Droxidopa
Encyclopedia
L-DOPS is a psychoactive drug
and synthetic
amino acid
precursor
which acts as a prodrug
to the neurotransmitter
s norepinephrine
(noradrenaline) and epinephrine
(adrenaline). Unlike norepinephrine and epinephrine themselves, L-DOPS is capable of crossing the protective blood-brain barrier
(BBB).
Droxidopa for the treatment
of hypotension
, including NOH, and NOH associated with various disorder
s such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan
and some surrounding Asia
n areas for these indication
s since 1989. Following a merge with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma
licensed L-DOPS to Chelsea Therapeutics to develop
and market
it world
wide except in Japan, Korea
, China
, and Taiwan
.
and Southeast Asia
already for some time, it is also currently in clinical trial
s at the phase III point in the United States
(U.S.), Canada
, Australia
, and throughout Europe
. Provided L-DOPS successfully completes clinical trials, it could be approved
for the treatment of NOH as early as 2011. Additionally, phase II clinical trial
s for IDH are also underway. Chelsea Therapeutics obtained orphan drug status (ODS) for L-DOPS in the U.S. for NOH, and that of which associated with PD, PAF, and MSA, and is the pharmaceutical company
developing
it in that country
.
of norepinephrine
and epinephrine
used to increase the concentration
s of these neurotransmitter
s in the body
and brain
. It is metabolized by aromatic L-amino acid decarboxylase
(AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted level
s of norepinephrine and epinephrine which leads to decreased blood pressure
or hypotension
upon orthostatic challenge. L-DOPS works by increasing the levels of norepinephrine and epinephrine in the peripheral nervous system
(PNS), which induces tachycardia
or increased heart rate
and hypertension
or increased blood pressure, thus enabling the body to maintain blood flow
upon and while standing.
L-DOPS can also cross the blood-brain barrier
(BBB) where it is converted to norepinephrine and epinephrine from within the brain. Increased levels of norepinephrine and epinephrine in the central nervous system
(CNS) may be beneficial to patients in a wide range of indications. L-DOPS can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or DOPA decarboxylase inhibitor
(DDC) such as carbidopa
(Lodosyn) to increase central norepinephrine and epinephrine concentrations while maintaining peripheral levels.
s of which most are mild. Patients have reported tachycardia, hypertension, nausea
and vomiting
, and headache
or migraine
.
Psychoactive drug
A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...
and synthetic
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
precursor
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
which acts as a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
to the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(noradrenaline) and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
(adrenaline). Unlike norepinephrine and epinephrine themselves, L-DOPS is capable of crossing the protective blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
(BBB).
Indications
- Neurogenic orthostatic hypotension (NOH), as well as NOH associated with multiple system atrophyMultiple system atrophyMultiple system atrophy is a degenerative neurological disorder. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance and other autonomic functions of the body such as bladder control or blood pressure...
(MSA), familial amyloid polyneuropathyFamilial amyloid polyneuropathyFamilial amyloid polyneuropathy , also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of paramyloidosis, and was first identified and described by Portuguese neurologist...
(FAP), pure autonomic failurePure autonomic failurePure autonomic failure, also known as Bradbury-Eggleston syndrome or idiopathic orthostatic hypotension, is a form of dysautonomia that first occurs in middle age or later in life; men are affected more often than women...
(PAF), and Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
(PD). - Intradialytic hypotension (IDH) or hemodialysisHemodialysisIn medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
-induced hypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
. - HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
associated with fibromyalgia syndrome (FMS) and chronic fatigue syndromeChronic fatigue syndromeChronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
(CFS).
History
L-DOPS was developed by Sumitomo Pharmaceuticals under the trade nameTrade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
Droxidopa for the treatment
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
of hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, including NOH, and NOH associated with various disorder
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
s such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
and some surrounding Asia
Asia
Asia is the world's largest and most populous continent, located primarily in the eastern and northern hemispheres. It covers 8.7% of the Earth's total surface area and with approximately 3.879 billion people, it hosts 60% of the world's current human population...
n areas for these indication
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
s since 1989. Following a merge with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma
Dainippon Sumitomo Pharma
is a pharmaceutical company based in Japan.The original Dainippon Pharmaceuticals was established in 1885 by Nagayo Sensai, a graduate of Tekijuku – the first private medical school in Japan established by Ogata Kōan. It was set up as a wholly private company invested by a number of people in...
licensed L-DOPS to Chelsea Therapeutics to develop
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
and market
Market
A market is one of many varieties of systems, institutions, procedures, social relations and infrastructures whereby parties engage in exchange. While parties may exchange goods and services by barter, most markets rely on sellers offering their goods or services in exchange for money from buyers...
it world
World
World is a common name for the whole of human civilization, specifically human experience, history, or the human condition in general, worldwide, i.e. anywhere on Earth....
wide except in Japan, Korea
Korea
Korea ) is an East Asian geographic region that is currently divided into two separate sovereign states — North Korea and South Korea. Located on the Korean Peninsula, Korea is bordered by the People's Republic of China to the northwest, Russia to the northeast, and is separated from Japan to the...
