D rug Eva lua tio n

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Autonomic & Neurovascular Medicine Unit, Division of Brain Sciences, Medicine, Imperial College London at St Mary’s Hospital, Praed Street, London, W2 1NY, UK 2 Autonomic Unit, National Hospital for Neurology & Neurosurgery, Queen Square, Division of Clinical Neurology, Institute of Neurology, University College London, London, UK 3 Department of Neurology, Chiba University School of Medicine, Chiba, Japan 4 Division of Physical Medicine & Rehabilitation, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Veruno, Veruno (NO), Italy *Author for correspondence: Tel.: +44 203 312 2106 n Fax: +44 203 312 1540 n [email protected] 1

Drug Evaluation

Ekawat Vichayanrat1,2, David A Low1,2, Masato Asahina3, Andrew P Owens1,2, Valeria Iodice1,2, Gianluigi Galizia4 & Christopher J Mathias*1,2

Future Neurology

L‑DOPS and the treatment of neurogenic orthostatic hypotension

l‑threo-dihydroxyphenylserine

(L-DOPS) is an oral prodrug that is converted to the sympathetic neurotransmitter noradrenaline through a single-step decarboxylation by the endogenous enzyme 3,4-dihydrophenylalanine decarboxylase. DOPS can provide an exogenous source of noradrenaline to adrenergic neurons that are involved in the maintenance of blood pressure. Impaired secretion of noradrenaline at the synaptic junction can result in neurogenic orthostatic hypotension and cause faints and falls. The safety and efficacy of DOPS has been evaluated in patients with neurogenic orthostatic hypotension caused by a variety of neurological conditions that can result in autonomic failure, such as Parkinson’s disease, multiple system atrophy, pure autonomic failure and dopamine-bhydroxylase deficiency. In this review, we include Phase II and III clinical trials undertaken that have examined the safety, efficacy and tolerability of DOPS in the treatment of neurogenic orthostatic hypotension. Drug mechanisms and pharmacology of the drug are also discussed.

The control of blood pressure, particularly upon assumption of the upright posture, is crucial in ensuring adequate perfusion of organs, especially those above the heart, such as the brain. Nor‑ mal physiologic feedback mechanisms work via the autonomic nervous system, through sympa‑ thetic and parasympathetic nerve pathways, and maintain blood pressure in a variety of situations. Failure or dysfunction of the autonomic nervous system can cause neurogenic orthostatic (or pos‑ tural) hypotension (NOH). NOH is defined as a decrease of systolic blood pressure of ≥20 mmHg or ≥10 mmHg diastolic blood pressure on either standing or head‑up tilt to at least 60° within 3 min [1]. A drop of systolic blood pressure of ≥30 mmHg has recently been suggested in patients with recumbent hypertension [2]. NOH may also be delayed and occur after 3 min, as described in Parkinson’s disease (PD) [3]. Incidence & prevalence of NOH

NOH can result from a range of pathophysi‑ ological processes, including, reduced intra‑ vascular volume (e.g., hemorrhage or dehydra‑ tion), cardiac abnormalities (e.g., arrhythmias or heart failure) or neurodegenerative and con‑ genital neurological disorders, such as patients with primary (e.g., multiple system atrophy 10.2217/FNL.13.28 © 2013 Future Medicine Ltd

[MSA], PD, pure autonomic failure [PAF] and dopamine-b-hydroxylase [DBH] deficiency) or secondary (e.g., diabetic neuropathy, amyloid neuropathy and spinal cord injury) autonomic failure. NOH is a diagnostic feature of MSA and PAF [4,5]. The prevalence of MSA is estimated to be one to nine in 100,000 [6,7]. The prevalence of PAF is unknown but it is relatively uncommon. A total of 30% of home-dwelling individuals of 70 years and over meet the criteria for NOH [8], which is of particular relevance to aging popula‑ tions, with NOH increasing with age [9]. Esti‑ mates for the prevalence of PD in the UK range from 105 to 178 persons per 100,000 of the population when adjusted for age [10,11]. The prev‑ alence of NOH in PD varies widely, reflecting the range of patient groups studied and protocols adopted. A recent meta-analysis has estimated that 30% of PD patients have NOH [12]. DBH deficiency is an extremely rare disorder that was first described in 1986. In 2004, only 12 patients were known to have the syndrome worldwide [13]. The prevalence of diabetic neuropathy is a func‑ tion of disease duration and approximately 50% of patients with diabetes will eventually develop neuropathy [14]. Familial amyloid polyneuro pathy or transthyretin amyloid polyneuropathy is generally considered to be a rare disease and Future Neurol. (2013) 8(4), 381–397

Keywords n autonomic failure n blood pressure n L‑DOPS n neurogenic orthostatic hypotension n noradrenaline n orthostatic intolerance

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ISSN 1479-6708

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Drug Evaluation

Vichayanrat, Low, Asahina et al.

the worldwide prevalence is unknown, but it is endemic in regions of Portugal, Sweden, Japan and Cyprus where the prevalence was estimated to be four in 100,000 [15]. Symptoms related to NOH are mainly due to reduction of blood flow to various organs, espe‑ cially the brain. Cerebral hypoperfusion can result in posturally induced dizziness, visual dis‑ turbances (e.g., blurring, color change, gray-out), transient cognitive impairment, and loss of con‑ sciousness (syncope). Hypoperfusion of muscles, may result in headache, neck pain (‘coat hanger’ ache) and lower back pain [16]. NOH may also cause fatigue, chest pain and dyspnea. It may also be aggravated by additional factors causing vaso‑ dilatation such as food ingestion, exercise, heat or drugs with hypotensive properties. Similarly, these stimuli alone can also cause hypotension in autonomic failure (e.g., postprandial hypoten‑ sion). NOH can be a severely disabling condi‑ tion that can have a profound negative impact on the ability to conduct activities of daily living that involve standing or walking, including the basic activities of personal hygiene and grooming, dressing/undressing and functional transferring. Patients with NOH who lose consciousness and fall are also at a greatly increased risk of hip frac‑ tures and head trauma [17]. Fear of NOH episodes can cause patients to limit their activities, which can cause a host of complications ranging from a reduction in muscle mass and physical capacity to depression and loss of independence [18]. Long itudinal studies have also shown that chronic NOH increases the risk of mortality [19], stroke [20], myocardial ischemia [21] and heart failure [22]. Pharmacological & nonpharmacological treatments of NOH

In individuals with NOH the compensatory mechanisms within the sympathetic nervous sys‑ tem that regulate blood pressure upon standing in autonomic failure are no longer adequately intact to provide organ perfusion [9,23]. Auto‑ nomic failure syndromes share a common pathophysiology – an inadequate noradrenaline response from sympathetic vasomotor neurons – resulting in autonomic failure and general‑ ized blood pressure dysregulation. Currently available therapeutic options for NOH typi‑ cally involve nonpharmacological and pharma‑ cological interventions. Most strategies provide some symptomatic relief in patients, but certain treatments can be relatively ineffective and are often accompanied by severe side effects that limit their usefulness. Support garments (tightfitting stockings/leggings) may prove useful in 382

