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Novel administration routes for levodopa and dopamine agonists
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 S ( 2 0 0 8 ) S7–S24
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L15 Clinical trials with catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone Vilho Myllyla¨ University of Oulu, Finland l-DOPA is the most effective orally active drug on all the cardinal parkinsonian motor signs. In long-term use motor fluctuations and dyskinesias develop and many strategies have used to improve the l-DOPA therapy. l-DOPA is metabolized via decarboxylation (by DDC) and O-methylation (by COMT). Blocking the peripheral DDC has been the routine but then O-methylation of l-DOPA by COMT prevails. COMT inhibition prolongs plasma l-DOPA levels. Two COMT-inhibitors are used: entacapone and tolcapone. Entacapone acts mainly on peripheral l-DOPA, while tolcapone enters better the brain and inhibits l-DOPA and dopamine degradation even there. Entacapone has a similar half-life as l-DOPA and both drugs need be given together. A triple treatment containing 200 mg of entacapone with three most commonly used l-DOPA/carbidopa doses is available. This simplifies the treatment and has a good compliance. Four prospective, randomized, controlled trials demonstrated the clinical benefit of entacapone in patients with motor fluctuations and found an increase of daily on-time of 1–1.7 h. In a recent comparative study, the decrease of off-time was found similar to that caused by rasagiline, a new MAO-B inhibitor. Entacapone seems to improve both ADL and motor sub-scores of UPDRS in PD patients. In most of the studies, a 12–16% reduction of the daily l-DOPA dose was possible. Animal studies suggest that early combined treatment with entacapone, l-DOPA and DDC-inhibitor would delay the appearance of motor fluctuations. The first clinical report from FIRST-STEP study with early Parkinson’s disease confirm that this combination provides better symptomatic benefit than the standard l-DOPA/carbidopa treatment. The other COMT inhibitor, tolcapone, has a longer half-life and it is administered three times a day at 100 or 200 mg. Several randomized, placebo-controlled multicenter trials have shown that tolcapone reduces off-time and l-DOPA requirements. The drug was shown to be well tolerated but the trials also demonstrated a dose-related increase in liver enzymes and the postmarketing surveillance revealed hepatotoxicity. Therefore, tolcapone was withdrawn from the market in many countries. Now its use is allowed obeying close safety monitoring. Severe liver injury is rare and tolcapone has returned to market in many countries. doi:10.1016/j.ejps.2008.02.030 L16 Comparative studies of dopamine agonists and other therapies ¨ Tapani Keranen Department of Neurology and Rehabilitation, Tampere University Hospital, Tampere, Finland
Dopamine agonists (DAs) are drugs which are widely used both as monotherapy in early Parkinson’s disease (PD) and as adjunctive treatment in advanced PD. The present discussion focuses on bromocriptine, cabergoline, pramipexole, ropinirole and rotigotine. All DAs are agonists of dopamine D2 receptors. Their affinities to D1 and D3 receptors, as well as their effects on noradrenergic and serotoninergic receptors are variable. The motor effects of DAs in PD are mediated through D2 receptors. In early PD, DAs have been compared with placebo and levodopa. Placebo controlled trials have demonstrated symptomatic efficacy of pramipexole, ropinirole and rotigotine. Based on comparison studies with levodopa, bromocriptine and cabergoline are probably effective as monotherapy in early PD. Compared with levodopa, monotherapy with cabergoline, pramipexole and ropinirole are less efficacious in improving motor symptoms. Bromocriptine, cabergoline, pramipexole and ropinirole have been shown to delay the incidence of motor complications versus levodopa. Placebo controlled studies in patients advanced PD have demonstrated that DAs effectively reduce off periods. Head to head comparison studies of DAs are sparse. There are no conclusive data suggesting any clinically relevant differences in the efficacy of various DAs. Comparison of DAs with other antiparkinsonian agents such as COMT inhibitors, are rare. DAs share a common profile of dopaminergic adverse effects. In comparison with levodopa, DAs cause more often hallucinations, peripheral leg edema, and sedation. DAs may be also associated with impulse control disorders such as pathological gambling and hypersexuality. Ergoline DAs cabergoline and pergolide are associated with an increased risk of cardiac-valve regurgitation. In this respect, these DAs differ from non-ergoline drugs pramipexole, ropinirole and rotigotine. These