survey was made of 10,506 reports to the WHO Collaboration Centre for International Drug Monitoring from five countries concerning headache, migraine, aggravated migraine and intracranial hypertension associated with drugs. The ten drugs most frequently reported to be associated with headache were indomethacin, nifedipine, cimetidine, atenolol, trimethoprim-sulphamethoxazole, zimeldine, glyceryl trinitrate, isosorbide dinitrate, zomepirac and ranitidine. Regarding migraine, oral contraceptives were also among the most implicated drugs. Most reports of intracranial hypertension concerned tetracyclines, isotretinoin and trimethoprim-sulphamethoxazole. Vasodilatation and salt and water retention with subsequent redistribution of intracranial fluid seem to be common mechanisms underlying drug-related headache. For certain frequently reported drugs, however, the mechanisms of the headache are unknown.
Drug-Related Side Effects and Adverse Reactions↗
Screening for neurotrophic disturbances in amyotrophic lateral sclerosis.
Neurotrophic activities in human serum and post-mortem muscle and spinal cord of possible relevance to pathophysiological mechanisms in amyotrophic lateral sclerosis (ALS) were studied. Tests included in vitro assays for nerve fibre outgrowth from sympathetic ganglia and for survival promotion of dissociated ciliary neurons, both types of neurons, of chicken embryo origin. Extracts of postmortem biceps muscle promoted survival of ciliary neurons in a dose-dependent manner. Half-maximum effect was found at a protein concentration of about 450 micrograms/ml for both ALS and control muscle. Ventral horn extracts were about 5 times as efficient as muscle in promoting neuron survival, again with no differences seen between control and ALS samples. Sera from patients suffering from ALS as well as normal sera did not enhance survival of ciliary neurons to any considerable extent, nor did they induce fibre outgrowth from sympathetic ganglia. Both groups of sera, if present above 5% in the medium, suppressed fibre outgrowth induced by added nerve growth factor (NGF). Sera from some of the ALS patients impaired survival in dissociated ciliary neurons supported by a trophic activity in choroid extract. The results do not indicate major neurotrophic deficits as the cause of ALS disease but suggest that a neurotoxic mechanism may be involved.
Aged↗
Induction of carbonic anhydrase III mRNA and protein by denervation of rat muscle.
Carbonic anhydrase III (CAIII) protein and mRNA amounts in fast- and slow-twitch rat muscles were examined after resection of the sciatic nerve. Striking changes occur in the fast-twitch anterior tibialis (AT) and extensor digitorum longus (EDL) muscles, where CAIII protein and mRNA are increased several-fold 16 days after denervation. The data suggest that these changes are regulated in part by changes in gene transcription and that they perhaps signal a fast-to-slow fibre type transition in these denervated muscles. AT and EDL show some differences in the effects of denervation, which are suggestive of variation in the timing of denervation-induced responses and/or the CAIII protein/mRNA turnover rates in the two muscles.
Actins↗
In vitro autoradiography of [3H]acetylcholine binding in rat hind limb muscles.
The morphological distribution of acetylcholine receptors in normal and denervated rat tibialis anterior and soleus muscles was studied by in vitro quantitative autoradiography with [3H]acetylcholine (ACh). In normal muscles [3H]ACh binding was restricted to the neuromuscular junction, while denervated muscles showed binding also in extrajunctional areas. After denervation there was also an increase in the junctional binding.
Acetylcholine↗
Induction of rat muscle carbonic anhydrase by denervation demonstrated with immunofluorescence.
Immunofluorescence microscopy of carbonic anhydrase III (CA III) was performed on sections of rat anterior tibialis (AT), extensor digitorum longus (EDL) and soleus after denervation. In contralateral control muscles, CAIII was located only in type I fibres whereas following the operation, CAIII was markedly induced in type II fibers of all the muscles, most strikingly in EDL.
Animals↗
Large-section cryomicrotomy for in vitro receptor autoradiography.
A method for processing human postmortem material for application of autoradiography to large cryosections is described. Whole organ or tissue slices 5 mm thick are frozen between copper plates cooled with liquid nitrogen. They are subsequently embedded in carboxymethyl-cellulose, and 40- to 80-microns sections are taken up on adhesive tape and paper and transferred to gelatinized glass plates. Two procedures for incubation of large sections are described. The method is exemplified by autoradiographs of human brain hemisphere ([ 3H]quinuclidinylbenzilate) and whole biceps muscle ([ 3H]alpha-bungarotoxin).
Autoradiography↗
Cholinesterase inhibitors lack therapeutic effect in amyotrophic lateral sclerosis. A controlled study of physostigmine versus neostigmine.
Seven patients with amyotrophic lateral sclerosis participated in a double-blind cross-over trial of oral physostigmine and neostigmine (10 and 45 mg/day, respectively, for 3 days). Six of the patients were also given intravenous injections (1 and 1.5 mg, respectively) of the drugs in an open trial. No significant effects on muscle strength or neurophysiological parameters were observed.
