Droxidopa, also known as L-''threo''-dihydroxyphenylserine (L-DOPS) and sold under the brand names Northera and Dops among others, is sympathomimetic

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

which is used in the treatment of

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

(low blood pressure) and for other indications. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of droxidopa include

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, and

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

, among others. Droxidopa is a

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

precursor which acts as a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

to the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

(noradrenaline). Hence, it acts as a non-selective

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the α- and

β-adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...

s. Unlike norepinephrine, but similarly to

levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...

(L-DOPA), droxidopa is capable of crossing the protective

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

(BBB). Droxidopa was first described by 1971. It was approved for use in

Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...

in 1989 and was introduced in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

in 2014.

Medical uses

Droxidopa is approved for use in the treatment of

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

, intradialytic hypotension (IDH;

hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

-induced

, and amyloid polyneuropathy. For hypotension, it is specifically used in the treatment of neurogenic orthostatic hypotension (NOH) in dopamine β-hydroxylase deficiency, as well as NOH associated with

multiple system atrophy Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progr ...

(MSA),

familial amyloid polyneuropathy Familial amyloid polyneuropathy, also called hereditary transthyretin amyloidosis (hATTR), or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by P ...

(FAP), and pure autonomic failure (PAF). The drug is also used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

in the treatment of freezing of gait in

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

Side effects

With over 20years on the market, droxidopa has proven to have few

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of which most are mild. The most common side effects reported in clinical trials include headache, dizziness, nausea, hypertension and fatigue.

Pharmacology

Droxidopa is a

used to increase the

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'', ...

s of these

s in the

body Body may refer to: In science * Physical body, an object in physics that represents a large amount, has mass or takes up space * Body (biology), the physical material of an organism * Body plan, the physical features shared by a group of anim ...

and

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. It is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine which leads to decreased

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

upon

orthostatic Standing, also referred to as orthostasis, is a position in which the body is held in an upright (orthostatic) position and supported only by the feet. Although seemingly static, the body rocks slightly back and forth from the ankle in the sag ...

challenge. Droxidopa works by increasing the levels of norepinephrine in the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...

(PNS), thus enabling the body to maintain

blood flow Hemodynamics American and British English spelling differences#ae and oe, or haemodynamics are the Fluid dynamics, dynamics of blood flow. The circulatory system is controlled by homeostasis, homeostatic mechanisms of autoregulation, just as hydrau ...

upon and while

standing Standing, also referred to as orthostasis, is a position in which the body is held in an upright (orthostatic) position and supported only by the feet. Although seemingly static, the body rocks slightly back and forth from the ankle in the ...

. Droxidopa can also cross the

(BBB) where it is converted to norepinephrine from within the brain. Increased levels of norepinephrine in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS) may be beneficial to patients in a wide range of indications. Droxidopa can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or

DOPA decarboxylase inhibitor An aromatic L-amino acid decarboxylase inhibitor (synonyms: DOPA decarboxylase inhibitor, extracerebral decarboxylase inhibitor, DDCI and AAADI) is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme ...

(DDC) such as

carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levo ...

(Lodosyn) to increase central norepinephrine concentrations while minimizing increases of peripheral levels.

Chemistry

Droxidopa, also known as (–)-''threo''-3-(3,4-dihydroxyphenyl)-L-serine (L-DOPS), is a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

and is chemically analogous to

(L-3,4-dihydroxyphenylalanine; L-DOPA). Whereas levodopa functions as a precursor and prodrug to

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, droxidopa is a precursor and prodrug of

History

Droxidopa was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 1971. Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of

, including NOH, and NOH associated with various

disorder Disorder may refer to randomness, a lack of intelligible pattern, or: Healthcare * Disorder (medicine), a functional abnormality or disturbance * Mental disorder or psychological disorder, a psychological pattern associated with distress or disab ...

s such as MSA, FAP, and PD, as well as IDH. The drug has been used in

and some surrounding

Asia Asia ( , ) is the largest continent in the world by both land area and population. It covers an area of more than 44 million square kilometres, about 30% of Earth's total land area and 8% of Earth's total surface area. The continent, which ...

n areas for these indications since 1989. Following a merger with Dainippon Pharmaceuticals in 2006,

Dainippon Sumitomo Pharma is a Japanese multinational pharmaceutical company. The company is focused on oncology, psychiatry, neurology, women's health issues, urological diseases among other areas. Its headquarters are located in Chuo-ku, Osaka. History The original ...

licensed droxidopa to Chelsea Therapeutics to develop and

market Market is a term used to describe concepts such as: *Market (economics), system in which parties engage in transactions according to supply and demand *Market economy *Marketplace, a physical marketplace or public market *Marketing, the act of sat ...

it worldwide except in Japan,

Korea Korea is a peninsular region in East Asia consisting of the Korean Peninsula, Jeju Island, and smaller islands. Since the end of World War II in 1945, it has been politically Division of Korea, divided at or near the 38th parallel north, 3 ...

China China, officially the People's Republic of China (PRC), is a country in East Asia. With population of China, a population exceeding 1.4 billion, it is the list of countries by population (United Nations), second-most populous country after ...

, and

Taiwan Taiwan, officially the Republic of China (ROC), is a country in East Asia. The main geography of Taiwan, island of Taiwan, also known as ''Formosa'', lies between the East China Sea, East and South China Seas in the northwestern Pacific Ocea ...

. In February 2014, the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

approved droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension.

Clinical trials

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

and

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

conducted on

clinical trials Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

comparing the clinical use of droxidopa and

midodrine Midodrine, sold under the brand names ProAmatine and Orvaten among others, is an antihypotensive medication used to treat orthostatic hypotension (low blood pressure when standing) and urinary incontinence. It is taken oral administration, by m ...

have found that midodrine was more likely to cause supine hypertension than droxidopa in patients with NOH. Midodrine was also found to be slightly more effective at raising blood pressure but not statistically significantly. Chelsea Therapeutics obtained

orphan drug status An orphan drug is a pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by the condition ...

(ODS) for droxidopa in the US for NOH, and that of which associated with PD, PAF, and MSA. In 2014, Chelsea Therapeutics was acquired by Lundbeck along with the rights to droxidopa which was launched in the US in Sept 2014.

Society and culture

Names

''Droxidopa'' is the generic name of the drug and its and . Brand names of droxidopa include ''Dops'' and ''Northera''.

Research

Droxidopa alone and in combination with

has been studied in the treatment of

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD). Droxidopa was under development for the treatment of ADHD,

chronic fatigue syndrome Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling Chronic condition, chronic illness. People with ME/CFS experience profound fatigue that does not go away with rest, as well as sleep issues and problems with memory ...

, and

fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...

, but development for these indications was discontinued.

References

External links

* {{Portal bar , Medicine Alpha-adrenergic agonists Alpha-Amino acids Antihypotensive agents Beta-adrenergic agonists Cardiac stimulants Catecholamines Monoamine precursors Phenylethanolamines Prodrugs Sympathomimetics Vasoconstrictors