adverse effects may be related to agonism of 5-HT2B receptors of cabergoline and pergolide. doi:10.1016/j.ejps.2008.02.031 L17 Novel administration routes for levodopa and dopamine agonists Dag Nyholm Uppsala University Hospital, Uppsala, Sweden Levodopa and dopamine receptor agonists constitute the mainstay of pharmacotherapy to treat the symptoms of Parkinson’s disease (PD). The aim is to replace the loss of dopamine and alleviate motor and non-motor symptoms as well as possible. Oral formulations of these drugs meet several difficulties. Levodopa is always administered in combination with a decarboxylase inhibitor, but the plasma elimination half-life is only about 1.5 h anyway. This causes pulsatile receptor stimulation, with long-term consequences such as dyskinesias, and a need for frequent administration in the advanced stages of PD. Levodopa is only absorbed in the proximal small intestine and is thus dependent on gastric emptying, which is erratic and slowed in PD. The transit time is
S14
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 S ( 2 0 0 8 ) S7–S24
about 3 h, which explains why sustained-release formulations have been disappointing. The fact that levodopa is a large neutral amino acid is another obstacle, because amino acids from dietary proteins may interfere with absorption from the intestine and/or the transport over the blood–brain barrier. These issues with oral levodopa administration become more problematic as the disease progresses and the therapeutic window gets narrower. Patients in advanced stages fluctuate between severe parkinsonism and choreatic dyskinesias, depending on the concentrations of levodopa that reach the brain. The situation is not as pronounced with the dopamine agonists because they have longer half-lives than levodopa. However, motor fluctuations and dyskinesias do occur also on dopamine agonist monotherapy, which is not a possible long-term alternative because of the inferior efficacy compared to levodopa. Non-oral routes of delivery of levodopa and dopamine agonists are interesting because they may provide continuous dopaminergic stimulation (CDS). According to the theories of the CDS concept, a constant-rate drug administration mimics the physiological situation better than the pulsatile stimulation provided by oral formulations. Today, in Europe, duodenal infusion of levodopa/carbidopa, subcutaneous infusion of apomorphine and transdermal delivery of rotigotine are available. Numerous studies of these new drug-delivery systems have demonstrated benefits for patients with advanced PD in terms of stable drug concentrations and reduced motor fluctuations.
protein. Delivery of neurturin is now being explored by the American biotech company Ceregene in a clinical trial using AAV vector-mediated delivery in patients in advanced stages of the disease. Direct in vivo gene transfer of the tyrosine hydroxylase gene can provide substantial functional improvement in both drug-induced and spontaneous behavior in rats with 6-hydroxydopamne (6-OHDA)-induced lesions of the nigrostriatal pathway provided that tyrosine hydroxylase is co-expressed with the co-factor producing enzyme, GTPcyclohydrolase. Complete reversal of motor deficits, and reversal of l-DOPA-induced dyskinesias have been obtained in 6-OHDA lesioned animals where part of the striatal dopamine innervation was left intact. Intrastriatal l-DOPA delivery may be a viable strategy for improved symptomatic treatment, and for control of adverse side-effects associated with oral l-DOPA therapy, such as on–off fluctuations and drug-induced dyskinesias, in patients with Parkinson’s disease. Clinical trials along these lines are now in progress. doi:10.1016/j.ejps.2008.02.033 L19 Experimental and alternative ways of drug treatment of Parkinson’s disease Seppo Kaakkola Helsinki University Hospital, Finland
doi:10.1016/j.ejps.2008.02.032 L18 Gene therapy for Parkinson’s disease ¨ Anders Bjorklund Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, Sweden Important progress has been made during recent years in the generation of efficient recombinant adeno-associated virus (AAV) or lentiviral vectors. These vector systems are highly useful, not only as experimenta tools, but hold great promise also for applications in patients. As a result of this technical advance gene transfer for neuroprotective or restorative therapies are now on the verge of becoming a clinical reality. Viral vector mediated gene transfer in Parkinson’s disease is currently pursued along two different lines: either by expression of potential neuroprotective molecules, or as a tool to supply dopamine locally in the affected striatum by supplying the enzymes responsible for l-DOPA or dopamine synthesis. Promising results have been obtained in rodent and primate Parkinson models by gene transfer using recombinant AAV and LV vectors carrying the GDNF or tyrosine hydroxylase genes. Nanogram amounts of GDNF, or its close relative neurturin, expressed by the transduced cells are highly effective in protecting the dopaminergic nigral neurons from the toxic insult and are also effective in promoting substantial, longterm functional recovery. This contrasts with the microgram amounts required to achieve a similar magnitude of protection by intracerebral injection or infusion of recombinant GDNF
