ergoline and Mental-Disorders

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann's discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer's and Parkinson's disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward "green" syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Topics: Amides; Animals; Chemistry Techniques, Synthetic; Chemistry, Pharmaceutical; Dopamine Agonists; Ergolines; Ergot Alkaloids; Green Chemistry Technology; Hallucinogens; Heterocyclic Compounds, 4 or More Rings; History, 20th Century; History, 21st Century; Humans; Lysergic Acid Diethylamide; Mental Disorders

Dopamine agonists have been associated with increased risk of cardiac valve regurgitation in patients with Parkinson's disease. Whether these drugs might be harmful for patients with hyperprolactinemia is still unsettled. Occasional case reports and 7 studies on the relationship between cabergoline and cardiac valve regurgitation have been published so far. Overall, cabergoline has been considered a safe therapy, although some studies suggested an increased prevalence of cardiac valve regurgitation. The aim of this meta-analysis was to assess the effects of cabergoline on cardiac valve regurgitation. Eligible studies were all trials using cabergoline in patients with either tumor or non-tumor hyperprolactinemia. Our search was updated to October 2008. Pooled data from the 6 selected studies showed that treatment with cabergoline was associated with increased risk of tricuspid valve regurgitation (fixed effects: prevalence ratio=1.40; 95% confidence interval: 1.17-1.67); on the contrary, patients treated with cabergoline and control subjects did not differ in prevalence of aortic or mitral valve regurgitation. This meta-analysis shows that patients with hyperprolactinemia treated with cabergoline are at increased risk of regurgitation of the tricuspid valve. However, regurgitation was only an echocardiographic finding since no patient had symptoms of valvular disease. This meta-analysis underscores that echocardiography is recommended in all patients with hyperprolactinemia who are candidate to be treated with or are under cabergoline therapy; monitoring cardiac valves is also recommended although precise follow- up for these patients will be likely provided by future longitudinal studies.

Topics: Aortic Valve; Cabergoline; Dopamine Agonists; Ergolines; Heart Valve Diseases; Humans; Hyperprolactinemia; Mental Disorders; Mitral Valve; Risk Factors; Tricuspid Valve

We present a PD patient in whom dopamine agonists awoke a hidden creativity that led to a gradual increase in painting productivity evolving to a disruptive impulsive behaviour that shared many features with punding. A dramatic change in painting style related to a more emotional experience during the process of creation developed after treatment onset. This case suggests that changes in creativity in PD seem to be related to dopaminergic imbalance in the limbic system.

Topics: Antiparkinson Agents; Arm; Art; Benzothiazoles; Brain; Cabergoline; Creativity; Depressive Disorder; Dopamine; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Male; Mental Disorders; Middle Aged; Motor Skills; Obsessive Behavior; Paintings; Parkinson Disease; Pramipexole

The classical neurotransmitters serotonin and dopamine are thought to be involved in the etiology or treatment of a variety of psychiatric disorders. Recent studies suggest that these neurotransmitters may also have roles as neural morphogens during brain development. Previously, we have demonstrated that stimulation of serotonin 5-HT1A receptors selectively inhibited neurite branching in an in vitro system (Sikich et al 1990). In the present study, the developmental role of dopamine D2 receptors in the control of neurite outgrowth has been investigated by quantitating the morphological response of cortical neurons to agonist stimulation in vitro. Cultures of fetal rat frontal, cortical neurons were shown to express both alternatively spliced forms of D2 receptor messenger RNA (mRNA). The larger mRNA form predominated (D2A444:D2A415 ratio of about 6:1). In a small but significant percentage of these neurons, culture in the presence of the D2 receptor selective agonist, quinpirole, resulted in a three-to ten-fold increase in the length of neurites and in the number of branch points per neurite. These effects were blocked by the D2 receptor antagonists eticlopride and spiperone. Early abnormalities in the stimulation of dopamine or serotonin receptor subtypes could lead to the types of neuroanatomical changes observed in studies of schizophrenia, bipolar affective disorder, and autism. These morphogenic effects of classical transmitters could unite neurodevelopmental and neurotransmitter theories of the etiology of severe psychiatric disorders.

Topics: Animals; Base Sequence; Brain; Cells, Cultured; Cerebral Cortex; Ergolines; Female; Male; Mental Disorders; Models, Biological; Molecular Sequence Data; Nerve Growth Factors; Neurites; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Serotonin; RNA, Messenger; Salicylamides; Spiperone

28 patients with Parkinson's disease showing complex "on-off" fluctuations in response to chronic levodopa plus dopa decarboxylase inhibitor (po) were treated with subcutaneous lisuride using a portable infusion pump. All patients improved initially during the first weeks of treatment. Four patients abandoned the trial within the first few weeks as a consequence of psychiatric complications (2 cases), inability to understand how to use the pump (one case) and subcutaneous nodule formation plus psychological rejections to wearing a pump (one case). All other 24 patients were treated for a minimum periods of 3 months (mean 9.6 months, maximum 24 months). The average daily dose of lisuride was 2.80 mg. The levodopa dose was reduced by 37%, but total withdrawal was not possible in any patient. Among the 18 patients who continued treatment at present, about 50% are independent and capable of undertaking most daily life activities. Psychiatric side-effects were present in 9 patients leading to permanent withdrawal in five. Subcutaneous lisuride infusions added to oral levodopa are clearly effective in patients with severe motor fluctuations. Careful selection of suitable patients and close monitoring is mandatory in order to obtain the best therapeutic results while reducing the risk of psychiatric adverse effects.

