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BACKGROUND: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. OBJECTIVES: To update LED conversion formulae based on a systematic review. METHODS: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. RESULTS: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. CONCLUSIONS: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Levodopa , Doença de Parkinson , Humanos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Resultado do TratamentoRESUMO
Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.
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Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.
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Infecções por Helicobacter , Helicobacter pylori , Doença de Parkinson , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/complicações , Antiparkinsonianos/uso terapêutico , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Trato GastrointestinalRESUMO
This corrects the article DOI: 10.1038/nrn.2017.62.
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Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.
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Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Sintomas Prodrômicos , Encéfalo/patologia , Constipação Intestinal/complicações , Depressão/complicações , Diagnóstico Precoce , Humanos , Neurotransmissores/fisiologia , Transtornos do Olfato/complicações , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Qualidade de Vida , Transtornos do Sono-Vigília/complicaçõesRESUMO
The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson's disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.
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Doença de Parkinson , Adenosina/farmacologia , Adenosina/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Adulto , Humanos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptor A2A de AdenosinaRESUMO
An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.
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Doenças dos Gânglios da Base/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Manganês/toxicidade , Propiofenonas/toxicidade , Substância Negra/efeitos dos fármacos , Animais , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/patologia , Comportamento Animal , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Masculino , Manganês/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Propiofenonas/administração & dosagem , Substância Negra/diagnóstico por imagem , Substância Negra/metabolismo , Substância Negra/patologia , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4-113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4-7 mg/kg). L-DOPA reversed motor disability, increased locomotor activity, and induced moderate dyskinesia. B. caapi did not increase locomotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved motor disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in motor disability without affecting locomotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.
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1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/uso terapêutico , Banisteriopsis/metabolismo , Doença de Parkinson/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Antiparkinsonianos , Callithrix , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Doença de Parkinson/patologiaRESUMO
BACKGROUND: The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from "off" periods, whereas continuous subcutaneous infusion is used to increase "on" periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of motor disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets. METHODS: Locomotor activity, motor disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral). RESULTS: Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of motor disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of motor disability and increased locomotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of motor disability reversal and increased locomotor activity. CONCLUSION: Oral administration of 11-OH-NPa valerate produced a rapid reversal of motor disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society.
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Apomorfina/farmacologia , Aporfinas/farmacologia , Comportamento Animal , Agonistas de Dopamina/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Intoxicação por MPTP/tratamento farmacológico , Animais , Apomorfina/administração & dosagem , Aporfinas/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Callithrix , Modelos Animais de Doenças , Agonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/etiologia , Feminino , Masculino , Valeratos/administração & dosagem , Valeratos/farmacologiaRESUMO
Nitrative stress is a key component of the pathogenic process in Parkinson's disease (PD), but the relative roles of constitutive neuronal nitric oxide synthase (n-NOS) and inducible nitric oxide synthase (i-NOS) in glial cells remain unresolved. We have investigated the effects of a range of concentrations of the selective n-NOS inhibitor ARR17477, and the selective i-NOS inhibitor 1400W, on MPP(+)-induced cell death in foetal ventral mesencephalic (VM) dopaminergic cultures. MPP(+) induced a loss of TH-positive neurones accompanied by an increase in immunoreactivity for GFAP and OX-6 as markers of astrocytes and activated microglia, respectively, and induced i-NOS immunoreactivity. Unexpectedly, MPP(+) treatment did not induce 3-NT immunoreactivity in the cultures. ARR17477 and 1400W alone had no effect on the number of TH-positive cells or on the number of GFAP or OX-6 positive cells. ARR17477 did not prevent the MPP(+)-induced decrease in TH-positive neurones and had no effect on the increased number of GFAP- and OX-6-positive cells. By contrast, 1400W caused a concentration-dependent preservation of TH-positive neurones in the presence of MPP(+). It also significantly reduced the number of OX-6-immunoreactive cells and there was a small reduction in GFAP immunoreactivity. The results suggest a major role for i-NOS-mediated nitrative stress in microglia in MPP(+)-induced dopaminergic cell death and this may have important implications for developing neuroprotective strategies for PD.