Future Neurol. (2013) 8(4)

some subjects, but are difficult without family or nursing assistance, especially for older sub‑ jects. Increasing salt and water intake are options but can be complicated by background blood pressure and urological symptoms, respectively. Many patients with NOH eventually require pharmacological interventions, the mainstays of which are volume expansion and vasocon‑ striction. The former includes fludrocortisone acetate, desmopressin and erythropoietin, and the latter includes ephedrine and midodrine. Other agents include acetylcholinesterase inhibitors (e.g., pyridostigmine) or somato statin analogs (e.g., octreotide). Fludrocorti‑ sone is typically used as a starter drug but can have various unwanted side effects, including sodium retention, hypertension, edema, hypoka‑ lemia and hypomagnesia [24]. Only midodrine is specifically approved for NOH and it increases standing blood pressure [25,26]. It is a synthetic sympathomimetic amine, which is a periph‑ eral, selective, direct a1 adrenoreceptor agonist [27]. However, there are several adverse effects of midodrine and 60% (15 out of 25) of NOH patients in a previous study reported an adverse reaction to one or more doses of midodrine [26]. The main adverse effects are those of pilomotor reactions, categorized as piloerection, tingling or paresthesiae of the scalp or other region, or pru‑ ritus, urinary retention and supine hypertension [25]. Supine hypertension, systolic blood pressure >200 mmHg, has been reported in up to 41% of NOH patients receiving 20 mg midodrine three times a day (t.i.d.) [26]. In 2010, the US FDA reversed a decision to remove midodrine from the market (based on the manufacturer, Shire PLC, failing to complete required post-approval studies) and has allowed it to remain available to patients while further data regarding the efficacy and safety of the drug is collected. The limitations of these currently available therapeu‑ tic options and the incapacitating nature and often progressive course of disease, point to the need for an improved therapeutic alternative. Naturally, noradrenaline is the most effective pressor drug, but it cannot be administrated orally. Alternatively, an oral precursor drug of noradrenaline, such as dihydroxyphenylserine (DOPS), a centrally and peripherally acting nor‑ adrenergic drug, has great potential efficacy for the treatment of NOH. The aim of this review is to discuss the drug mechanisms and pharma cology of DOPS and examine Phase I, II and III clinical trials undertaken that have examined the safety, efficacy and tolerability of DOPS in the treatment of NOH. future science group

L‑DOPS & the treatment of neurogenic orthostatic hypotension

Overview of the market

DOPS was first described in 1919 by Rosen‑ mund and Dornsaft, who suggested that it might be a precursor of adrenaline [28]. Blaschko et al. found that DOPS is converted to noradrenaline by the decarboxylase of Streptococcus faecalis R in vitro [29], and that noradrenaline is formed from DOPS in various mammalian tissues [30,31]. It was also established that the DOPS compound can be classified into four optical isomers; l‑threo-DOPS (or L‑DOPS), d‑threo-DOPS, l‑erythro-DOPS, and d‑erythro-DOPS (see ‘Chemistry’ section). The Japanese pharmaceutical company Sumitomo Pharmaceutical Co., Ltd. (current name Dainippon Sumitomo Pharma, Co., Ltd, Osaka, Japan) succeeded in isolating and puri‑ fying L‑DOPS for the replacement therapy of noradrenaline in 1977. Araki et al. reported that L‑DOPS had pressor effects in rats in 1981 [32]. In humans, the first efficacy studies of L‑DOPS for NOH was reported in PD [33], MSA [34] and familial amyloid neuropathy [35,36]. L‑DOPS was then discovered to be spectacularly effective in the treatment of NOH in patients with DBH deficiency [37,38]. L‑DOPS was approved as an agent for NOH in patients with MSA and famil‑ ial amyloid neuropathy by the Japanese govern‑ ment in 1989 and also approved as a treatment for akinesia and freezing in PD in Japan in 1989. The use of L‑DOPS for NOH associated with hemodialysis was also approved by the Japanese Government in 2001. In Europe and the USA, Chelsea Therapeutics, Inc. (NC, USA) acquired the development and commercialization rights to L‑DOPS from Dainippon Sumitomo Pharma Co., Ltd. in 2006, in all territories except some Asian countries. In January 2007, the FDA granted orphan drug status for L‑DOPS for the treatment of NOH in patients with primary autonomic failure (PD, MSA and PAF), DBH deficiency or nondiabetic autonomic neuropathy. In August 2007, the drug was granted orphan medicinal product designation by the EMA for the treatment of NOH in patients with PAF and MSA. In September 2011, Chelsea Therapeutics, Inc. submitted a new drug application to the FDA seeking approval to market L‑DOPS in the USA for the treatment of NOH, based on the results of Phase III trials. Altered noradrenaline activity has also been implicated in akinesia and freezing in parkin‑ sonian syndromes [39], the modulation of pain in the CNS [40] and in arousal, attention, and stress response via the locus coeruleus–noradren‑ aline system [41]. Clinical trials of parkinsonian future science group

Drug Evaluation

patients have reported favorable effects of L‑DOPS on akinesia [39], dose-dependent anal‑ gesia in patients with chronic pain [42] and poten‑ tial benefits for dementia [43,44] and depression [45]. Therefore, L‑DOPS may possess potential benefits for several neurological or psychiatric disorders associated with noradrenaline defi‑ ciency, as well as NOH. However, it is beyond the scope of this article to adequately review the use of L‑DOPS in motor dysfunction treatment in PD, or neurological or psychiatric disorders. Chemistry Introduction to the compound

The chemical name of DOPS is (2S,3R)-2-amino3-hydroxy-3-(3,4-dihydroxyphenyl) propionic acid and the chemical formula is C9H11NO5 (Figure 1). DOPS has a structure which is similar to noradrenaline but with a carboxyl group. It is a water soluble compound with a molecular weight of 213.19. It can be administered orally, and is converted to noradrenaline, which acts on peripheral postsynaptic a- and b‑adrenergic receptors, through a single step of decarboxyl‑ ation by the endogenous enzyme 3,4-dihdroxy‑ phenylalanine (DOPA) decarboxylase in the presence of pyridoxal phosphate. L‑DOPS is lipophilic and has the ability to enter the CNS [46]. The DOPS compound is optically active and can be classified into four optical isomers; L‑DOPS, l‑threo-DOPS, d‑erythro-DOPS and d‑erythro-DOPS. The racemic mixture contains both the d‑ and l‑isoforms of DOPS, but only the l‑isoform is decarboxylated to biologically active l‑noradrenaline due to the stereospecific‑ ity of DOPA decarboxylase. In addition, it has been suggested that d‑threo-DOPS could inhibit decarboxylation of L‑DOPS [47]. Furthermore, in studies of dl-threo-3,4-dihydroxyphenylserine (DL‑DOPS) only approximately 2.2% (range: 0.65–3.8%) of the dose is converted to noradren‑ aline over 24 h [48] and it has been suggested that the effects on plasma noradrenaline and blood pressure of oral L‑DOPS were essentially equal to those of twice as large a dose of DL‑DOPS [49]. Given these findings, L‑DOPS has predomi‑ nantly been used in the treatment of NOH and as such this review will predominantly focus on the L‑DOPS isoform of DOPS, but findings from clinical trials of DL‑DOPS are included for completeness (see ‘Clinical efficiency’ section). Pharmacodynamics

The major metabolites (and the key enzymes responsible for their production) of L‑DOPS are noradrenaline (converted by DOPA www.futuremedicine.com

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NH2 Tyrosine

COOH

OH

OH

Tyrosine hydroxylase NH2

HO

DOPA COOH HO

DOPA decarboxylase

NH2

HO

COOH HO

DL–DOPS NH2

HO

Dopamine HO

Dopamine-β-hydroxylase

Noradrenaline

OH NH2

HO

HO Phenylethanolamine N-methyltransferase

OH

HO

NH

Adrenaline

HO

Figure 1. The chemical structures and pathways of the catecholamines and dihydroxyphenylserine. Biosynthetic pathway of the formation of noradrenaline and adrenaline. DL-DOPS is converted directly to noradrenaline by DOPA decarboxylase (dashed arrow), thus bypassing dopamine-b-hydroxylase. DL-DOPS: dl-threo-3,4-dihydroxyphenylserine; DOPA: 3,4-dihdroxyphenylalanine. Adapted with permission from [80] .

