Dopamine Agonists In Patients Research Articles

0699 Longitudinal Assessment of Buprenorphine Effectiveness for Severe Restless Legs Syndrome and Dopaminergic Augmentation

Abstract Introduction Opioids are a consensus second-line treatment for moderate-to-severe restless legs syndrome (RLS). Due to its partial mu-opioid receptor agonist mechanism, buprenorphine (bup) has lower risk of respiratory depression, euphoria, and dependence than full-agonist opioids. We hypothesize that with long-term administration for severe RLS, bup is both effective and well-tolerated and can facilitate successful weaning off dopamine agonists (DA) for patients with augmentation. Methods We conducted a longitudinal examination of a retrospective cohort of patients prescribed bup over a 21-month period by a tertiary RLS specialist. Patient-reported outcomes were administered through patient-completed electronic health record-based questionnaires or by clinician interview: International RLS Study Group(IRLS-SG,primary outcome), Clinical Global Impressions of Improvement(CGI-I), Epworth Sleepiness Scale(ESS), Insomnia Severity Index(ISI), Patient Health Questionnaire(PHQ-9), and Patient-Reported Outcomes Measurement Information System-Sleep Disturbance domain(PROMIS-SD). A linear mixed model assuming compound symmetry correlation structure was used (least square means,95%CI) to test the change from baseline to 6-week, 3-month, 6-month, and 1-year intervals, and the final visit, irrespective of time from baseline, with adjustment of age, sex, other RLS meds at final visit, and administration of iron infusion. Results 55 patients (56.4% female, 64.9±12.1 years) started bup for RLS, and 42(76.3%) remained on bup at the final visit. IRLS-SG was 27.8(25.3,30.3) at baseline and was significantly reduced at every interval (p of trend < 0.001), including 11.4(7.4,15.4) at 1 year. Of the 39(70.9%) patients that were on a DA with augmentation at baseline, 32(82.1%) had discontinued DAs with 5(12.8%) on a reduced dose at the final visit. Of those remaining on bup at the final visit, 93.8% were CGI-I responders, There was a statistically significant longitudinal trend in 1-year improvement in ESS:9.9(8.0,11.8) to 6.9(4.5,9.4),p=0.003, ISI:18.0(15.9,20.1) to 15.0(11.6,18.3),p=0.048, PHQ-9:10.4(8.2,12.5) to 6.1(3.6,8.6),p< 0.001, and PROMIS-SD:63.0(60.2,65.7) to 53.8(49.8,57.8),p< 0.001. 13(23.6%) discontinued bup with nausea, cognitive complaints, and dizziness as the most common side effects. Conclusion In this largest cohort to date to examine buprenorphine in severe RLS, our findings show buprenorphine markedly reduced RLS symptoms, effectively enabled the elimination of dopamine agonists in patients with augmentation, improved sleep and other health quality measures, and was tolerated comparably to other RLS medications. Support (if any)

Dose Optimization of Apomorphine Sublingual Film for OFF Episodes in Parkinson's Disease: Is the Prophylactic Use of an Antiemetic Necessary?

Nausea is common upon initiating dopamine agonists in patients with Parkinson's disease (PD); however, pretreatment with an antiemetic is recommended only when initiating apomorphine formulations. Evaluate the need for prophylactic antiemetic use during dose optimization of apomorphine sublingual film (SL-APO). A post hoc analysis of a Phase III study evaluated nausea and vomiting treatment-emergent adverse events in patients with PD who underwent SL-APO dose optimization (10-35 mg; 5-mg increments) to achieve a tolerable FULL ON. Frequencies of nausea and vomiting were described for patients who did versus did not use an antiemetic during dose optimization and by patient subgroups based on extrinsic and intrinsic factors. Overall, 43.7% (196/449) of patients did not use an antiemetic during dose optimization; most of these patients (86.2% [169/196]) achieved an effective and tolerable SL-APO dose. In patients who did not use an antiemetic, nausea (12.2% [24/196]) and vomiting (0.5% [1/196]) were uncommon. An antiemetic was used in 56.3% (253/449) of patients, with 17.0% (43/253) and 2.4% (6/253) experiencing nausea and vomiting, respectively. All events of nausea (14.9% [67/449]) and vomiting (1.6% [7/449]) were of mild-to-moderate severity except for 1 event each. Irrespective of antiemetic use, among patients without baseline dopamine agonist use, nausea and vomiting rates were 25.2% (40/159) and 3.8% (6/159); in those already using dopamine agonists, rates were 9.3% (27/290) and 0.3% (1/290). Prophylactic treatment with an antiemetic is not necessary for most patients who initiate SL-APO for the treatment of OFF episodes in PD.

