Rotigotine is a non-ergoline, high lipophilic dopamine agonist. It is indicated as the first-line therapy for Parkinson's disease (PD) and Restless Leg Syndrome (RLS). However, the precise mechanism of rotigotine is yet to be known. Rotigotine has similar safety and tolerability to the other oral non-ergolinic dopamine antagonists in clinical trials, which include nausea, dizziness and somnolence. Neupro® was the first marketed transdermal patch formulation having rotigotine. The transdermal delivery system is advantageous as it enables continuous administration of the drug, thus providing steady-state plasma drug concentration for 24-hours. Intranasal administration of rotigotine allows the drug to bypass the blood-brain barrier enabling it to reach the central nervous system within minutes. Rotigotine can also be formulated as an extended-release microsphere for injection. Some challenges remain in other routes of rotigotine administration such as oral, parenteral and pulmonary, whereby resolving these challenges will be beneficial to patients as they are less invasive and comfortable in terms of administration. This review compiles recent work on rotigotine delivery, challenges and its future perspective.
Alcohol consumption is a widespread behaviour that may eventually result in the development of alcohol use disorder (AUD). Alcohol, however, is rarely consumed in pure form but in fruit- or corn-derived preparations, like beer. These preparations add other compounds to the consumption, which may critically modify alcohol intake and AUD risk. We investigated the effects of hordenine, a barley-derived beer compound on alcohol use-related behaviours. We found that the dopamine D2 receptor agonist hordenine (50 mg/kg) limited ongoing alcohol consumption and prophylactically diminished relapse drinking after withdrawal in mice. Although not having reinforcing effects on its own, hordenine blocked the establishment of alcohol-induced conditioned place preference (CPP). However, it independently enhanced alcohol CPP retrieval. Hordenine had a dose-dependent inhibitory effect on locomotor activity. Chronic hordenine exposure enhanced monoamine tissue levels in many brain regions. Further characterization revealed monoaminergic binding sites of hordenine and found a strong binding on the serotonin and dopamine transporters, and dopamine D3 , and adrenergic α1A and α2A receptor activation but no effects on GABAA receptor or glycinergic signalling. These findings suggest that natural ingredients of beer, like hordenine, may work as an inhibitory and use-regulating factor by their modulation of monoaminergic signalling in the brain.
Brexpiprazole (OPC-34712) is a novel serotonin-dopamine activity modulator, which has recently been approved by the U.S Food and Drug Administration for the treatment of schizophrenia. The aim of this paper is to systematically synthesize all data of the efficacy, safety and tolerability of Brexpiprazole in treating schizophrenia. The terms 'Brexpiprazole', 'OPC-34712' and 'schizophrenia' were searched. A total of 12 clinical trials with 7 available data records were found. The pooled effect size of Brexpiprazole 1 mg, 2 mg and 4 mg were all superior to placebo in terms of the change from baseline in positive and negative syndrome scale (PANSS) total score at week 6 (weighted mean difference = -3.74, p = 0.044; weighted mean difference = -5.76, p
Macroprolactinoma has the potential to cause base of skull erosion and often extends into the sphenoid sinus. Rapid shrinkage of this invasive tumor following dopamine agonist therapy has been postulated to cause unplugging of the eroded area, leading to cerebrospinal fluid leakage. To the best of our knowledge, the occurrence of spontaneous cerebrospinal fluid leak in treatment-naive prolactinomas is very rare, the majority of which involve undiagnosed macroprolactinomas. We describe here a lady presented late with giant macroprolactinoma, complicated by cerebrospinal fluid leakage. This case raised the dilemma in the management pertaining to the role of either pharmacotherapy or surgical intervention, or combination of both. As she strictly refused surgery, she was treated with bromocriptine which was later changed to cabergoline. On follow-up, there was cessation of cerebrospinal fluid leak, marked reduction of serum prolactin level, and imaging evidence of tumor shrinkage. The majority of patients with medically induced cerebrospinal fluid leakage will require surgical procedures to overcome this complication; however, there are isolated cases of leakage resolution on continuing dopamine agonist therapy while awaiting surgery. The use of dopamine agonist does not necessarily cause worsening of cerebrospinal fluid leakage and instead may produce spontaneous resolution as in this case.