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Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Picolinas/toxicidade , Amidinas/farmacologia , Animais , Anticorpos Monoclonais/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Benzilaminas/farmacologia , Contagem de Células , Células Cultivadas , Neurônios Dopaminérgicos/enzimologia , Neurônios Dopaminérgicos/patologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/enzimologia , Mesencéfalo/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologia , Cultura Primária de Células , Ratos Wistar , Tiofenos/farmacologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
In Parkinson's disease (PD), destruction of noradrenergic neurons in the locus coeruleus (LC) may precede damage to nigral cells and subsequently exaggerate dopaminergic cell loss. We examine if destruction of the locus coeruleus with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) alters dopaminergic cell loss in substantia nigra (SN) initiated by lipopolysaccharide (LPS) in the rat through an effect on glial cell activation. In rats, a single intraperitoneal dose of DSP-4 administered 8 days previously, caused a marked loss of tyrosine hydroxylase positive neurons in LC but no change in dopaminergic cell number in SN. Unilateral nigral LPS administration resulted in marked dopaminergic cell death with reactive microgliosis associated with enhanced p47 phox in OX-6 and OX-42 positive microglia. There was proliferation of inducible nitric oxide synthase (iNOS)-positive cells, formation of 3-nitrotyrosine (3-NT) and proliferation of astrocytes that expressed glial cell line-derived neurotrophic factor (GDNF). Following combined DSP-4 treatment and subsequent administration of LPS, unexpectedly, no further loss of tyrosine hydroxylase (TH)-immunoreactivity (-ir) occurred in the SN compared to the effects of LPS alone. However, there was a marked alteration in the morphology of microglial cell and a reduction of 3-NT- and iNOS-ir was evident. Expression of p47 phox was downregulated in microglia but up-regulated in TH-ir neurons. No further change in GFAP-ir was observed compared to that produced by DSP-4 alone or LPS alone, but the expression of GDNF was markedly reduced. This study suggests that in contrast to previous reports, prior LC damage does not influence subsequent nigral dopaminergic cell degeneration induced by LPS. Rather it appears to attenuate the microglial response thought to contribute to disease progression in PD.
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Neurônios Adrenérgicos/fisiologia , Encefalite/induzido quimicamente , Encefalite/patologia , Lipopolissacarídeos/toxicidade , Locus Cerúleo/citologia , Substância Negra/patologia , Adrenérgicos/toxicidade , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Benzilaminas/toxicidade , Antígeno CD11b/metabolismo , Contagem de Células , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Locus Cerúleo/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/fisiologiaRESUMO
The adenosine A2A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson's disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with sub-maximal doses of L-DOPA. However, the effects of combining istradefylline with sub-optimal L-DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to L-DOPA. In these animals, single dose acute oral administration of istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of L-DOPA (2.5 mg/kg). The chronic co-administration of istradefylline (10 mg/kg) with L-DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that istradefylline can be used to potentiate the effects of sub-optimal doses of L-DOPA in the treatment of Parkinson's disease without causing or worsening dyskinesia.
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Antagonistas do Receptor A2 de Adenosina/farmacologia , Antiparkinsonianos/farmacologia , Discinesias/fisiopatologia , Levodopa/farmacologia , Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/fisiopatologia , Purinas/farmacologia , Administração Oral , Animais , Antiparkinsonianos/administração & dosagem , Callithrix , Sinergismo Farmacológico , Feminino , Levodopa/administração & dosagem , Masculino , Purinas/administração & dosagemRESUMO
Non-motor symptoms are a key component of Parkinson's disease, possibly representing a clinical biomarker of its premotor phase. The burden of non-motor symptoms can define a patient's health-related quality of life. Non-motor symptoms substantially increase the cost of care-requiring increased hospitalisation and treatment-and pose a major challenge to healthcare professionals. However, clinicians often regard non-motor symptoms and their management as peripheral to that of the motor symptoms. Here, we address the clinical issues and unmet needs of non-motor symptoms in Parkinson's disease.
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Doença de Parkinson/complicações , Antiparkinsonianos/efeitos adversos , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Doença de Parkinson/psicologia , Qualidade de Vida , Índice de Gravidade de DoençaRESUMO
The multifunctional protein osteopontin (OPN) is expressed in the substantia nigra (SN) and protects nigral dopaminergic neurones against toxic insult in animal models of Parkinson's disease, although the mechanisms involved are uncertain. In the periphery, OPN regulates inflammatory processes by interacting with integrin and CD44 receptors but the presence and distribution of these sites in SN is unknown. We investigated the expression of integrin receptor subunits and CD44 receptors in the normal SN and after induction of inflammation by lipopolysaccharide (LPS), and their interaction with OPN. In normal rat SN, integrin αv , ß3 and ß1 , and CD44, receptors were expressed on neurones including TH-positive cells but not on glia. LPS administration induced a loss of TH-positive neurones in SN and increased expression of glial cells as shown by GFAP, OX-6 and ED-1 immunoreactivity. In LPS-lesioned SN, there was up-regulation of the expression of integrin ß3 and CD44 receptors. Co-localisation studies showed that this related to their increased expression on OX-6-, ED-1- and GFAP-positive cells. Furthermore, OPN interacted with integrin and CD44 receptors in the normal rat SN as demonstrated by co-immunoprecipitation and pull-down techniques. These data show that integrin and CD44 receptors are present on neurones in normal rat SN and that they are up-regulated on glial cells following LPS-mediated inflammation in SN, suggesting that they are functionally important in the inflammatory process. The interaction of OPN with these receptors suggests a role in the neuroprotective effect of this protein in the LPS model of Parkinson's disease.