decarboxylase); (-)-(2S,3R)-2-amino-3-hydroxy3-(4-hydroxy-3-methoxyphenyl) propionic acid (3-OM-DOPS; converted by catechol‑Omethyltransferase [COMT]); and glycine and protocatechualdehyde (3,4-dihydroxybenz‑ aldehyde; converted by DOPS aldolase; see igure 2) [50–52]. These primary metabolites are F further metabolized. 3-OM-DOPS is converted to vanillic acid. Noradrenaline is converted to 3-methoxy-4-hydroxy-phenylglycol (HMPG) by COMT and monoamine oxidase, which may then be converted to the tertiary metabolite dihy‑ droxyphenylglycol (DHPG) by aldehyde/aldose reductase. l‑aromatic amino acid decarboxylase, the enzyme responsible for the decarboxylation of L‑DOPS to noradrenaline, is a neutral amino acid and is extensively expressed in neural and non-neural tissues (e.g., stomach, liver 384


and kidney) [53]. Similar noradrenaline and DHPG responses to L‑DOPS in PAF (post‑ ganglionic lesion) and MSA (preganglionic lesion) patients, as well as a lack of an effect of entacapone (COMT inhibitor) on the pressor response to L‑DOPS, suggests that production of noradrenaline from L‑DOPS occurs mainly in non-neuronal cells [54,55]. The conversion of L‑DOPS to noradrenaline in humans correlates with the relief of NOH and its symptoms via the increased binding of noradrenaline to adrenore‑ ceptors and subsequent elevation in sympathetic nerve activity resulting in vasoconstriction and increased vascular resistance and blood pressure. In addition, it has also been shown that in small Phase I and II studies of MSA patients, L‑DOPS reduced the fall of both diastolic blood pressure and cerebral blood flow while sitting [56], and the reduction in the decline of systolic blood future science group


pressure during 60° head‑up tilt with L‑DOPS was accompanied by significantly increased plasma renin and angiotensin II activity [57].

Drug Evaluation

with NOH. L‑DOPS remains detectable for at least 22 h in the plasma [54,58]. In middle-aged healthy individuals a bioavailability of 80% was reported (20% of L‑DOPS was recovered unchanged in the urine within 12 h) [49]. The mean volume of distribution of L‑DOPS is approximately 88 ± 13 l in MSA and 33 ± 5 l in PAF patients with a clearance of 374 ± 58 ml/min and 165 ± 21 ml/min, respectively [54]. Greater neuronal uptake of L‑DOPS in MSA compared with PAF could explain these differences [54]. Noradrenaline Cmax values of 1.3 µg/ml [58] and 7 nmol/l [54] have been reported in autonomic fail‑ ure. These peaks occur approximately 3–6 h after L‑DOPS dosage [49,54,58]. Since l‑aromatic amino acid decarboxylase, which catalyzes the conver‑ sion of L‑DOPS to noradrenaline, is an intracel‑ lular enzyme, the approximately simultaneous attainment of peak plasma levels of L‑DOPS and of noradrenaline indicate rapid intracellu‑ lar conversion of L‑DOPS to noradrenaline and

Pharmacokinetics & metabolism

Very few pharmokinetic studies of L‑DOPS and resultant noradrenaline activity have been con‑ ducted; most of those which have are in auto‑ nomic failure patients. Mean peak plasma con‑ centrations (Cmax) of L‑DOPS have been reported to be in the 1.1–1.9 µg/ml range in healthy control and autonomic failure patients [49,54,58]. These peak concentrations occur approximately 3 h (Tmax) after dosage [49,54,58], while higher Tmax (~6 h) were evident for familial amyloid poly‑ neuropathy and dialysis patients [49,59]. There‑ after, the plasma L‑DOPS content undergoes a mono-exponential decline with a plasma halflife of 2–3 h [54]. Based on its pharmacokinetic properties (e.g., a Tmax of ~3 h), DOPS is gener‑ ally administered three times daily in patients

Protocatechualdehyde

Glycine

NH2

HO O

DOPS aldolase

+

COOH

HO

3-OM-DOPS

OH

H3CO

NH2 COOH

HO

DOPS

COMT

HO

NH2 COOH

HO

DHPG NE

OH

OH

HO

OH

MAO –

HO

NH2

LAAD

HO

OH

AR

HO

Carbidopa DOPA HO

NH2 COOH

HO

–

DA HO

NH2

LAAD HO

Figure 2. Overview of the metabolic fate of l‑threo-3,4-dihydroxyphenylserine, compared with that of l‑3,4-dihdroxyphenylalanine. 3-OM-DOPS: (-)-(2S,3R)-2-amino-3-hydroxy-3-(4-hydroxy-3-methoxyphenyl) propionic acid; AR: Aldehyde/aldose reductase; COMT: Catechol‑O-methyltransferase; DA: Dopamine; DHPG: Dihydroxyphenylglycol; DOPA: 3,4-dihdroxyphenylalanine; DOPS: Dihydroxyphenylserine; LAAD: l‑aromatic-amino-acid decarboxylase; MAO: Monoamine oxidase; NE: Noradrenaline. Reproduced with permission from [81] .

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rapid exit of the noradrenaline from cells into the extracellular fluid [54]. Noradrenaline levels decline multi-exponentially with an initial halftime of 8.8 h [54]. Plasma levels of noradrenaline remain significantly elevated for at least 46 h post L‑DOPS dosage [54,58]. The slow decline in plasma noradrenaline probably reflects ongoing production of noradrenaline from L‑DOPS and ongoing entry of the produced noradrenaline into the bloodstream [54]. Clinical efficacy Phase I & II studies

A variety of smaller acute studies of DOPS administration in various patients with NOH and/or NOH symptoms have been conducted (Table 1). In an acute study of 600–800 mg DLDOPS there was no effect on upright blood pressure in six patients with severe NOH, two of whom had NOH due to PAF [48]. In a random‑ ized, double-blind, placebo-controlled crossover acute trial of 1000 mg DL-DOPS in ten patients with severe symptomatic NOH (six MSA and four PAF patients) systolic blood pressure and diastolic blood pressure increased in the supine and upright positions and the blood pressure fell in response to head‑up tilt decreased [60]. The study authors also noted that an increase in nor‑ adrenaline with DL‑DOPS occurred and there was a trend toward improvement in symptoms of NOH [60]. Using the same design and dose of DL‑DOPS the postprandial fall in blood pressure was attenuated in 11 patients with autonomic failure (six MSA and five PAF patients) which was associated with an increase in plasma nor‑ adrenaline and forearm vascular resistance [61]. In 20 patients with idiopathic PD who had symp‑ toms of dizziness and NOH, oral and intravenous administration of DL‑DOPS (570 ± 34.1 mg) significantly improved orthostatic symptoms in 15 out of 20 patients [33]. In an acute study of familial amyloid polyneu‑ ropathy patients, L‑DOPS (100 mg) produced a pressor (28 ± 6 mmHg systolic blood pres‑ sure increase) response [36]. In a chronic study of familial amyloid polyneuropathy patients, who, because of severe NOH, were bedridden or constrained to a sitting life, L‑DOPS, 100 mg two times a day (b.i.d.) for 6 months caused a marked improvement in orthostatic tolerance as reflected by their ability to walk freely around after 3–5 days, which was sustained through‑ out treatment. The fall in mean blood pres‑ sure in response to head‑up tilt diminished by 13 mmHg (range: 7–17 mmHg) and head‑up tilt time became longer than 600 s in all patients 386


[62].