The present drug treatment of Parkinson’s disease (PD) is based on the substitution of dopamine deficiency due to degeneration of nigrostriatal dopaminergic neurons. l-DOPA, dopamine agonists and MAO B inhibitors are currently the most effective symptomatic agents. Unfortunately, it is uncertain that they slow or delay the progression of disease. In recent years, considerable advances have been made in understanding the pathogenetic processes of neurodegeneration in PD and these advances may provide novel strategies for drug development. The main pathogenetic mechanisms include mitochondrial function deficiency, abnormal protein aggregation, increased oxidative stress, apoptosis, excitotoxicity and inflammation. Much effort is being focused on these processes to develop an agent or agents with neuroprotective properties. Coenzyme q10 and creatine may improve mitochondrial function and are under clinical testing. Many anti-excitotoxic agent are under preclinical and clinical development. Both NMDA and AMPA antagonists may in addition to putative neuroprotective effect have also symptomatic effect, particularly antidyskinetic action. Several anti-inflammatory agents have been tested both preclinically and clinically. These include both an antibiotic minocycline and COX inhibitors. No breakthrough has been so far achieved. Recently, a phase II/III trial with an antiapoptotic agent CEP-1347 showed negative results. Many other putative antiapoptotic agents have shown promising results in animal studies. A novel strategy is to design inhibitors of alpha-synuclein aggregation. Some effort is still exert on substances affecting dopamine system, e.g. safinamide, a MAO B inhibitor with many other mechanisms of action is in phase III trials. Some new dopamine agonists and dopamine uptake inhibitors are also
S13
L15 Clinical trials with catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone Vilho Myllyla¨ University of Oulu, Finland l-DOPA is the most effective orally active drug on all the cardinal parkinsonian motor signs. In long-term use motor fluctuations and dyskinesias develop and many strategies have used to improve the l-DOPA therapy. l-DOPA is metabolized via decarboxylation (by DDC) and O-methylation (by COMT). Blocking the peripheral DDC has been the routine but then O-methylation of l-DOPA by COMT prevails. COMT inhibition prolongs plasma l-DOPA levels. Two COMT-inhibitors are used: entacapone and tolcapone. Entacapone acts mainly on peripheral l-DOPA, while tolcapone enters better the brain and inhibits l-DOPA and dopamine degradation even there. Entacapone has a similar half-life as l-DOPA and both drugs need be given together. A triple treatment containing 200 mg of entacapone with three most commonly used l-DOPA/carbidopa doses is available. This simplifies the treatment and has a good compliance. Four prospective, randomized, controlled trials demonstrated the clinical benefit of entacapone in patients with motor fluctuations and found an increase of daily on-time of 1–1.7 h. In a recent comparative study, the decrease of off-time was found similar to that caused by rasagiline, a new MAO-B inhibitor. Entacapone seems to improve both ADL and motor sub-scores of UPDRS in PD patients. In most of the studies, a 12–16% reduction of the daily l-DOPA dose was possible. Animal studies suggest that early combined treatment with entacapone, l-DOPA and DDC-inhibitor would delay the appearance of motor fluctuations. The first clinical report from FIRST-STEP study with early Parkinson’s disease confirm that this combination provides better symptomatic benefit than the standard l-DOPA/carbidopa treatment. The other COMT inhibitor, tolcapone, has a longer half-life and it is administered three times a day at 100 or 200 mg. Several randomized, placebo-controlled multicenter trials have shown that tolcapone reduces off-time and l-DOPA requirements. The drug was shown to be well tolerated but the trials also demonstrated a dose-related increase in liver enzymes and the postmarketing surveillance revealed hepatotoxicity. Therefore, tolcapone was withdrawn from the market in many countries. Now its use is allowed obeying close safety monitoring. Severe liver injury is rare and tolcapone has returned to market in many countries. doi:10.1016/j.ejps.2008.02.030 L16 Comparative studies of dopamine agonists and other therapies ¨ Tapani Keranen Department of Neurology and Rehabilitation, Tampere University Hospital, Tampere, Finland