Adult↗
Serum carbonic anhydrase III in neuromuscular disorders and in healthy persons after a long-distance run.
A radioimmunosorbent technique was used for the assay of the skeletal muscle specific enzyme, carbonic anhydrase III (CA III). The usefulness of serum CA III determinations for detecting skeletal muscle damage was evaluated by comparing the serum levels of this enzyme and of myoglobin and creatine kinase in 64 patients with neuromuscular disorders and in 13 healthy volunteers before and after a long-distance run. Increased serum CA III levels were found in all patients with muscular dystrophy, chronic polymyositis and amyotrophic lateral sclerosis and in many with myasthenia gravis. In patients with polymyositis who were followed up with repeated blood sampling, the time courses of serum CA III levels, myoglobin levels and clinical symptoms were closely related. In all the runners the serum CA III level immediately after the run was increased. In the present study serum CA III and myoglobin seemed to be equally sensitive as biochemical markers of muscular damage and more sensitive than creatine kinase.
Adult↗
Autoradiographic visualization of extrajunctional acetylcholine receptors in whole human biceps brachii muscle. Changes in amyotrophic lateral sclerosis.
The morphological distribution of acetylcholine receptors in the whole biceps brachii muscle from a patient with amyotrophic lateral sclerosis (ALS) and from a control patient was studied by in vitro autoradiography with 3H-alpha-bungarotoxin (alpha-Btx). In ALS, 3H-alpha-Btx binding occurred over the entire muscle, while in the control case the binding was restricted to the motor end-plate region.
Amyotrophic Lateral Sclerosis↗
Autoradiographic changes of 3H-alpha-bungarotoxin binding in rat hind limb muscles after a cryoinjury of the sciatic nerve and in acrylamide intoxication.
The morphological distribution of acetylcholine receptors in rat tibialis anterior and soleus muscles after a cryoinjury of the sciatic nerve was studied by in vitro autoradiography with 3H-alpha-bungarotoxin (3H-alpha-Btx). Tibialis anterior from rats intoxicated with acrylamide was also investigated by this technique. A computer system was used for densitometry and colour coding of the autoradiographs. In normal muscle, 3H-alpha-Btx binding was observed only at the motor endplates. From the second day after the nerve lesion the area of binding spread from the motor endplate region towards the muscle-tendon regions and on the 16th day almost all parts of the muscles showed increased binding. The binding had begun to decrease in the middle parts of the muscles on the 20th day and on the 30th day binding was observed only in the motor endplate area. Tibialis anterior from rats intoxicated with acrylamide (total dose 1100 mg X kg-1) showed 3H-alpha-Btx binding over the entire muscle.
Acrylamide↗
Topographical localization of motor endplates in cryosections of whole human muscles.
The distribution of motor endplates in biceps brachii, tibialis anterior, and sartorius muscles from human adults was studied by staining longitudinal cryosections of whole muscle for cholinesterase. A special freezing technique was used to prevent the muscle from cracking before sectioning on a heavy cryostat microtome. The results from a large number of cryosections from biceps brachii and tibialis anterior muscles were analyzed by a computer and the topographical distributions of endplates in different views of the muscles were reconstructed. In the biceps brachii muscle, the endplates formed a fairly distinct, slightly V-shaped band through the middle of the two heads. In the tibialis anterior muscle, the majority of the endplates were superficially distributed along the whole muscle. In the longitudinal sections from the middle part of the muscle, they gave the pattern of a parabola with its apex at the proximal end of the muscle. In the sartorius muscle, the endplates were scattered throughout the muscle and no endplate band was observed. The findings are in accordance with results obtained 30 years ago in investigations of muscle from small children and stillborn infants.
Adult↗
Myoglobin in rat hind limb muscles after denervation and during reinnervation.
Radioimmunoassay of myoglobin (Mb) was performed in rat hind limb muscles after surgical denervation and during reinnervation following cryolesion of the sciatic nerve. Muscles of the contralateral leg served as controls. After resection of the sciatic nerve, decreased Mb concentrations were noted on the fourth day in the tibialis anterior, peroneus longus, and extensor digitorum longus (EDL) muscles. Thereafter, the levels increased up to the last observation on day 32. The increases in Mb levels in the tibialis anterior and EDL muscles were considerably more pronounced (305% and 324%, respectively) than in the peroneus longus and soleus muscles (148% and 137%, respectively). After cryolesion of the sciatic nerve, the Mb concentrations in the tibialis anterior, peroneus longus, and EDL muscles increased, reaching maximal values on days 16-21. The levels then decreased and normal values were observed 2 months postoperatively. The normalization of the Mb levels during reinnervation corresponded fairly well in time with the clinical recovery and neurophysiological findings observed in a previous study.
Animals↗
In vitro autoradiographic studies of 3H-alpha-bungarotoxin and 3H-quinuclidinylbenzilate binding in rat hind limb muscles.
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Animals↗