Similar beneficial effects of L‑DOPS on NOH in patients with familial amyloid poly‑ neuropathy were also obtained with intrana‑ sal administration of L‑DOPS for 1 week [63]. These findings in familial amyloid polyneurop‑ athy were accompanied by increases in plasma, serum and urinary excretion of noradrenaline [36,63]. In 34 hemodialyzed patients exhibiting dialysis-induced hypotension, 200–400-mg L‑DOPS 1 h before dialysis prevented dialysisinduced hypotension and decreased the number of concurrent treatments required for hypo tension. The signs and symptoms of hypoten‑ sion were improved in 74% of the patients and persisted after dialysis in 65%. The preventive effect of L‑DOPS was significantly more promi‑ nent in patients with a predialysis systolic blood pressure less than 100 mmHg and in patients with nondiabetic neuropathy [59]. In a recent escalating dose (100, 200 and 400 mg) study of L‑DOPS in nine hypotensive subjects with spinal cord injury (C3 to T10), seated blood pressure was significantly increased 4 h after dose-dependent administration of L‑DOPS (100 mg: 94 ± 15/61 ± 8 mmHg; 200 mg: 98 ± 14/62 ± 8 mmHg; 400 mg: 108 ± 12/68 ± 9 mmHg) and did not increase supine blood pressure [64]. In longer term Phase II studies, titration procedures were typically incorporated to obtain the optimum doses of L‑DOPS that were typically in the range 200–2000 mg, usually based on clinical need until orthostatic blood pressure and symptoms improved. In an early study, L‑DOPS significantly increased upright blood pressure in patients with MSA but had no significant effect on upright blood pressure of PAF patients [65]. In an international open label dose-ranging study (6 weeks) of 32 patients (26 MSA and six PAF patients) L‑DOPS reduced the fall (by 22 ± 28 mmHg; decrease of 54 ± 28 mmHg at baseline) in systolic blood pressure during orthostatic challenge compared to pretreatment values [66]. By the end of the study, 25 patients (78%) were considered clinically improved, and 14 patients (44%) no longer met criteria for NOH. An attenuated systolic blood pressure drop occurred in 22% (7 out of 32), 24% (6 out of 25), and 61% (11 out of 18) of patients treated with 100, 200 and 300 mg L‑DOPS b.i.d., respectively. The reduction in orthostatic blood pressure decrease was comparable between PAF and MSA patients and there were significant improvements in symptoms associated with NOH including lightheadedness, dizziness and blurred vision [66]. In a future science group


3-day, double-blind, placebo-controlled, singledose crossover trial of 19 patients (11 MSA and eight PAF) administered with a higher dose of L‑DOPS (average of 1137 mg), standing blood pressure was significantly increased (from 60 ± 6 to 100 ± 6 mmHg) for several hours and orthostatic tolerance was improved in all patients. Blood pressure increases were also closely associated with increases in plasma noradrenaline levels [58]. Carbidopa is a DOPA decarboxylase inhibi‑ tor outside the blood–brain barrier, which is often used with L‑DOPA in the treatment of movement disorders, especially PD. Given its antagonistic effects on DOPA decarboxylase it could therefore inhibit the effects of L‑DOPS in such patient groups. In a follow-up trial to the above study, six patients received L‑DOPS alone on day 1, followed by 200 mg of carbi‑ dopa alone on day 2 and 200 mg of carbidopa combined with L‑DOPS on day 3. Carbidopa blunted both the increase in plasma noradrena‑ line and the pressor response to L‑DOPS in all patients. Similar results with the same dose of carbidopa, but not during entacapone (COMT inhibitor) coadministration, have also been reported in autonomic failure (seven PAF, three PD and two MSA patients) [55]. It is impor‑ tant to note that the doses of carbidopa used in these studies were substantially higher than the doses typically used in clinical preparations when combined with L‑DOPA; these usually being 25 mg for 100 mg of L‑DOPA. Although there are no studies specifically looking at the efficacy of L‑DOPS in combination with lower doses of carbidopa, as used in clinical prepara‑ tions, a few studies have still reported a beneficial pressor effect of L‑DOPS despite the presence of relatively low doses of DOPA decarboxylase inhibitors, which may reflect incomplete inhi‑ bition of DOPA decarboxylase with the clini‑ cal preparations used to treat motor deficits of Parkinsonism [66–68]. In a follow-up study to that of Mathias et al. [66], a European multicenter trial was conducted in order to ascertain the minimum effective dose of DOPS that safely reduced the orthostatic fall in systolic blood pressure in comparison with placebo [68]. A total of 55 patients with MSA and 66 with PD were randomized and received doses of 100, 200 or 300 mg of L‑DOPS or matching placebo t.i.d. for 28 days. In the previous study the same patient received escalating doses with individual comparisons, whereas in this study different individuals were on different L‑DOPS doses. L‑DOPS treatment resulted in a reduction future science group

Drug Evaluation

in NOH in each of the DOPS dose, unlike with placebo. There was no clear dose-response improvement, but the 300 mg dose was most effective in reducing NOH. The drug remained efficacious over the 28 days of treatment. There was an overall trend towards improvement in symptoms but this did not reach statistical sig‑ nificance. This dissociation may reflect the dif‑ ferent individual characteristics of each group, or insensitivity of the symptom scales used [67,68]. In a 4‑week study of an average maintenance dose of 460 mg/day of L‑DOPS decreases in blood pressure with postural change and symptoms of orthostatic intolerance were all significantly improved in 15 PD patients [69]. Summary of results from Phase I & II studies

The results from several small Phase I and II studies illustrate the beneficial effect of DOPS in different groups of patients with NOH, including PAF, MSA, idiopathic PD, familial amyloid polyneuropathy and dialysis-induced hypotension. These beneficial effects consisted of an improvement in blood pressure and plasma noradrenaline during orthostasis, as well as orthostatic symptoms in acute studies. The find‑ ings were also consistent with 90%) occurred in a smaller group of patients who fell more frequently. The repeat fallers group (n = 22) showed greater benefit from L‑DOPS therapy than the nonrepeat fallers group (n = 29) by a number of clinical measures, including dizziness (the difference favoring L‑DOPS over placebo was 2.1 units among repeat fallers, compared with 0.1 among nonrepeat fallers), Hoehn and Yahr scores (improvement in scores between L‑DOPS and placebo was greater for repeat vs non-repeat fallers; 0.6 vs 0.2) and UPDRS scores (repeat fallers experienced an improvement of 17.7 units while on L‑DOPS compared to placebo) [78]. Summary of results from Phase III studies

L‑DOPS efficacy in patients with NOH was revealed in Phase III randomized double-blind placebo-controlled studies. Orthostatic blood www.futuremedicine.com

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pressure changes during standing and OHQ scores were improved after L‑DOPS and more importantly these effects remained during longterm follow-up studies (at 3 and 12 months of treatment). In addition, the latest results from study 306 also showed that L‑DOPS seems to help motor, in addition to orthostatic, symptoms in PD patients with NOH who have a history of multiple falls. Safety & tolerability