, China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
, and Taiwan
Taiwan
Taiwan , also known, especially in the past, as Formosa , is the largest island of the same-named island group of East Asia in the western Pacific Ocean and located off the southeastern coast of mainland China. The island forms over 99% of the current territory of the Republic of China following...
.
Clinical Trials
Though L-DOPS has been used in JapanJapan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
and Southeast Asia
Southeast Asia
Southeast Asia, South-East Asia, South East Asia or Southeastern Asia is a subregion of Asia, consisting of the countries that are geographically south of China, east of India, west of New Guinea and north of Australia. The region lies on the intersection of geological plates, with heavy seismic...
already for some time, it is also currently in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s at the phase III point in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
(U.S.), Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
, Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
, and throughout Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
. Provided L-DOPS successfully completes clinical trials, it could be approved
Approved drug
In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo an extensive FDA approval process. This process involves first testing the drug on animals or in medical labs. If found to be safe by the FDA and approved for the next phase of study, the drug is then...
for the treatment of NOH as early as 2011. Additionally, phase II clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s for IDH are also underway. Chelsea Therapeutics obtained orphan drug status (ODS) for L-DOPS in the U.S. for NOH, and that of which associated with PD, PAF, and MSA, and is the pharmaceutical company
Pharmaceutical company
The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
developing
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
it in that country
Country
A country is a region legally identified as a distinct entity in political geography. A country may be an independent sovereign state or one that is occupied by another state, as a non-sovereign or formerly sovereign political division, or a geographic region associated with a previously...
.
Pharmacology
L-DOPS is a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
used to increase the concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s of these neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s in the body
Body
With regard to living things, a body is the physical body of an individual. "Body" often is used in connection with appearance, health issues and death...
and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. It is metabolized by aromatic L-amino acid decarboxylase
Aromatic L-amino acid decarboxylase
Aromatic L-amino acid decarboxylase is a lyase enzyme.-Reactions:It catalyzes several different decarboxylation reactions:* L-DOPA to dopamine - a neurotransmitter* 5-HTP to serotonin - also a neurotransmitter...
(AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted level
Chemical imbalance
Chemical imbalance is one hypothesis about the cause of mental illness. Other causes that are debated include psychological and social causes....
s of norepinephrine and epinephrine which leads to decreased blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
or hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
upon orthostatic challenge. L-DOPS works by increasing the levels of norepinephrine and epinephrine in the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(PNS), which induces tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
or increased heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
and hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
or increased blood pressure, thus enabling the body to maintain blood flow
Blood flow
Blood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
upon and while standing.
L-DOPS can also cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
(BBB) where it is converted to norepinephrine and epinephrine from within the brain. Increased levels of norepinephrine and epinephrine in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) may be beneficial to patients in a wide range of indications. L-DOPS can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or DOPA decarboxylase inhibitor
Dopa decarboxylase inhibitor
An aromatic L-amino acid decarboxylase inhibitor is a drug which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase ....
(DDC) such as carbidopa
Carbidopa
Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa.- Pharmacology :...
(Lodosyn) to increase central norepinephrine and epinephrine concentrations while maintaining peripheral levels.
Side Effects
With close to 20 years on the market, L-DOPS has proven to have very few side effectAdverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s of which most are mild. Patients have reported tachycardia, hypertension, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, and headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
or migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
.
See also
- D-DOPAD-dopaD-DOPA is similar to L-DOPA , but with opposite chirality. Levo- and dextro- rotation reference a molecule's ability to rotate planes of polarized light in either direction...
(Dextrodopa) - L-DOPA (Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc)
- MethyldopaMethyldopaMethyldopa is an alpha-adrenergic agonist psychoactive drug used as a sympatholytic or antihypertensive. Its use is now mostly deprecated following the introduction of alternative safer classes of agents...
(Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc) - DopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
(Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc) - NorepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(Noradrenaline; Levophed, etc) - EpinephrineEpinephrineEpinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
(Adrenaline; Adrenalin, EpiPed, Twinject, etc)