Dopamine agonists (DAs) are drugs which are widely used both as monotherapy in early Parkinson’s disease (PD) and as adjunctive treatment in advanced PD. The present discussion focuses on bromocriptine, cabergoline, pramipexole, ropinirole and rotigotine. All DAs are agonists of dopamine D2 receptors. Their affinities to D1 and D3 receptors, as well as their effects on noradrenergic and serotoninergic receptors are variable. The motor effects of DAs in PD are mediated through D2 receptors. In early PD, DAs have been compared with placebo and levodopa. Placebo controlled trials have demonstrated symptomatic efficacy of pramipexole, ropinirole and rotigotine. Based on comparison studies with levodopa, bromocriptine and cabergoline are probably effective as monotherapy in early PD. Compared with levodopa, monotherapy with cabergoline, pramipexole and ropinirole are less efficacious in improving motor symptoms. Bromocriptine, cabergoline, pramipexole and ropinirole have been shown to delay the incidence of motor complications versus levodopa. Placebo controlled studies in patients advanced PD have demonstrated that DAs effectively reduce off periods. Head to head comparison studies of DAs are sparse. There are no conclusive data suggesting any clinically relevant differences in the efficacy of various DAs. Comparison of DAs with other antiparkinsonian agents such as COMT inhibitors, are rare. DAs share a common profile of dopaminergic adverse effects. In comparison with levodopa, DAs cause more often hallucinations, peripheral leg edema, and sedation. DAs may be also associated with impulse control disorders such as pathological gambling and hypersexuality. Ergoline DAs cabergoline and pergolide are associated with an increased risk of cardiac-valve regurgitation. In this respect, these DAs differ from non-ergoline drugs pramipexole, ropinirole and rotigotine. These adverse effects may be related to agonism of 5-HT2B receptors of cabergoline and pergolide. doi:10.1016/j.ejps.2008.02.031 L17 Novel administration routes for levodopa and dopamine agonists Dag Nyholm Uppsala University Hospital, Uppsala, Sweden Levodopa and dopamine receptor agonists constitute the mainstay of pharmacotherapy to treat the symptoms of Parkinson’s disease (PD). The aim is to replace the loss of dopamine and alleviate motor and non-motor symptoms as well as possible. Oral formulations of these drugs meet several difficulties. Levodopa is always administered in combination with a decarboxylase inhibitor, but the plasma elimination half-life is only about 1.5 h anyway. This causes pulsatile receptor stimulation, with long-term consequences such as dyskinesias, and a need for frequent administration in the advanced stages of PD. Levodopa is only absorbed in the proximal small intestine and is thus dependent on gastric emptying, which is erratic and slowed in PD. The transit time is
S14
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 S ( 2 0 0 8 ) S7–S24
about 3 h, which explains why sustained-release formulations have been disappointing. The fact that levodopa is a large neutral amino acid is another obstacle, because amino acids from dietary proteins may interfere with absorption from the intestine and/or the transport over the blood–brain barrier. These issues with oral levodopa administration become more problematic as the disease progresses and the therapeutic window gets narrower. Patients in advanced stages fluctuate between severe parkinsonism and choreatic dyskinesias, depending on the concentrations of levodopa that reach the brain. The situation is not as pronounced with the dopamine agonists because they have longer half-lives than levodopa. However, motor fluctuations and dyskinesias do occur also on dopamine agonist monotherapy, which is not a possible long-term alternative because of the inferior efficacy compared to levodopa. Non-oral routes of delivery of levodopa and dopamine agonists are interesting because they may provide continuous dopaminergic stimulation (CDS). According to the theories of the CDS concept, a constant-rate drug administration mimics the physiological situation better than the pulsatile stimulation provided by oral formulations. Today, in Europe, duodenal infusion of levodopa/carbidopa, subcutaneous infusion of apomorphine and transdermal delivery of rotigotine are available. Numerous studies of these new drug-delivery systems have demonstrated benefits for patients with advanced PD in terms of stable drug concentrations and reduced motor fluctuations.