L‑DOPS has a good safety profile and is mostly well tolerated. In 2473 Japanese patients with PD, MSA and familial amyloidotic polyneuropathy (621 patients in Phase III studies and 1852 patients in the postmarketing surveillance studies), side effects reported were nausea (1.5%), blood pressure elevation (1.3%), headache (1.2%), hallucination (1.1%), appetite loss (0.8%), dizziness (0.8%), upper gastric symptoms (0.6%) and palpitations (0.6%). Concerns have mostly revolved around the effect of the drug on resting supine (e.g., nonorthostatic blood pressure as well as other effects of increased sympathetic nerve activity). In the smaller Phase I and II studies, the side effects noted have been transient restlessness and malaise 6–7 h after receiving an 800-mg dose of DL-DOPS in two of six subjects [48], severe headache in one PAF patient, which was resolved following discontinuation of L‑DOPS [65]. Other Phase I/ II studies have reported no major side effects with 1000 mg of DL-DOPS [56,57,60]. In a larger Phase II study (Table 3), two serious adverse events were reported (laryngeal dyspnea and syncope at doses of L‑DOPS 100 mg b.i.d. and 300 mg b.i.d., respectively) but were considered possible complications of the disease under study, whereas four patients discontinued treatment due to an adverse event, reported as dystonia, laryngeal dyspnea, lymphocytopenia (mild intensity) and palpitations [66]. In this same study, there were no reports of supine hypertension [66]. Similar findings were evident in familial amyloidotic polyneuropathy [62]. By contrast, there was a trend toward supine hypertension in two other studies associated with DL‑DOPS [61] and L‑DOPS treatment (from 101 ± 4 to 141 ± 5 mmHg) [58]. In a larger Phase II study, L‑DOPS was well tolerated, with similar adverse effects in the treatment groups when compared with placebo. Most of the symptoms were mild and one patient had supine hypertension [67,68]. In the recent Phase III studies (Ta bl e 3), supine hypertension, (systolic blood pres‑ sure >180 mmHg) occurred in four (5%) 392


L‑DOPS-treated versus two (3%) placebotreated patients [72] and in the post hoc analy‑ ses of midodrine versus L‑DOPS, the patients treated with L‑DOPS experienced a lower incidence of supine hypertension (systolic blood pressure >200 mmHg) at the end of the study compared with while on midodrine (3.3 vs 8.5%, respectively) [76]. In the 301 and 302 studies the most frequent adverse events in L‑DOPS-treated versus placebo-treated patients were headache (11 vs 0%), dizziness (8 vs 1%), nausea (5 vs 0%), and fatigue (4 vs 3%), respectively [72] and in study 303 the most frequent drug-related adverse events were head‑ ache (7.8%), somnolence (4.9%) and muscle spasms (2.9%) [77]. In study 304, which was a long-term extension (189 days) safety study of L‑DOPS (mean dose was 416 mg t.i.d.) in 213 primary autonomic failure patients (PD: 48.4%; PAF: 31.0%; MSA: 14.6%) the most frequent adverse events were headache (12.2%), falls (8.5%), urinary tract infections (7.5%) and dizziness (7%). The incidence of these individ‑ ual adverse events did not correlate with dose. The incidence of elevated blood pressure was low (hypertension: 2.8%; hypertensive crisis: 1.4%; blood pressure increase: 1.4%), and 3.8% had adverse cardiac events (atrial fibril‑ lation and flutter). Of all adverse events, 1.4% were classified as ‘definitely related’ to the study drug [79]. The authors concluded that L‑DOPS was safe and well‑tolerated in this interim analy‑ sis of a long-term, open-label Phase III safety study in patients with symptomatic NOH. Conclusion

NOH causes syncope and falls, and can be a disabling condition that seriously impairs the quality of life of afflicted individuals. Moreover, NOH can be difficult to manage and may be aggravated by additional factors causing vaso‑ dilatation, such as food ingestion, exercise, heat or drugs with hypotensive properties. NOH can result from reduced intravascular volume, cardiac abnormalities or neurodegenerative and congeni‑ tal neurological disorders, such as patients with primary or secondary autonomic failure. NOH is believed to result from an inadequate supply of noradrenaline at the synaptic junction. Currently available therapeutic options for NOH typically involve nonpharmacological and pharmacologi‑ cal interventions that promote volume expansion and vasoconstriction, such as fludrocortisone acetate and midodrine, respectively. Certain nonpharmacological treatments can be relatively ineffective and fludrocortisone and midodrine future science group


Drug Evaluation

Table 3. Summary of safety data from Phase II and III l‑threo-dihydroxyphenylserine and autonomic failure studies. Study Patients reporting Side effect or AE (year), side effects or AEs study (n) reference

Serious AEs

Patients Reasons for withdrawn patient from withdrawal study (n)

Matsubara 0 et al. (1990)

N/A

0

0

N/A

[56]

Freeman et al. (1996)

8

Supine hypertension (SBP) in five 0 patients on DL‑DOPS and three patients on placebo

0

N/A

[61]

Freeman et al. (1999)

9

Supine hypertension (SBP) in six patients 0 on DL‑DOPS and three patients on placebo

0

N/A

[60]

Mathias et al. (2001)

17 (total of 67 AEs) 24 AEs from 13 of 33 patients who received 100 mg b.i.d. 18 AEs from eight of 25 patients who received 200 mg b.i.d. 25 AEs from nine of 17 patients who received 300 mg b.i.d.

Increased lactate dehydrogenase (mild intensity; 12.1%) Urinary tract infection (12.1%) Akinesia (9.1%) Headache (9.1%) Stomach upset (9.1%)

1 × dystonia 1 × laryngeal dyspnea 1 × lymphocytopenia (mild intensity) 1 × palpitations

[66]

[58]

1 × laryngeal 4 dyspnea (100 mg b.i.d.) 1 × syncope (300 mg b.i.d.) Both could be attributed to the disease itself rather than to the drug

Ref.

Kaufmann 2 et al. (2003)

Supine hypertension after L‑DOPS 0 (45%) vs placebo (23%) 1 × hyponatremia (reversed after saline infusion) 1 × angina pain with electrocardiographic ST-segment depression

0

N/A

Kaufmann NR et al. (2012), 301 and 302

DOPS vs placebo: NR Supine hypertension (SBP >180 mmHg); 5 vs 3% Headache 11 vs 0% Dizziness 8 vs 1% Nausea 5 vs 0% Fatigue 4 vs 3%

NR

NR

[71,72]

Isaacson et al. (2012), 303

NR

DOPS-related side effects: Headache (7.8%) Somnolence (4.9%) Muscle spasms (2.9%)

NR

NR

NR

[77]

Shill et al. (2012), 304

NR

DOPS-related side effects: Headache (12.2%) Falls (8.5%) Urinary tract infections (7.5%) Dizziness (7.0%) Elevated blood pressure (hypertension, 2.8%; hypertensive crisis, 1.4%; blood pressure increase, 1.4%) Cardiac (3.8%; atrial fibrillation and flutter most common) Incidence of AEs did not appear to correlate with increasing dose 1.4% of all AEs were classified as definitely related to DOPS

NR

NR

NR

[79]

AE: Adverse event; b.i.d.: Two times a day; DL-DOPS: dl-threo-3,4-dihydroxyphenylserine; DOPS: Dihydroxyphenylserine; N/A: Not applicable; NR: Not reported or unclear in source material; SBP: Systolic blood pressure.