Topics: Drug Eruptions; Dyskinesia, Drug-Induced; Equipment Failure; Ergolines; Female; Humans; Infusion Pumps; Injections, Subcutaneous; Lisuride; Male; Mental Disorders; Movement; Movement Disorders; Parkinson Disease; Platelet Aggregation

Thirteen patients with idiopathic Parkinson's disease and "on-off" fluctuations on oral levodopa plus dopa decarboxylase inhibitor (DDI) were treated with continuous (24 hour) subcutaneous lisuride infusions together with a reduced dose of levodopa (plus DDI). An improvement in motor performance was seen in 10 patients, with a mean increase in percentage of waking time spent "on" of 32 per cent (range 13-59 percent). However, adverse effects were common, especially psychiatric effects, leading to treatment withdrawal in 11 of 13 subjects after a mean of 40 days' treatment. Continuous lisuride infusion together with a small dose of levodopa (plus DDI) are effective treatment for "on-off" fluctuations in Parkinson's disease, but the frequency of adverse effects limits the number of patients who can be treated successfully with this technique.

Topics: Adult; Aged; Drug Eruptions; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Hypotension; Infusion Pumps; Lisuride; Male; Mental Disorders; Middle Aged; Movement; Parkinson Disease

Four patients with Parkinson's disease and severe fluctuating responses to levodopa and oral dopamine agonists were treated with continuous administration of lisuride infusions, administered by means of an externally worn pump. Levodopa dosage ranged from 300 to 687 mg/day and was kept stable throughout the study. In addition increasing doses of lisuride were injected subcutaneously in the abdomen. Lisuride doses ranged from 41 to 104 micrograms/h. A marked improvement in mobility was observed in every patient while severe biphasic dyskinesais almost remitted in one of them. The most common side-effect was the presence of subcutaneous nodules appearing at the injection site. Two cases had mild hemorrhagic complications and one initially had nausea. One patient developed acute psychiatric disturbances severe enough to be excluded from the study. Our findings suggest that lisuride subcutaneous infusions can be useful in severily handicapped parkinsonian patients, however local and psychiatric side-effects may be a serious threat in the long-term care.

Topics: Aged; Drug Eruptions; Drug Therapy, Combination; Ergolines; Female; Hematoma; Humans; Infusion Pumps; Levodopa; Lisuride; Male; Mental Disorders; Middle Aged; Movement Disorders; Parkinson Disease

Two patients, ages 66 and 72, with complications of chronic levodopa therapy (random fluctuations, end of dose deterioration and dyskinesias) who were treated with Lisuride by means of a portable subcutaneous infusion pump are reported. Results obtained show significant improvement in disability through a net increase in the number of hours spent "on". Dyskinesias remained unmodified. Limiting psychiatric side effects were observed in one of the patients. Practical and technical aspects of the management of this therapeutic method are discussed.

Topics: Aged; Drug Administration Schedule; Drug Eruptions; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Humans; Levodopa; Lisuride; Mental Disorders; Parkinson Disease

On-off fluctuations in longstanding Parkinson's disease initially respond well to a combined drug regime of Levodopa with direct dopamine agonists and L-deprenyl. L-Dopa infusions are efficient, but not applicable for longer use. S.c.-Lisuride-infusions reduce markedly motor-response fluctuations, dystonias and hyperkinesias, but bear the risk of inducing confusion or even psychosis. In patients with coexisting response fluctuations and psychiatric disturbances a therapeutic approach is outlined to preserve still some favourable effects on motor performance avoiding severe psychosis. Side-effects and possible complications of that therapy are discussed as are some further indications for the clinical use of Lisuride in akinetic crisis, the neuroleptic malignant syndrome and in dyskinesias.

Topics: Aged; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Infusion Pumps; Lisuride; Male; Mental Disorders; Middle Aged; Movement; Parkinson Disease

Topics: Antiparkinson Agents; Domperidone; Ergolines; Humans; Levodopa; Mental Disorders; Parkinson Disease; Parkinson Disease, Postencephalitic; Pergolide

Topics: Adult; Aged; Ergolines; Female; Humans; Hypotension; Lisuride; Male; Mental Disorders; Middle Aged; Nausea; Parkinson Disease; Sleep Wake Disorders; Vertigo; Vomiting

Topics: Aged; Bromocriptine; Cognition Disorders; Confusion; Dose-Response Relationship, Drug; Electroencephalography; Ergolines; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Personality Disorders; Psychoses, Substance-Induced; Schizophrenia

Topics: Aged; Bromocriptine; Confusion; Depression; Ergolines; Female; Hallucinations; Humans; Male; Mental Disorders; Middle Aged; Neurocognitive Disorders; Parkinson Disease; Schizophrenia, Paranoid

Topics: Cerebral Cortex; Electroencephalography; Epilepsy; Ergolines; Humans; Mental Disorders; Nicergoline