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Blood Pressure Abstract
Blood Pressure Claims 1. A pharmaceutical composition which comprises a mixture of a therapeutically effective amount of an alpha-2 adrenoceptor antagonist which is an indole derivative selected from the group consisting of yohimbine and derivatives thereof and a therapeutically effective amount of a catecholamine precursor which is a member selected from the group consisting of tyrosine, phenylalanine, dihydroxyphenylalanine, dopamine and L-dihydroxyphenylserine. 2. A composition as claimed in claim 1 which additionally comprises an inhibitor of aromatic L-amino acid decarboxylase which is a member selected from the group consisting of carbidopa, benserazide, m-hydroxybenzylhydrazine, and beta -alphahydrazino-alpha-methyl-propionic acid. 3. A composition as claimed in claim 1 wherein there is also present a pharmaceutically acceptable diluent or carrier. 4. A composition as claimed in claim 1 which is in unit dosage form. 5. A composition as claimed in claim 4 wherein each unit dosage contains from 1 to 200 mg of alpha-2 adrenoceptor antagonist. 6. A composition as claimed in claim 1 wherein the catecholamine precursor is tyrosine, phenylalanine, dihydroxyphenylalanine, or dopamine. 7. A composition as claimed in claim 4 wherein the solid unit dosage form contains from 5 to 40 mg of the alpha-2 adrenoceptor antagonist and 250 mg to 40 g of the catecholamine precursor. 8. A composition as claimed in claim 7 wherein the composition contains carbidopa in a weight ratio relative to the alpha-2 adrenoceptor antagonist of from 2:1 to 1:4. 9. A composition as claimed in claim 4 wherein the injectable unit dosage form contains from 5 to 15 milligrams of the alpha-2 adrenoceptor antagonist and from 50 to 750 mg of the catecholamine precursor. 10. A pharmaceutical composition as claimed in claim 1, wherein said alpha-2 adrenoceptor antagonist is yohimbine. 11. A pharmaceutical composition as claimed in claim 10, wherein said catecholamine precursor is phenylalanine. 12. A pharmaceutical composition as claimed in claim 2, wherein said alpha-2 adrenoceptor antagonist is yohimbine, said catecholamine precursor is phenylalanine and said inhibitor of aromatic L-amino acid decarboxylase is carbidopa. 13. A pharmaceutical composition as claimed in claim 1, wherein said alpha-2 adrenoceptor antagonist is rauwolscine. 14. A pharmaceutical composition as claimed in claim 1, wherein the catecholamine precursor is a member selected from the group consisting of tyrosine, phenylalanine, dihydroxyphenylalanine and dopamine. 15. A pharmaceutical composition as claimed in claim 2, wherein said inhibitor of aromatic L-amino acid decarboxylase is carbidopa. 16. The method of treatment of low blood pressure which comprises administering to a person requiring treatment a therapeutically effective amount of the pharmaceutical composition as claimed in claim 1. 17. A method of treatment of endogenous depression which comprises administering to persons requiring treatment a therapeutically effective amount of the pharmaceutical composition as claimed in claim 1. 18. A method of treatment of endogenous depression which comprises administering to a person requiring treatment a therapeutically effective amount of the pharmaceutical composition as claimed in claim 2. Patent Information Search Body
Blood Pressure Description Adrenaline and noradrenaline are substances that are released from nerve endings in the brain and in the periphery, and from the adrenal glands. They act as chemical messengers or `neurotransmitters`. Adrenaline, noradrenaline and a related substance, dopamine, belong to a class of chemicals known as the catecholamines. They are synthesised in the body from the amino acid tyrosine. Tyrosine is a natural dietary amino acid, but the body can also synthesise tyrosine from the amino acid phenylalanine. Tyrosine is converted into dihydroxyphenylalanine, which is in turn converted to dopamine, noradrenaline, and finally to adrenaline. Adrenergic receptors (usually known as adrenoceptors) are the sites of action of adrenaline and noradrenaline. They mediate physiological or pharmacological effects upon stimulation by an appropriate chemical, be it an endogenous substance or a synthetic drug with similar activity (agonist drug). By using a variety of pharmacological techniques, these receptors have been classified into alpha and beta adrenoceptors. Alpha adrenoceptors have in turn been subdivided into alpha-1 and alpha-2 adrenoceptor subtypes. Alpha-2 adrenoceptors are located in the membranes both of the target cells for adrenaline and noradrenaline (known as post synaptic alpha-2 adrenoceptors), and in the noradrenergic neurones themselves (known as presynaptic alpha-2 adrenoceptors). The presynaptic alpha-2 adrenoceptors inhibit the release