Ergot-derived dopamine D2 receptor agonists are the usual treatment of hyperprolactinemia and Parkinson's disease and recently bromocriptine has been approved for the treatment of type 2 diabetes. The aim of this study was the evaluation of short-term effect of cabergoline in poorly controlled diabetic patients with oral agent failure who refused insulin therapy.
There are limited data on the prevalence of impulsive-compulsive behaviors and subsyndromal impulsive-compulsive behaviors in Asian patients with Parkinson's disease, who are treated with lower dosages of dopaminergic medications.
Matched MeSH terms: Dopamine Agonists/therapeutic use
In earlier ex vivo studies, we reported the biphasic effect of a methanolic extract of unripe Morinda citrifolia fruit (MMC) on dopamine-induced contractility in isolated rat vas deferens preparations. The present in vivo study was designed and undertaken to further explore our earlier ex vivo findings. This study examined the effect of the ethyl acetate fraction of a methanolic extract of unripe Morinda citrifolia Linn. fruit (EA-MMC; 5-100 mg/kg, p.o.) on the dopaminergic system using mouse models of apomorphine-induced climbing time and climbing behavior, methamphetamine-induced stereotypy (sniffing, biting, gnawing, and licking) and haloperidol-induced catalepsy using the bar test. Acute treatment with EA-MMC at a low dose (25 mg/kg, p.o.) significantly attenuated the apomorphine-induced climbing time and climbing behavior in mice. Similarly, EA-MMC (5 and 10 mg/kg, p.o.) significantly inhibited methamphetamine-induced stereotyped behavior in mice. These results demonstrated that the antidopaminergic effect of EA-MMC was observed at relatively lower doses (<25 mg/kg, p.o.). On the other hand, EA-MMC showed dopaminergic agonistic activity at a high dose (3,000 mg/kg, p.o.), which was evident from alleviation of haloperidol (a dopamine D2 blocker)-induced catalepsy in mice. Therefore, it is concluded that EA-MMC might possess a biphasic effect on the dopaminergic system, i.e., an antagonistic effect at lower doses (<25 mg/kg, p.o.) and an agonistic effect at higher doses (>1,000 mg/kg, p.o.). However, further receptor-ligand binding assays are necessary to confirm the biphasic effects of M. citrifolia fruit on the dopaminergic system.
Thyrotoxicosis due to Graves disease is a relatively common endocrine disorder. The occurrence of a prolactinoma with co-secretion of growth hormone (GH) is on the other hand, rare. We report the rare co-existence of Graves' disease in a patient with macroprolactinoma and GH hypersecretion and describe the successful response to medical therapy with dopamine agonist and antithyroid therapy. We hypothesize that hyperprolactinaemia played a role in promoting autoimmune thyroid disease in our patient and that treatment of hyperprolactinaemia may have been important in suppressing autoimmune disease activity in Graves' disease. This case also reflects on the close and complex interactions between thyroid hormones, prolactin (PRL), GH and testosterone (T).
Matched MeSH terms: Dopamine Agonists/therapeutic use
Parkinson's disease (PD) is characterized by neurodegeneration and a progressive functional impairment of the midbrain nigral dopaminergic neurons. The cause remains unknown; however, several pathological processes and central factors, such as protein aggregation, mitochondrial dysfunction, iron accumulation, neuroinflammation and oxidative stress, have been reported. The current treatment method primarily targets symptoms by using anti-Parkinson drugs such as levodopa, carbidopa, dopamine (DA) agonists, monoamine oxidase type B inhibitors and anticholinergics to replace DA. When drug therapy is not satisfactory, surgical treatments are recommended. Unfortunately, the existing conventional strategies that target PD are associated with numerous side effects and possess an economic burden. Therefore, novel therapeutic approaches that regulate the pathways leading to neuronal death and dysfunction are necessary. For many years, nature has provided the primary resource for the discovery of potential therapeutic agents. Remarkably, many natural products from medicinal plants, fruits and vegetables have been demonstrated to be efficacious anti-Parkinson agents. These products possess neuroprotective properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding iron accumulation, protein misfolding and the maintenance of proteasomal degradation, as well as mitochondrial homeostasis. The aim of this review is to report the available anti-Parkinson agents based on natural products and delineate their therapeutic actions, which act on various pathways. Overall, this review emphasizes the types of natural products that are potential future resources in the treatment of PD as novel regimens or supplementary agents.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM).
