Research in Review

• In vivo pharmacodynamic interactions between two drugs used in orthostatic hypotension - midodrine and dihydroergotamine
• A Comparison of Self-reported Quality of Life between Patients with Epilepsy and Neurocardiogenic Syncope
• Laser Doppler Method in Evaluation of Vasovagal Syncope Induced by Tilt Table Test
• Is vasovagal syncope a disease?
• L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug

In Vivo Pharmacodynamic Interactions Between Two Drugs Used in Orthostatic Hypotension - Midodrine and Dihydroergotamine.

Fundam Clin Pharmacol. 2007 Feb;21(1):45-53.

Jourdan G, Verwaerde P, Pathak A, Tran MA, Montastruc JL, Senard JM.
Inserm, U586, Unite de Recherches sur les Obesites, F-31432 Toulouse, France.

A combination of midodrine and dihydroergotamine (DHE) is frequently used clinically in patients suffering from severe orthostatic hypotension (OH). Whereas midodrine acts as a selective, peripheral alpha1-receptor agonist, DHE displays complex pharmacology and can behave as an alpha-adrenergic receptor agonist or antagonist. Surprisingly, the consequences of such a combination on blood pressure have never been investigated. The present study was performed in order to evaluate the pressor effects induced by the administration of both midodrine and DHE in old conscious dogs (n = 6) in experimental condition reproducing autonomic failure-related baroreflex dysfunction (atropine 0.1 mg/kg). For this purpose, we first studied the relative potency and intrinsic activity of each agonist and noradrenaline (NA) for the alpha1-adrenergic receptor. The orders of potency obtained in our study were 0.35, 11 and 400 mug/kg for NA, DHE and midodrine, and intrinsic activity: NA > midodrine > DHE. These results strongly suggest that DHE really acts in vivo as an alpha1-adrenoceptor partial agonist. Afterwards, the pressor effects of coadministration of midodrine (0.4 mg/kg) and DHE (15 mug/kg) were investigated: in one setting, midodrine was first administered, followed by DHE; in another, DHE was first administered, followed by midodrine. Our results show that in conscious dogs, the combination of midodrine and DHE leads to near-complete abolition of the pressor effect induced by the first administered drug. This in vivo proof of such antagonistic effects on blood pressure could explain clinical observations of worsening of OH in humans administered midodrine plus DHE. Although in vivo results obtained in conscious healthy dogs need to be experimentally and clinically confirmed in humans suffering from OH, these results strongly suggest that a midodrine-DHE combined treatment should be avoided in clinical practice.

PMID: 17227444

A Comparison of Self-reported Quality of Life between Patients with Epilepsy and Neurocardiogenic Syncope.

Epilepsia. 2007 Feb 5.

Santhouse J, Carrier C, Arya S, Fowler H, Duncan S.

Department of Neurology, Greater Manchester Neurosciences Centre Hope Hospital, Salford, United Kingdom.

Epilepsy and neurocardiogenic syncope share a final common pathway of loss of consciousness and consequent social disruption. We compared 52 patients with syncope, 96 with epilepsy and 100 controls. Epilepsy and syncope patients expressed significantly higher levels of anxiety and depression and reported significantly less good quality of life (QoL) compared with controls. There were no significant differences on any of the QoL parameters measured between the syncope and epilepsy patients. These findings suggest the main contributor to poor QoL in epilepsy may be the unpredictable loss of control that is the hallmark of the condition.

PMID: 17284295

Laser Doppler Method in Evaluation of Vasovagal Syncope Induced by Tilt Table Test.

Conf Proc IEEE Eng Med Biol Soc. 2004;3:2315-7.

Maniewski R, Szufladowicz E, Nosek A, Walczak F.

Institute of Biocyberaetics & Biomedical Eng. PAS, Warsaw, Poland.

