Nerve conduction sensitivity in diabetic neuropathy.
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Diabetic Neuropathies↗
Biomedical subjects
M D Ferrari
Publications and source records attributed to M D Ferrari.
Coronary side-effect potential of current and prospective antimigraine drugs.
BACKGROUND: The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan). METHODS AND RESULTS: Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/EC50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the receptor biophase. Compared with sumatriptan, all drugs were more potent (lower EC50 values) in contracting the coronary artery but had similar efficacies (Emax <25% of K+-induced contraction). The Cmax of avitriptan was 7- to 11-fold higher than its EC50 value, whereas those of the other drugs were <40% of their respective EC50 values. The contractile responses to ergotamine and dihydroergotamine persisted even after repeated washings, but those to the other drugs declined rapidly after washing. CONCLUSIONS: All current and prospective antimigraine drugs contract the human coronary artery in vitro, but in view of low efficacy, these drugs are unlikely to cause myocardial ischemia at therapeutic plasma concentrations in healthy subjects. In patients with coronary artery disease, however, these drugs must remain contraindicated. The sustained contraction by ergotamine and dihydroergotamine seems to be an important disadvantage compared with sumatriptan-like drugs.
Adolescent↗
Chromosomal localization of the 5-HT1F receptor gene: no evidence for involvement in response to sumatriptan in migraine patients.
The 5-HT1F receptor, which is present in both human vascular and neuronal tissue, may mediate the therapeutic effect and/or side-effects of sumatriptan. We investigated the chromosomal localization of the 5-HT1F receptor gene and the relation between eventually existing polymorphisms and the clinical response to sumatriptan in migraine patients. The 5-HT1F receptor gene was localized using a monochromosomal mapping panel, followed by a radiation-reduced hybrid mapping and fluorescent in situ hybridization. The results of these techniques show that the 5-HT1F receptor gene is localized at 3p12. We investigated the presence of polymorphisms by single strand conformation polymorphism analysis in 14 migraine patients who consistently responded well to sumatriptan, 12 patients who consistently experienced recurrence of the headache after initial relief, 12 patients with no response to sumatriptan, and in 13 patients who consistently experienced chest symptoms after use of sumatriptan. No polymorphisms were detected in any of the patients. We therefore conclude that genetic diversity of the 5-HT1F receptor gene is most probably not responsible for the variable clinical response to sumatriptan.
Adult↗
[Channelopathies: a genetic explanation of migraine and other paroxysmal neurologic disorders].
There is increasing evidence of involvement of genes coding for ion channels in the pathogenesis of paroxysmal neurological disorders. Recently for instance, mutations in the calcium channel gene on chromosome 19 were identified in migraine, ataxia, and epilepsy. With the current research into inherited 'channelopathies' a new approach has been established. A better understanding of the pathophysiology of paroxysmal neurological disorders may lead to new therapeutic strategies.
Epilepsy↗
P/Q-type Ca2+ channel defects in migraine, ataxia and epilepsy.
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Animals↗
The transition G to A at position 20210 in the 3'-untranslated region of the prothrombin gene is not associated with migrainous infarction.
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Adolescent↗
5-HT1B receptor polymorphism and clinical response to sumatriptan.
The 5-HT1 receptor agonist, sumatriptan, is highly effective in the treatment of migraine. Some patients, however, do not respond or experience recurrence of the headache. In addition, some patients report chest symptoms after sumatriptan. We investigated whether these different responses could be attributed to genetic diversity of the 5-HT1B receptor, which most likely mediates the therapeutic action and the coronary side effects of sumatriptan. Allele frequencies of two polymorphisms in the 5-HT1B receptor gene (G861C and T-261G) were investigated in migraine patients with consistently good response to sumatriptan (n = 14), with no response (n = 12), with recurrence of the headache (n = 12), with chest symptoms (n = 13), and in patients without chest symptoms (n = 27). Allele frequencies (G:0.74; C:0.26 at nt 861 and T:0.39; G:0.61 at nt -261) did not differ between patient groups, indicating that genetic diversity of the 5-HT1B receptor does not seem to be involved in the different clinical responses to sumatriptan.
Adult↗
Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon.
We describe an extended Dutch family with a new hereditary disorder: autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Information was obtained on 289 family members (151 males, 138 females), of whom 198 were personally interviewed. Retinopathy was found in 20 (6.9%) of the family members, migraine in 65 (22.5%) and Raynaud's phenomenon in 50 (17.3%). A combination of all three symptoms was found in 11 subjects. In a genetic linkage analysis we firstly excluded several candidate loci. Subsequently, 75% of the autosomal genome was excluded in a genome-wide search. The following conclusions were drawn. First, genetic factors are involved in Raynaud's phenomenon. Secondly, the genetic linkage of migraine with vascular retinopathy and Raynaud's phenomenon supports a vascular aetiology of this disorder. Finding the gene for this family may help to elucidate the genetic background of migraine and of vascular disorders in general.