Restless legs syndrome (RLS) is a common sensory motor neurological disorder that is characterised by an irresistible urge to move the legs that significantly affects the quality of life of the patient. Prevalence in the general population is 5-25% and it is twice as prevalent in women as in men. RLS is the most common movement disorder in pregnancy with a fourfold increased risk of developing this disorder later in life. The pathophysiology of RLS is centred on dopaminergic dysfunction, reduced central nervous system iron, genetic linkages, or alteration in neurotransmitters such as hypocretins, endorphins levels and immune dysfunction and inflammatory mechanisms. With the emergence of new evidence, there are changes to the previous treatment recommendations for RLS. There is sufficient evidence to conclude that dopamine agonists such as rotigotine transdermal patch, pramipexole, ropinirole, gabapentin enacarbil, pregabalin and gabapentin are effective in the short-term treatment of RLS and rotigotine, followed by gabapentin enacarbil, ropinirole, pramipexole and gabapentin for long-term treatment. Based on expert consensus, the recommendation for daily RLS is dopamine agonists or gabapentin or low-potency opioids. Levodopa is less preferred for treating daily RLS due to its high risk of augmentation. For intermittent RLS, it is levodopa or dopamine agonists or low-potency opioids or benzodiazepines. For refractory RLS, the choice is to change to gabapentin or a different dopamine agonist, addition of a second agent like gabapentin or benzodiazepine to the existing drug or changing to a high-potency opioid or tramadol. Medications with safety record in pregnancy include opioids and antiepileptics such as carbamazepine and gabapentin. There are concerns that patients with RLS are at risk for metabolic deregulation, autonomic dysfunction and cardiovascular morbidity. However, a recent study concluded that RLS is not associated with increased risk of cardiovascular complications.
Orexins (also called hypocretins) are implicated in reward and addiction, but little is known about their role(s) in the association between hippocampal synaptic plasticity and drug preference. Previously, we found that exogenous orexin via OX1 and OX2 receptors can impair low frequency stimulation-induced depotentiation, i.e. restoring potentiation of excitatory synaptic transmission (re-potentiation) in mouse hippocampal slices. Here, we found this re-potentiation in hippocampal slices from mice that had acquired conditioned place preference (CPP) to cocaine. Both 10 and 20 mg/kg of cocaine induced similar magnitudes of CPP in mice and re-potentiation in their hippocampal slices, but differed in their susceptibility to TCS1102, a dual (OX1 and OX2 ) orexin receptor antagonist. TCS1102 significantly attenuated CPP and hippocampal re-potentiation induced by cocaine at 10 mg/kg but not at 20 mg/kg. Nonetheless, SCH23390, an antagonist of dopamine D1-like receptors (D1-likeRs), inhibited the effects induced by both doses of cocaine. SKF38393, a D1-likeR-selective agonist, also induced hippocampal re-potentiation in vitro. Interestingly, this effect was attenuated by TCS1102. Conversely, SCH23390 prevented orexin A-induced hippocampal re-potentiation. These results suggest that endogenous orexins are released in mice during cocaine-CPP acquisition, which sustains potentiated hippocampal transmission via OX1 /OX2 receptors and may contribute to the addiction memory of cocaine. This effect of endogenous orexins, however, may be substituted by dopamine that may dominate hippocampal re-potentiation and CPP via D1-likeRs when the reinforcing effect of cocaine is high.