393

Drug Evaluation


are often accompanied by severe side effects that limit their usefulness, including sodium reten‑ tion, edema, hypokalemia and hypomagnesia with fludrocortisone, pilomotor reactions, uri‑ nary retention and supine hypertension. L‑DOPS is an oral prodrug that is converted to the sympa‑ thetic neurotransmitter, noradrenaline through a single step decarboxylation by the endogenous enzyme DOPA decarboxylase. L‑DOPS can provide an exogenous source of noradrenaline to adrenergic neurons that are involved in the sympathetic maintenance of blood pressure. It has been demonstrated in randomized, controlled, double-blind studies that L‑DOPS can reduce NOH severity and symptoms, as well as reduce the number of falls in autonomic failure patients within 4 h of administration and over 12‑month treat‑ ment regimes. Adverse events have included headache, supine hypertension, dizziness, nausea, urinary tract infections and fatigue. Other adverse events are generally mild. It is recommended that blood pressure (in both supine and upright positions) is monitored after L‑DOPS administration. L‑DOPS is an effective treatment of NOH and its symptoms in autonomic failure.

Such indices may help to facilitate the diagnosis of NOH and thus identify those individuals at greater risk of falls. Similar strategies are being employed for identifying and differentiating par‑ kinsonian disorders (e.g., PD and MSA), where NOH can frequently occur. Not all patients with NOH are symptomatic, the reasons for which are not entirely clear but likely relate to alterations in autoregulation of the cerebrovasculature but such adaptations alongside other cardiovascular and symptomatic adjustments, and their prognosis, have not been systematically investigated. Cur‑ rent pharmacological treatments for NOH are not totally effective in reversing the condition. With increasing knowledge of the pathophysi‑ ology of pre- and post-ganglionic sympathetic nervous system dysfunction in NOH, the devel‑ opment of pharmacological strategies for NOH as well as the delicate balance of simultaneously treating NOH and supine hypertension can be greatly improved.

Future perspective

NOH is a clear feature of autonomic failure with well-defined diagnostic criteria. Increasing efforts are being made to identify indices of cardiovas‑ cular autonomic dysfunction that are simply and noninvasively assessed in both patient popula‑ tions and the ever-increasing healthy elderly.

Financial & competing interests disclosure

CJ Mathias has received personal compensation for activities with Chelsea Therapeutics. CJ Mathias has received personal compensation in an editorial capacity for Clinical Autonomic Research. CJ Mathias has received research support from Chelsea Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary Mechanisms of action l-threo-dihydroxyphenylserine (L‑DOPS) is an oral prodrug that is converted to the sympathetic neurotransmitter noradrenaline through a single step decarboxylation by the endogenous enzyme 3,4-dihydrophenylalanine decarboxylase. Pharmokinetic properties Peak concentrations of L‑DOPS occur approximately 3 h after dosage. L‑DOPS undergoes a mono-exponential decline with a plasma half-life of 2–3 h. L‑DOPS undergoes renal elimination. Peak concentrations of noradrenaline occur approximately 3–6 h after L‑DOPS dosage. Noradrenaline levels decline multiexponentially with an initial half-time of 8.8 h. Clinical efficacy L‑DOPS can reduce neurogenic orthostatic hypotension severity and improve symptoms of neurogenic orthostatic hypotension, as well as reduce falls in autonomic failure patients within 4 h and over 12 months in randomized controlled, double-blind studies. Safety & tolerability Possible adverse events to L‑DOPS include headache, supine hypertension, dizziness, nausea, urinary tract infections and fatigue. Dosage & administration The recommended daily dose of L‑DOPS is approximately 600–900 mg administered orally three times during the day. It is prudent to monitor blood pressure (in both supine and upright positions) at the start of L‑DOPS treatment.

394




References

12. Velseboer DC, De Haan RJ, Wieling W,

Goldstein DS, De Bie RM. Prevalence of orthostatic hypotension in Parkinson’s disease: a systematic review and metaanalysis. Parkinsonism Relat. Disord. 17(10), 724–729 (2011).

Papers of special note have been highlighted as: n of interest nn of considerable interest 1.

2.

n

3.

4.

5.

6.

7.

8.

9.

Lahrmann H, Cortelli P, Hilz M, Mathias CJ, Struhal W, Tassinari M. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur. J. Neurol. 13(9), 930–936 (2006). Freeman R, Wieling W, Axelrod FB et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin. Auton. Res. 21(2), 69–72 (2011).

13. Timmers HJ, Deinum J, Wevers RA, Lenders

JW. Congenital dopamine-b-hydroxylase deficiency in humans. Ann. NY Acad. Sci. 1018, 520–523 (2004). 14. Edwards JL, Vincent AM, Cheng HT,

Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol. Ther. 120(1), 1–34 (2008). 15. Dardiotis E, Koutsou P, Papanicolaou EZ

et al. Epidemiological, clinical and genetic study of familial amyloidotic polyneuropathy in Cyprus. Amyloid 16(1), 32–37 (2009).

Latest guidelines on definitions of orthostatic hypotension. Jamnadas-Khoda J, Koshy S, Mathias CJ, Muthane UB, Ragothaman M, Dodaballapur SK. Are current recommendations to diagnose orthostatic hypotension in Parkinson’s disease satisfactory? Mov. Disord. 24(12), 1747–1751 (2009). Gilman S, Wenning GK, Low PA et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(9), 670–676 (2008). Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology 46(5), 1470 (1996). Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy. Lancet Neurol. 3(2), 93–103 (2004). Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 49(5), 1284–1288 (1997). Luukinen H, Koski K, Laippala P, Kivela SL. Prognosis of diastolic and systolic orthostatic hypotension in older persons. Arch. Intern. Med. 159(3), 273–280 (1999). Mathias C. Disorders of the autonomic nervous system. In: Oxford Textbook of Medicine. Warrell DA, Cox TM, Firth JD (Eds). Oxford University Press, Oxford, UK, 5055–5068 (2010).

16. Mathias CJ, Mallipeddi R, Bleasdale-Barr K.

Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy. J. Neurol. 246(10), 893–898 (1999). 17. Goldstein DS, Sharabi Y. Neurogenic

orthostatic hypotension: a pathophysiological approach. Circulation 119(1), 139–146 (2009). n

18. Vellas BJ, Wayne SJ, Romero LJ, Baumgartner

RN, Garry PJ. Fear of falling and restriction of mobility in elderly fallers. Age Ageing 26(3), 189–193 (1997). 19. Masaki KH, Schatz IJ, Burchfiel CM et al.

Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation 98(21), 2290–2295 (1998). 20. Eigenbrodt ML, Rose KM, Couper DJ,

Arnett DK, Smith R, Jones D. Orthostatic hypotension as a risk factor for stroke: the atherosclerosis risk in communities (ARIC) study, 1987–1996. Stroke J. Cereb. Circ. 31(10), 2307–2313 (2000). 21. Rose KM, Tyroler HA, Nardo CJ et al.

Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities study. Am. J. Hypertens. 13(6 Pt 1), 571–578 (2000). 22. Fedorowski A, Engstrom G, Hedblad B,

Melander O. Orthostatic hypotension predicts incidence of heart failure: the Malmo preventive project. Am. J. Hypertens. 23(11), 1209–1215 (2010).

10. Hobson P, Gallacher J, Meara J. Cross-

sectional survey of Parkinson’s disease and parkinsonism in a rural area of the United Kingdom. Mov. Disord. 20(8), 995–998 (2005).

23. Goldstein DS, Holmes C, Sharabi Y, Brentzel

S, Eisenhofer G. Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension. Neurology 60(8), 1327–1332 (2003).

11. Mutch WJ, Dingwall-Fordyce I, Downie AW,

Paterson JG, Roy SK. Parkinson’s disease in a Scottish city. Br. Med. J. Clin. Res. 292(6519), 534–536 (1986).