The laser Doppler flowmetry offers a new noninvasive, real-time technique for monitoring of the blood perfusion in living tissue. In spite of some instrumental problems, e.g. relative calibration and unknown sampling measurement depth, this method has already been used in clinical examination. The purpose of presented study was the application of the laser Doppler method in evaluation of the vasovagal syncope induced in the tilt-table test. Twelve patients with the history of syncopal episodes were examined using the head-up tilt-table test. In the some condition three normal subjects were also examined as the reference. Results of examination have showed that the changes measured by laser Doppler method are clearly visible during the pre-syncope and syncope period. These changes in perfusion precede the subjective clinical symptoms as well as decrease in the blood pressure, blood oxygen saturation and heart rate.

PMID: 17272192

Is Vasovagal Syncope a Disease?

Europace. 2007 Feb;9(2):83-7.

Alboni P, Brignole M, Degli Uberti EC.

1 Division of Cardiology and Arrhythmologic Center, Ospedale Civile, Via Vicini 2, 44042 Cento (FE), Italy.

Vavovagal syncope (VVS) is not generally associated with cardiovascular, neurological or other diseases, and, therefore, represents an isolated manifestation. Isolated VVS cannot be regarded as a disease for several reasons: spontaneous syncope occurs in about half of individuals during their lives, and the unidentified neural pathways involved in the vasovagal response are probably present in all healthy humans, with individual differences in susceptibility; VVS is induced during tilt testing in several subjects with no history of syncope; during haemorrhagic shock, the vasovagal reaction can be observed in subjects with no history of syncope; about 20% of astronauts, who are selected on the basis of their great resistance to orthostatic stress, experience syncope or presyncope on landing after a short-duration space flight; to date, no genetic basis of VVS has been demonstrated; subjects with VVS are generally normotensive and, importantly, have normal blood pressure regulation apart from the episodes of syncope; hormonal disorders or a generalized state of autonomic involvement, although frequently investigated, have never been clearly demonstrated. Isolated VVS should be distinguished from those forms that start in old age and which are often associated with cardiovascular or neurological disorders, and other dysautonomic disturbances such as carotid sinus hypersensitivity, post-prandial hypotension, and symptoms of autonomic dysfunction. In these subjects, VVS appears as an expression of a pathological process, i.e. a disease, mainly related to a generalized involvement of the autonomic nervous system, which is not yet well-defined from a nosological point of view.

PMID: 17272328

L-Dihydroxyphenylserine (L-DOPS): A Norepinephrine Prodrug.

Cardiovasc Drug Rev. 2006 Fall-Winter;24(3-4):189-203.

Goldstein DS.

Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA. goldsteind@ninds.nih.gov

L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxydopa) is a synthetic catecholamino acid. When taken orally, L-DOPS is converted to the sympathetic neurotransmitter, norepinephrine (NE), via decarboxylation catalyzed by L-aromatic-amino-acid decarboxylase (LAAAD). Plasma L-DOPS levels peak at about 3 h, followed by a monoexponential decline with a half-time of 2 to 3 h. Plasma levels of NE and of its main neuronal metabolite, dihydroxyphenylglycol (DHPG) peak approximately concurrently but at much lower concentrations. The relatively long half-time for disappearance of L-DOPS from plasma, compared to that of NE, explains their very different attained plasma concentrations. In patients with neurogenic orthostatic hypotension, L-DOPS increases blood pressure and ameliorates orthostatic intolerance. Inhibition of LAAAD, such as by treatment with carbidopa, which does not penetrate the blood-brain barrier, prevents the blood pressure effects of the drug, indicating that L-DOPS increases blood pressure by augmenting NE production outside the brain. Patients with pure autonomic failure (which usually entails loss of sympathetic noradrenergic nerves), and patients with multiple system atrophy (in which noradrenergic innervation remains intact) have similar plasma NE responses to L-DOPS. This suggests mainly non-neuronal production of NE from L-DOPS. L-DOPS is very effective in treatment of deficiency of dopamine-beta-hydroxylase (DBH), the enzyme required for conversion of dopamine to NE in sympathetic nerves. L-DOPS holds promise for treating other much more common conditions involving decreased DBH activity or NE deficiency, such as a variety of syndromes associated with neurogenic orthostatic hypotension.

PMID: 17214596

Research abstracts obtained from PubMed.

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