protein. Delivery of neurturin is now being explored by the American biotech company Ceregene in a clinical trial using AAV vector-mediated delivery in patients in advanced stages of the disease. Direct in vivo gene transfer of the tyrosine hydroxylase gene can provide substantial functional improvement in both drug-induced and spontaneous behavior in rats with 6-hydroxydopamne (6-OHDA)-induced lesions of the nigrostriatal pathway provided that tyrosine hydroxylase is co-expressed with the co-factor producing enzyme, GTPcyclohydrolase. Complete reversal of motor deficits, and reversal of l-DOPA-induced dyskinesias have been obtained in 6-OHDA lesioned animals where part of the striatal dopamine innervation was left intact. Intrastriatal l-DOPA delivery may be a viable strategy for improved symptomatic treatment, and for control of adverse side-effects associated with oral l-DOPA therapy, such as on–off fluctuations and drug-induced dyskinesias, in patients with Parkinson’s disease. Clinical trials along these lines are now in progress. doi:10.1016/j.ejps.2008.02.033 L19 Experimental and alternative ways of drug treatment of Parkinson’s disease Seppo Kaakkola Helsinki University Hospital, Finland
doi:10.1016/j.ejps.2008.02.032 L18 Gene therapy for Parkinson’s disease ¨ Anders Bjorklund Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, Sweden Important progress has been made during recent years in the generation of efficient recombinant adeno-associated virus (AAV) or lentiviral vectors. These vector systems are highly useful, not only as experimenta tools, but hold great promise also for applications in patients. As a result of this technical advance gene transfer for neuroprotective or restorative therapies are now on the verge of becoming a clinical reality. Viral vector mediated gene transfer in Parkinson’s disease is currently pursued along two different lines: either by expression of potential neuroprotective molecules, or as a tool to supply dopamine locally in the affected striatum by supplying the enzymes responsible for l-DOPA or dopamine synthesis. Promising results have been obtained in rodent and primate Parkinson models by gene transfer using recombinant AAV and LV vectors carrying the GDNF or tyrosine hydroxylase genes. Nanogram amounts of GDNF, or its close relative neurturin, expressed by the transduced cells are highly effective in protecting the dopaminergic nigral neurons from the toxic insult and are also effective in promoting substantial, longterm functional recovery. This contrasts with the microgram amounts required to achieve a similar magnitude of protection by intracerebral injection or infusion of recombinant GDNF
The present drug treatment of Parkinson’s disease (PD) is based on the substitution of dopamine deficiency due to degeneration of nigrostriatal dopaminergic neurons. l-DOPA, dopamine agonists and MAO B inhibitors are currently the most effective symptomatic agents. Unfortunately, it is uncertain that they slow or delay the progression of disease. In recent years, considerable advances have been made in understanding the pathogenetic processes of neurodegeneration in PD and these advances may provide novel strategies for drug development. The main pathogenetic mechanisms include mitochondrial function deficiency, abnormal protein aggregation, increased oxidative stress, apoptosis, excitotoxicity and inflammation. Much effort is being focused on these processes to develop an agent or agents with neuroprotective properties. Coenzyme q10 and creatine may improve mitochondrial function and are under clinical testing. Many anti-excitotoxic agent are under preclinical and clinical development. Both NMDA and AMPA antagonists may in addition to putative neuroprotective effect have also symptomatic effect, particularly antidyskinetic action. Several anti-inflammatory agents have been tested both preclinically and clinically. These include both an antibiotic minocycline and COX inhibitors. No breakthrough has been so far achieved. Recently, a phase II/III trial with an antiapoptotic agent CEP-1347 showed negative results. Many other putative antiapoptotic agents have shown promising results in animal studies. A novel strategy is to design inhibitors of alpha-synuclein aggregation. Some effort is still exert on substances affecting dopamine system, e.g. safinamide, a MAO B inhibitor with many other mechanisms of action is in phase III trials. Some new dopamine agonists and dopamine uptake inhibitors are also