Excellent recent review of orthostatic hypotension and the assessment approaches.

n

Excellent investigation of sympathoneural and adrenomedullary abnormalities in autonomic failure.


Drug Evaluation

24. Hussain RM, McIntosh SJ, Lawson J, Kenny

RA. Fludrocortisone in the treatment of hypotensive disorders in the elderly. Heart Br. Cardiac Soc. 76(6), 507–509 (1996). 25. Low PA, Gilden JL, Freeman R, Sheng KN,

McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA 277(13), 1046–1051 (1997). 26. Wright RA, Kaufmann HC, Perera R et al.

A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 51(1), 120–124 (1998). 27. Robertson D, Davis TL. Recent advances in

the treatment of orthostatic hypotension. Neurology 45(4 Suppl. 5), S26–S32 (1995). 28. Rosenmund KW, Dornsaft H. [Oxy-and

dioxyphenyl-serine and the parent substance of adrenaline]. Ber. Dtsch Chem. 52(8), 1734–1749 (1919). 29. Blaschko H, Holton P, Stanley GH.

The decarboxylation of -3: 4-dihydroxyphenylserine (noradrenaline carboxylic acid). Br. J. Pharmacol. Chemother. 3(4), 315–319 (1948). 30. Blaschko H, Burn JH, Langemann H.

The formation of noradrenaline from dihydroxyphenylserine. Br. J. Pharmacol. Chemother. 5(3), 431–437 (1950). 31. Beyer KH, Blaschko H, Burn JH, Langemann

H. Enzymic formation of noradrenaline in mammalian tissue extracts. Nature 165(4206), 926 (1950). 32. Araki H, Tanaka C, Fujiwara H, Nakamura

M, Ohmura I. Pressor effect of L-threo-3,4dihydroxyphenylserine in rats. J. Pharm. Pharmacol. 33(12), 772–777 (1981). 33. Birkmayer W, Birkmayer G, Lechner H,

Riederer P. DL-3,4-threo-DOPS in Parkinson’s disease: effects on orthostatic hypotension and dizziness. J. Neural Transm. 58(3–4), 305–313 (1983). 34. Sakoda S, Suzuki T, Higa S et al. Treatment

of orthostatic hypotension in Shy-Drager syndrome with DL-threo-3,4dihydroxyphenylserine: a case report. Eur. Neurol. 24(5), 330–334 (1985). 35. Suzuki T, Higa S, Sakoda S et al. Orthostatic

hypotension in familial amyloid polyneuropathy: treatment with DL-threo3,4-dihydroxyphenylserine. Neurology 31(10), 1323–1326 (1981). 36. Suzuki T, Higa S, Tsuge I et al. Effect of

infused L-threo-3,4-dihydroxyphenylserine on adrenergic activity in patients with familial amyloid polyneuropathy. Eur. J. Clin. Pharmacol. 17(6), 429–435 (1980). 37. Biaggioni I, Robertson D. Endogenous

restoration of noradrenaline by precursor

395

Drug Evaluation


therapy in dopamine-b-hydroxylase deficiency. Lancet 2(8569), 1170–1172 (1987). n

49. Suzuki T, Higa S, Sakoda S et al.

One of the first papers to report the use of l‑threo-dihydroxyphenylserine (L-DOPS) in autonomic failure.

38. Mathias CJ, Bannister RB, Cortelli P et al.

Clinical, autonomic and therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthesize noradrenaline from dopamine because of a deficiency of dopamine b hydroxylase. Q. J. Med. 75(278), 617–633 (1990).

n

One of the first studies to report the pharmacokinetics of L-DOPS in healthy individuals and autonomic failure.

50. Maruyama W, Naoi M, Narabayashi H.

[Study on the metabolism of droxidopa in humans]. Rinsho Shinkeigaku 34(10), 991–995 (1994).

39. Narabayashi H, Kondo T, Yokochi F, Nagatsu

51. Maruyama W, Naoi M, Narabayashi H. The

T. Clinical effects of L-threo-3,4dihydroxyphenylserine in cases of parkinsonism and pure akinesia. Adv. Neurol. 45, 593–602 (1987).

metabolism of L-DOPA and L-threo-3,4dihydroxyphenylserine and their effects on monoamines in the human brain: analysis of the intraventricular fluid from parkinsonian patients. J. Neurol. Sci. 139(1), 141–148 (1996).

40. Ossipov MH, Dussor GO, Porreca F. Central

modulation of pain. J. Clin. Invest. 120(11), 3779–3787 (2010).

n

41. Benarroch EE. The locus ceruleus

norepinephrine system: functional organization and potential clinical significance. Neurology 73(20), 1699–1704 (2009).

L-threo-3,4-dihydroxyphenylserine (DOPS) aldolase: a new enzyme cleaving DOPS into protocatechualdehyde and glycine. Biochem. Biophys. Res. Commun. 143(2), 482–488 (1987).

L-threo-3,4-dihydroxyphenylserine (L-DOPS) in patients with chronic pain. Eur. Neuropsychopharmacol. 6(1), 43–47 (1996).

53. Ichinose H, Sumi-Ichinose C, Ohye T,

Hagino Y, Fujita K, Nagatsu T. Tissue-specific alternative splicing of the first exon generates two types of mRNAs in human aromatic L-amino acid decarboxylase. Biochemistry 31(46), 11546–11550 (1992).

L-threo-3,4-dihydroxyphenylserine treaatment for dementia of various etiology. Neurol. Ther. 5(4), 355–360 (1988). 44. Kalinin S, Polak PE, Lin SX, Sakharkar AJ,

Pandey SC, Feinstein DL. The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer’s disease. Neurobiol. Aging 33(8), 1651–1663 (2012).

54. Goldstein DS, Holmes C, Kaufmann H,

Freeman R. Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure. Clin. Auton. Res. 14(6), 363–368 (2004).

45. Hirayama E, Yamagami A, Onishi H, Mui K,

Fukushima K, Kawakita Y. Clinical trial of L-threo-DOPS on depression and depressive state. Jpn Pharmacol. Ther. 220(3), 957–964 (1992).

nn

46. Kachi T, Iwase S, Mano T, Saito M,

Kunimoto M, Sobue I. Effect of L-threo-3,4dihydroxyphenylserine on muscle sympathetic nerve activities in Shy-Drager syndrome. Neurology 38(7), 1091–1094 (1988). n

One of the first studies to directly show an increase in sympathetic nerve activity with L-DOPS.

47. Inagaki C, Fujiwara H, Tanaka C. Inhibitory

effect of (+)threo-3,4-dihydroxy-phenylserine (DOPS) on decarboxylation of (-)threo-dops. Jpn J. Pharmacol. 26(3), 380–382 (1976). 48. Hoeldtke RD, Cilmi KM, Mattis-Graves K.

DL-Threo-3,4-dihydroxyphenylserine does not exert a pressor effect in orthostatic hypotension. Clin. Pharmacol. Ther. 36(3), 302–306 (1984).

396

Excellent insight into the metabolites of L-DOPS and associated monoamines in human brains.

52. Naoi M, Takahashi T, Kuno N, Nagatsu T.

42. Takagi H, Harima A. Analgesic effect of

43. Otsuka M, Shimizu N, Dohbutsu M et al.

57. Yoshizawa T, Fujita T, Mizusawa H, Shoji S.

Pharmacokinetic studies of oral L-threo-3,4dihydroxyphenylserine in normal subjects and patients with familial amyloid polyneuropathy. Eur. J. Clin. Pharmacol. 23(5), 463–468 (1982).