of noradrenaline from its nerve terminals and act as a `negative feedback` mechanism following the release of noradrenaline from its nerve terminals. Thus, stimulation of alpha-2 adrenoceptors by agonists, including the endogenous neurotransmitters adrenaline and noradrenaline, reduces the amount of neurotransmitter released from the neuron. Conversely, administration of an alpha-2 adrenoceptor antagonist drug will increase the amount of neurotransmitter released from the neuron, by blocking the presynaptic alpha-2 adrenoceptors. Alpha-2 adrenoceptor antagonists are currently being investigated for a possible therapeutic effect in illnesses that are believed to be associated with reduced noradrenaline activity, such as endogenous depression. It has also been proposed that alpha-2 adrenoceptor antagonists may be therapeutically useful in the treatment of low blood pressure states, by increasing the output of noradrenaline, which increases the blood pressure. One of the most effective alpha-2 adrenoceptor antagonists is idazoxan which has been developed by Reckitt & Colman Pharmaceutical Division; this drug is described and claimed in GB-B-2068376, which is incorporated herein by reference. The present invention is based upon the surprising discovery that the effectiveness of an alpha-2 adrenoceptor antagonist in causing noradrenaline release from nerve endings is enhanced significantly by administration of a catecholamine precursor to increase the amount of catecholamine that is available for release from the neuron. Accordingly the present invention provides a pharmaceutical composition for the treatment of depression and/or low blood pressure which comprises a mixture of an alpha-2 adrenoceptor antagonist, preferably idazoxan, or a pharmaceutically acceptable salt thereof, and either a catecholamine precursor or an inhibitor of aromatic L-amino acid decarboxylase. Preferably the composition comprises a catecholamine precursor and an inhibitor of aromatic amino acid decarboxylase. In the treatment of depression, the oral route of administration is preferable in view of the long term nature of this condition and the requirement for prolonged therapy. However, under some circumstances administration by injection of a single or repeated doses of the antidepressant drug is desirable. This may be so if it is important to attain adequate blood level of the drugs rapidly, or if a patient is unable to take the drug orally. In the treatment of low blood pressure states, the intravenous route of administration is preferable, as a rapid response is usually desirable. In one of the aspects the invention provides a composition wherein the risk of side effects from alpha-2 adrenoceptor antagonists is reduced by the addition of a compound that inhibits the synthesis of the catecholamine neurotransmitters in the peripheral nervous system, but not in the brain. The increased output of noradrenaline in the periphery caused by alpha-2 adrenoceptor antagonists results in elevation of blood pressure, awareness of heart beat and sweating. These effects can be reduced or eliminated by compounds which inhibit the aromatic L-amino acid decarboxylase enzyme. Aromatic L-amino acid decarboxylase is an enzyme that is widely distributed in the body, including the brain (Lovenberg et al, 1962, The Journal of Biological Chemistry, 237, 89). In catecholamine neurons, it catalyses the conversion of L-dihydroxyphenylalanine (L-DOPA) to L-dihydroxyphenylethylamine (dopamine), so it is sometimes known by its trivial name, `DOPA decarboxylase`. The decarboxylation of L-DOPA is one of the steps in the synthesis of the catecholamine neurotransmitters (dopamine, noradrenaline and adrenaline) from tyrosine. Inhibition of this enzymatic step results in a fall in the rate of synthesis of the catecholamine neurotransmitters. Several compounds have been described with the ability to inhibit this enzyme. These include carbidopa (alpha-methyl-L-DOPA hydrazine), benserazide (N-[DL-seryl]-N'-[2,3,4-trihydroxybenzyl]hydrazine), NSD 1015 (m-hydroxybenzylhydrazine) and MK 485 (beta-[3,4-dihydroxyphenyl]-alphahydrazino-alpha-methyl propionic acid). Some of these inhibitory compounds, such as carbidopa and MK 485 do not reach the brain following peripheral administration, even when given in apparently large doses. Other compounds, such as benserazide, only reach the brain when given in large doses (Bartholini & Pletscher, 1969, Journal of Pharmacy & Pharmacology, 21, 323). It follows that using a compound such as carbidopa, it is possible to inhibit the synthesis of the catecholamine neurotransmitters in the peripheral sympathetic nervous system without affecting the equivalent process in the brain (Wurtman & Watkins, 1977, Nature, 265, 79). The peripheral effects of alpha-2 adrenoceptor antagonists, alone or in combination with catecholamine