Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment.

The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack.

Methysergide.

Methysergide is a semisynthetic ergot alkaloid ergometrine derivative, introduced in pharmacotherapy for migraine prophylaxis as a specific serotonin (5HT) receptor antagonist. Methysergide is not just a 5HT2 antagonist, it is also a 5HT1 agonist. Open and controlled studies attest to methysergide's efficacy. It may be more effective in resistant cases with a high attack frequency and may act synergistically with ergotamine and dihydroergotamine (DHE) for breakthrough attacks. Contraindications include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Methysergide can induce retroperitoneal fibrosis and pleural and heart valve fibrosis with an estimated incidence of 1 in 5,000 treated patients. Therefore, it should be reserved for severe cases in which other migraine preventive drugs are not effective.

In vivo evaluation of the semi-simultaneous method for bioavailability estimation using controlled intravenous infusion as an 'extravascular' route of administration.

A recently proposed method for bioavailability estimation, called the semi-simultaneous method, was evaluated in vivo in rats using methysergide as a test substance. In this method the test and the reference dose are administered with a short time interval and a model including the bioavailability parameters is fitted to the concentration-time profile. In the present study, in order to control the true bioavailability, intravenous infusion was used to mimic extravascular administration and various input profiles were produced. Mono-, bi- and triexponential disposition functions with the true and also various erroneous input models were fitted to the individual data sets. The models were also fitted to truncated data sets to mimic a situation where a long duration of sampling is precluded. A combined fitting-deconvolution procedure was also applied. The simi-simultaneous method gave precise and accurate estimates of the bioavailability in most groups and a robustness in the estimate concerning the model fitted was noted. The true input model could be identified for all data sets using common goodness-of-fit criteria. In the groups where a 'flip-flop' situation was created (slower input than elimination) a poorer precision and accuracy and a higher sensitivity concerning the model fitted was observed. The model fitting and the fitting-deconvolution procedure generally gave very similar results.

Pharmacokinetics of methysergide and its metabolite methylergometrine in the rat.

The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 ml/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 ml/min per kg for the low and the high rate of iv infusion of MS, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)