One of the first studies to assess the pharmacokinetics of L-DOPS in multiple system atrophy and pure autonomic failure.

55. Goldstein DS, Holmes C, Sewell L, Pechnik

S, Kopin IJ. Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS. J. Clin. Pharmacol. 51(1), 66–74 (2011). n

Excellent study that assesses the effects of carbidopa and entacapone on L-DOPS metabolism, as well as further outlines the metabolic fate of L-DOPS.

56. Matsubara S, Sawa Y, Yokoji H, Takamori M.

Shy-Drager syndrome. Effect of fludrocortisone and L-threo-3,4dihydroxyphenylserine on the blood pressure and regional cerebral blood flow. J. Neurol. Neurosurg. Psychiatry 53(11), 994–997 (1990).


L-threo-3,4-dihydroxyphenylserine enhances the orthostatic responses of plasma renin activity and angiotensin II in multiple system atrophy. J. Neurol. 246(3), 193–197 (1999). 58. Kaufmann H, Saadia D, Voustianiouk A et al.

Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 108(6), 724–728 (2003). 59. Iida N, Tsubakihara Y, Shirai D, Imada A,

Suzuki M. Treatment of dialysis-induced hypotension with L-threo-3,4dihydroxyphenylserine. Nephrol. Dial. Transplant. 9(8), 1130–1135 (1994). 60. Freeman R, Landsberg L, Young J.

The treatment of neurogenic orthostatic hypotension with 3,4-DL-threodihydroxyphenylserine: a randomized, placebo-controlled, crossover trial. Neurology 53(9), 2151–2157 (1999). n

Very good study that uses a double-blind, placebo-controlled, crossover trial to investigate the effects of L-DOPS on blood pressure and orthostatic tolerance in autonomic failure.

61. Freeman R, Young J, Landsberg L, Lipsitz L.

The treatment of postprandial hypotension in autonomic failure with 3,4-DL-threodihydroxyphenylserine. Neurology 47(6), 1414–1420 (1996). 62. Carvalho MJ, Van Den Meiracker AH,

Boomsma F et al. Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydroxyphenylserine. J. Auton. Nerv. Syst. 62(1–2), 63–71 (1997). 63. Ando Y, Gotoh T, Kawaguchi Y, Tanaka Y,

Sakashita N, Ando M. Intranasal L-threo3,4,-dihydroxyphenylserine in treating diarrhea associated with familial amyloidotic polyneuropathy. Pharmacotherapy 15(3), 345–349 (1995). 64. Wecht J, Rosado-Rivera D, Yen C, Radulovic

M, Bauman W. Blood pressure effect of droxidopa in hypotensive individuals with spinal cord injury. Clin. Auton. Res. 22, 254 (2012). 65. Kaufmann H, Oribe E, Yahr MD.

Differential effect of L-threo-3,4dihydroxyphenylserine in pure autonomic failure and multiple system atrophy with autonomic failure. J. Neural. Transm. Park. Dis. Dement. Sect. 3(2), 143–148 (1991). 66. Mathias CJ, Senard JM, Braune S et al.

L-threo-dihydroxyphenylserine (L-threoDOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multinational, multi-center, dose-ranging study in multiple system atrophy and pure autonomic



failure. Clin. Auton. Res. 11(4), 235–242 (2001). n

One of the first reports of a clinical trial of L-DOPS in autonomic failure.

67. Mathias CJ. L-dihydroxyphenylserine

(Droxidopa) in the treatment of orthostatic hypotension: the European experience. Clin. Auton. Res. 18(Suppl. 1), S25–S29 (2008). 68. Mathias CJ, Senard JM, Cortelli P. A double-

blind, randomized, placebo-controlled study to determine the efficacy and safety of droxidopa in the treatment of orthostatic hypotension associated with multiple system atrophy or Parkinson’s disease. Clin. Auton. Res. 17, 272 (2007). 69. Yanagisawa N, Ikeda S, Hashimoto T et al.

[Effects of L-threo-Dops on orthostatic hypotension in Parkinson’s disease]. No To Shinkei 50(2), 157–163 (1998). 70. Kaufmann H, Malamut R,

Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic Hypotension Questionnaire (OHQ ): validation of a novel symptom assessment scale. Clin. Auton. Res. 22(2), 79–90 (2012). 71. Mathias CJ, Low P, Freeman R, Hewitt A,

Kaufmann H. Integrated efficacy analysis of droxidopa in 2 double-blind, placebocontrolled Phase 3 studies in patients with neurogenic orthostatic hypotension. Mov. Disord. 27(Suppl. 1), S1296 (2012).


72. Kaufmann H, Freeman R, Biaggioni I et al.

Treatment of neurogenic orthostatic hypotension with droxidopa: results from a multi-center, double-blind, randomized, placebo-controlled, parallel group, induction design study (PL02.001). Neurology 78(Meeting Abstracts 1), PL02.001 (2012). 73. Wenning G, Low P, Szakacs C, Kaufmann H.

Orthostatic hypotension questionnaire composite score in patients with neurogenic orthostatic hypotension treated with droxidopa. Mov. Disord. 27(Suppl. 1), 1305 (2012). 74. Biaggioni I, Low P, Rowse G, Kaufmann H.

Analysis of efficacy in patients with symptomatic neurogenic orthostatic hypotension treated with droxidopa and dopa-decarboxylase inhibitors. Mov. Disord. 27(Suppl. 1), 1284 (2012). 75. Wenning GK, Kaufmann H, Mathias CJ,

Cortelli P. Safety and efficacy of Northera (droxidopa) in multiple system atrophy. Mov. Disord. 26(Suppl. 2), 778 (2011). 76. Low P, Nelson J, Stacy M. Safety and efficacy

of droxidopa in patients previously treated with midodrine. Mov. Disord. 27(Suppl. 1), 1295 (2012). 77. Isaacson S, Shill H, Vernino S, Cioffi C,

Hutchman R. Durability of effect with longterm, open-label droxidopa treatment in patients with symptomatic neurogenic orthostatic hypotension (NOH 303). Mov. Disord. 27(Suppl. 1), 1291 (2012).


Drug Evaluation

78. Hauser RA, Schweiterman W, Isaacson S.

Impact of treatment with droxidopa in repeat fallers with parkinson’s disease and symptomatic neurogenic orthostatic hypotension. Mov. Disord. 27(Suppl. 1), 1287 (2012). 79. Shill H, Vernino S, Hutchman R, Adkins L,

Isaacson S. A multicenter, open-label study to assess the long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension. Mov. Disord. 27(Suppl. 1), 1302 (2012). 80. Mathias CJ, Bannister R. Dopamine

b-hydroxylase deficiency – with a note on other genetically determined causes of autonomic failure. In: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System (5th Edition). Mathias CJ, Bannister R (Eds). Oxford University Press, Oxford, UK, 597–612 (2013). 81. Goldstein DS. L-Dihydroxyphenylserine

(L-DOPS): a norepinephrine prodrug. Cardiovasc. Drug Rev. 24(3–4), 189–203 (2006). 82. Kaufmann H, Mathias CJ, Freeman R, Low

P, Biaggioni I; the Droxidopa Study Group. Treatment with droxidopa – a Phase III multinational, placebo-controlled, parallel group, withdrawal-design study in subjects with neurogenic orthostatic hypotension and non-diabetic autonomic neuropathy. Clin. Auton. Res. 19(5), Abstract 281 (2009).

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