Adolescent↗
Pharmacokinetic and pharmacodynamic profile of oral and intravenous meta-chlorophenylpiperazine in healthy volunteers.
meta-Chlorophenylpiperazine (mCPP) is a compound that is frequently used in challenge tests of the serotonergic system. Its human pharmacology is largely unexplored. The objective of this study was to investigate the pharmacokinetic and pharmacodynamic profile of mCPP. Eight female and six male healthy volunteers were included in a randomized, double-blind, double-dummy, three-way crossover design of single-dose intravenous (0.1 mg/kg), oral (0.5 mg/kg), and placebo treatment, with 24-hour follow-up. mCPP showed a large variability in clearance (11-92 mL/hr) and bioavailability (14-108%). Two female subjects dropped out because of headache and dysphoria. During the 27 occasions in which mCPP was administered, autonomic physical symptoms were observed in 23 subjects and disturbances of mood in 6 subjects. Oral and intravenous mCPP caused sudden increases in cortisol levels, prolactin levels, and total scores of the Body Sensation Questionnaire. Administration of mCPP also led to concentration-dependent increases of saccadic peak velocity and adaptive tracking performance and to a decrease of electroencephalographic occipital theta activity. No clinically relevant effects on electrocardiogram, temperature, and blood pressure were found. In conclusion, it is doubtful whether mCPP is a useful compound for challenge tests in view of the large pharmacokinetic variability after intravenous and oral administration. The effects of mCPP are consistent with disinhibition of the central nervous system.
Administration, Oral↗
Prothrombotic mutations and ischaemic stroke at a young age in two sisters.
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Adult↗
Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Dutch Migraine Genetics Research Group.
Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with aura, with half of the families being assigned to chromosome 19p13. We identified missense mutations in a brain-specific calcium channel alpha1A-subunit (CACNA1A) gene on 19p13 segregating with FHM and truncating mutations in families with episodic ataxia type 2 (EA-2). Expansions of an intragenic CAG repeat have been shown in autosomal dominant cerebellar ataxia (SCA6). Hence, FHM, EA-2, and SCA6 are allelic ion channel disorders. We analyzed the phenotype-genotype relation in three unrelated FHM families with the calcium channel alpha1A-subunit gene mutations I1811L (two families) and V714A (one family). We found mutations in all but three patients with FHM (i.e., three phenocopies). In addition, the I1811L mutation occurred in two patients with "nonhemiplegic" migraine and in one subject without migraine. Cerebellar ataxia was found in both families with the I1811L mutation but not in the family with the V714A mutation. We failed to find expansions of the intragenic CAG repeat in FHM patients with cerebellar ataxia. We conclude that the I1811L mutation causes both FHM and cerebellar ataxia independent of the number of CAG repeats. The I1811L mutation may also occur in "normal" migraine patients, supporting the hypothesis that FHM is part of the migraine spectrum.
Adolescent↗
Genetics and pathology of voltage-gated Ca2+ channels.
Neurotransmitter release, neuronal excitation, and a whole variety of other neuronal functions are controlled by the intra/extra cellular Ca2+ gradient. The major pathway for entry of Ca2+ into the excitable cells is mediated by voltage-gated Ca2+ channels. Several functional subclasses of voltage-dependent Ca2+ channels have been identified, based on their pharmacological, biophysical properties, and molecular cloning. Recently, three human diseases (familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia 6) were added to the growing list of ion-channel disorders, all caused by different mutations in the P/Q-type Ca2+ channel alpha 1 subunit. Molecular analysis of the Ca2+ channelopathies will provide new insights into the role, function and pathology of these voltage-gated Ca2+ channels.
Animals↗
Genetics of migraine.
Although family studies and twin studies are not sufficiently reliable to establish this theory with certainty, migraine likely is influenced by hereditary susceptibility. The association of migraine with a large number of hereditary diseases opens the possibility to choose candidate chromosomes for linkage studies. A rare subtype of migraine, familial hemiplegic migraine, is linked to chromosome 19p and at least one other locus. The chromosome 19p also seems to be involved in "normal" migraine, although conflicting results have been reported.