precursors, can be reduced or abolished by these aromatic L-amino acid decarboxylase inhibitors. A particularly preferred decarboxylase inhibitor for use in the composition of the invention is carbidopa although appropriate doses of benserazide, and MK 485 may also be used. Several classes of drugs have been described with alpha-2 adrenoceptor antagonist activity and any of these may be used in compositions according to this invention; these include: 1. Imidazole derivatives such as Idazoxan (RX 781094) which acts as a competitive antagonist at alpha-2 adrenoceptors. Its pharmacological characteristics make it one of the most highly selective of the available antagonists at alpha-2 adrenoceptors; the drug has minimal activity at alpha-1 adrenoceptors and no significant activity at beta adrenergic, opiate, histaminergic, cholinergic and serotonergic receptors (Doxey, JC et al, 1983, British Journal of Pharmacology, 78, 489). Idazoxan increases noradrenaline release from neurons in the brain and in the periphery following oral administration. Idazoxan is currently undergoing clinical trials as an antidepressant. It is available for investigative use as a solution for intravenous injection (10 mg per ampoule) and as tablets containing 5, 10, 20 and 40 mg of the drug. Several other derivatives and analogues have alpha-2 adrenoceptor antagonists activity, including imiloxan (RS 21361; Doxey, JC et al, 1983, British Journal of Pharmacology, 78, 489), the 2-methoxy analogue of idazoxan (RX 821002) (Doxey, JC et al, 1984, British Journal of Pharmacology, 81, 181P), the 2-isoprenyl analogue (RX 811005) (Doxey et al, 1984, British Journal of Pharamcology, 83, 713,) the 2-ethyl analogue (RX 811033) (Gadie, B et al, 1984, British Journal of Pharmacology, 83, 707), the dihydrofuran ring substituted analogue S 9871 (Joly, G et al, 1984, Archives Internationales Pharmacodynamie & Therapie, 269, 277) and the dihydrobenzofuranyl analogue (Chapleo CB, et al, 1984, Journal of Medicinal Chemistry, 27, 570) ([imidazolinyl-2-]-2 dihydro 2,3 benzofurane). 2. The quadricyclic compound mianserin is an established antidepressant in clinical practice. It has prominent alpha-2 adrenoceptor antagonist activity, but in addition, it is active at receptors for serotonin and histamine. Several derivatives of mianserin possess alpha-2 adrenoceptor antagonist activity, including desmethylmianserin (Nickolson, V. J. et al, 1982, Archives of Pharmacology, 319, 48), 8-hydroxymianserin (Nickolson et al, 1982, Archives of Pharmacology, 319, 48), S (+)-mianserin (Nickolson, V. J. & Wieringa, J. H., 1981, Journal of Pharmacy and Pharmacology, 33, 760), the 6-aza analogue Org-3770 (Nickolson, V. J. et al, 1982, Archives of Pharmacology, 319, 48), aptazapine (Nickolson, V. J. & Wieringa, J. H., 1981, Journal of Pharmacy & Pharmacology, 33, 760), CGS-7525A (1,3,4,14b-tetrahydro-2-methyl-10H-pyrazino-[1,2-a]pyrrolo[2,1-c][1,4]benz odiazepine maleate) (Liebman, J. M. et al, 1983, Life Sciences, 32, 355), 1(3-fluoro-2-pyridinyl) piperazine, its methyl derivative (Saari, W. S. et al, 1983, Journal of Medicinal Chemistry, 26, 1696) and 4-(3-fluoro- 2-pyridinyl)-1,2,5,6-tetrahydropyridine (Saari, W. S. et al, 1984, Journal of Medicinal Chemistry, 27, 1182). 3. Yohimbine is an indole derivative found in a variety of plants. It has several pharmacological actions including alpha-2 adrenoceptor antagonist activity, as does its derivative rauwolscine. 4. The newly synthesised benzoquinolizine drugs from Wyeth Laboratories Wy 26703, N-((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-yl )-N-methylisobutanesulphonamide, hydrochloride) and WY 26392 (N-((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo-(a)-quinolizin-2 -yl)-N-methylpropanesulphonamide, hydrochloride) and WY25309 (N-((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-y l)-N-methylmethanesulphonamide hydrochloride), have been reported to have alpha-2 adrenoceptor antagonist activity (Paciorek, P. M. et al, 1984, British Journal of Pharmacology, 82, 127). 5. The azepine compounds B-HT-958(2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolozepine)[5 ,4-d]azepine) (Hortnagl, H. et al, 1984, European Journal of Pharmacology, 106, 335) and SK & F 86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl1H-3-benzazepine; DeMarinis, R. M. et al, 1983Journal of Medicinal Chemistry, 26, 1213) also possess alpha-2 adrenoceptor antagonist activity. The following are examples of pharmaceutical compositions according to the invention. It is to be understood however that apart from the alternative alpha-2 adrenoceptor antagonists listed below other aromatic L-amino acid decarboxylase inhibitors may be substituted for carbidopa. Benserazide, 100 mg, is a particularly suitable substitute for carbidopa in the following compositions.
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