Humans↗
The factor V Leiden mutation (R506Q) is not a major risk factor for migrainous cerebral infarction.
The etiology of migrainous cerebral infarction is unknown, but may involve prothrombotic coagulation abnormalities. Therefore, we studied resistance to activated protein C and the presence of the Arg506Gln factor V Leiden mutation in 20 patients with migrainous cerebral infarction. Only one heterozygous carrier of the mutation was found, whereas other patients did not carry the mutation. This indicates that the factor V Leiden mutation is not a major risk factor for migrainous cerebral infarction.
Adolescent↗
Double-blind, placebo-controlled, dose-finding study of rizatriptan (MK-462) in the acute treatment of migraine.
Rizatriptan (MK-462) is a potent 5HTID receptor agonist. This multicenter, double-blind, placebo-controlled, outpatient study investigated the clinical efficacy, safety, and tolerability of rizatriptan (2.5, 5, and 10 mg) as a function of dose for acute migraine. Patients with moderate or severe migraine (n = 417) were treated with placebo (n = 67), rizatriptan 2.5 mg (n = 75), 5 mg (n = 130), or rizatriptan 10 mg (n = 145). Headache severity, functional disability, and migraine symptoms were measured immediately before dosing (0) and at 0.5, 1, 1.5, 2, 3, and 4 h post-dose. Patients were permitted to take a second dose of test drug at 2 h if their headache pain was moderate or severe (i.e., placebo initially-->rizatriptan 10 mg as optional second dose; rizatriptan 2.5 mg, 5 mg, or 10 mg initially-->placebo as optional second dose). An upward dose-response relationship was observed among placebo, rizatriptan 2.5 mg, 5 mg, and 10 mg in the primary efficacy measure of proportion of patients reporting pain relief, i.e., a change in headache severity to "no pain or mild pain" at 2 h post-dose. The relationship was evident even at the first recorded timepoint, 30 min, and was statistically significant at 1.5 h and beyond. At the primary timepoint of 2 h after the initial dose, the proportion of patients reporting pain relief was 47.6% for rizatriptan 10 mg; 45.4% for rizatriptan 5 mg; 21.3% for rizatriptan 2.5 mg; and 17.9% for placebo. Seventy percent of patients on rizatriptan 10 mg reported pain relief at 4 h. Patients who took rizatriptan 5 mg and 10 mg were significantly less functionally disabled than those who took placebo at 1.5 and 2 h post-dose. Rizatriptan 10 mg was consistently more effective than 5 mg, although the differences were not statistically significant. The most frequent clinical adverse events were dizziness, somnolence, and asthenia/fatigue. No patients were discontinued for any adverse experiences and there were no serious adverse experiences.
Acute Disease↗
Wolff Award 1997. Involvement of a Ca2+ channel gene in familial hemiplegic migraine and migraine with and without aura. Dutch Migraine Genetics Research Group.
A gene for familial hemiplegic migraine, a subtype of migraine with aura, was assigned to chromosome 19p13. In this region, we identified a brain-specific P/Q-type calcium-channel alpha 1A-subunit gene, CACNA 1A, with 47 exons covering 300 kb. Sequencing of all exons and their flanking surroundings revealed polymorphic variations, including a (CA)n-repeat and a (CAG)n-repeat in the 3' untranslated region. In patients with familial hemiplegic migraine, we found four different missense mutations in conserved functional domains. One of the mutations has occurred on two different haplotypes in unrelated familial hemiplegic migraine families. Moreover, in episodic ataxia type 2, we found two mutations disrupting the reading frame. Thus, familial hemiplegic migraine and episodic ataxia type 2 can be considered as allelic channelopathies. Involvement of this familial hemiplegic migraine locus in migraine with and without aura was demonstrated by sib-pair analysis. We showed an increase of shared marker alleles of locus D19S394, which is tightly linked to the gene. The association between the alpha 1A calcium channel and familial hemiplegic migraine, and the increase of shared alleles in migraine-affected sib-pairs, have uncovered a new pathway for the pathophysiology of migraine. This finding may provide a rationale for the development of specific prophylactic therapy for migraine and other (paroxysmal) cerebral disorders.
Alleles↗
The quest for migraine genes.
Research into the genetics of migraine remains difficult because of the involvement of polygenetic and environmental factors. The discovery of the gene for familial hemiplegic migraine on chromosome 19p 13 is an important step forward. This brain specific P/Q-type calcium channel alpha 1-subunit gene opens new avenues for studying the genetics of migraine, the pathophysiology of the onset of migraine attacks and the development of novel specific prophylactic drugs.
Family Health↗