Prolactinoma and pregnancy: a review article

Prolactinomas usually lead to infertility and medical treatment restores fertility. Prolactinoma size might increase during pregnancy (2.1% for microprolactinomas and 21% for macroprolactinomas). In this review article, multiple aspects of prolactinomas care during and before pregnancy were discussed. Dopamine agonists are the treatment of choice, if indicated during pregnancy (cabergoline and bromocriptine, while quinagolide is not recommended). It is recommended to stop dopamine agonists in patients with microprolactinoma during pregnancy and follow the patients for mass effect symptoms and visual disturbances every trimester. Dopamine agonists could be stopped as well in a patient with intra-seller macroprolactinomas with more frequent clinical follow ups during pregnancy. Magnetic resonance imaging without contrast is indicated for patients suspected to have tumor enlargement. Dopamine agonists (cabergoline or bromocriptine) are the treatment of choice for invasive/metastatic macroprolactinomas during pregnancy, and neurosurgery is rarely indicated.

Dopamine-induced changes to thalamic GABA concentration in impulsive Parkinson disease patients

Impulsivity is inherent to behavioral disorders such as substance abuse and binge eating. While the role of dopamine in impulse behavior is well established, γ-aminobutyric acid (GABA) therapies have promise for the treatment of maladaptive behaviors. In Parkinson disease (PD), dopaminergic therapies can result in the development of impulsive and compulsive behaviors, and this clinical syndrome shares similar pathophysiology to that seen in addiction, substance abuse, and binge-eating disorders. We hypothesized that impulsive PD patients have a reduced thalamic GABAergic response to dopamine therapy. To test this hypothesis, we employed GABA magnetic resonance spectroscopy, D2-like receptor PET imaging, and clinical and quantitative measures of impulsivity in PD patients (n = 33), before and after dopamine agonist administration. We find a blunted thalamic GABA response to dopamine agonists in patients with elevated impulsivity (p = 0.027). These results emphasize how dopamine treatment differentially augments thalamic GABA concentrations, which may modify behavioral impulsivity.

Impulse control disorders, dopamine dysregulation syndrome and sex dysfunction in Parkinson's disease.

Hypersexuality (HS), characterized by an aberrant, compulsive and inappropriate sexual drive, is an underreported and undermanaged complication of the treatment with dopamine agonists in patients with Parkinson's disease (PD). HS is part of the spectrum of impulse control disorders (ICDs). The failure to control these addictive behaviors is distressing for the patient and it is associated with important consequences. Reports of the prevalence of HS showed different results, due to the lack of standardized diagnostic criteria, but also due to the embarrassment or guilt feelings that patients experience regarding their sexual behaviors. Overall, it is considered that HS may occur in 1.92-22.8% of PD patients and the main risk factors involved could be male sex and genetic susceptibility. The pathophysiology of HS is unknown, but several degenerative mechanisms were proposed, involving dopaminergic, serotoninergic and noradrenergic pathways in cerebral regions responsive for planning and rewarding. There are no standardized tools for the assessment of HS in PD patients; however, several scales and questionnaires were developed with the aim of screening and rating the severity of ICDs, including HS. The management of HS is challenging. Discontinuation or reducing the dopaminergic treatment was effective in some cases, but it might lead to worsening of the motor function. A multidisciplinary approach is mandatory to manage the other associated aspects, such as psychological and social consequences of HS.

The Vanishing Pituitary Tumor: A Case Report

Prolactinomas are the most common functional pituitary tumors and present with elevated serum prolactin levels. This may or may not be accompanied by mass-related clinical symptoms. Dopamine agonists are its principal treatment. Data on prolactinoma remission and relapse after treatment withdrawal are limited. Here we report a patient presenting with headache, amenorrhea, galactorrhea, visual field impairments and a high serum prolactin level. After a definitive diagnosis of pituitary macroadenoma, the patient was treated with bromocriptine. Twelve months after treatment, tumor size markedly reduced, there was resolution of symptoms and patient was eventually lost to follow-up. After 10 months without treatment, tumor recurred. Bromocriptine was resumed for 5 more years and discontinued thereafter. Since then, the patient has been asymptomatic for the past 12 years; surveillance imaging showed no tumor recurrence with annual prolactin level all within normal range. This case adds to the limited data confirming that dopamine agonists in patients with prolactinomas can be successfully discontinued with a high remission rate, provided that there is adequate duration of treatment and sufficient follow-up. J Endocrinol Metab. 2021;11(3-4):91-93 doi: https://doi.org/10.14740/jem753

The Interplay Between Prolactin and Reproductive System: Focus on Uterine Pathophysiology.

Over the last years, increasing evidence has focused on crucial pathogenetic role of PRL on malignant, premalignant and benign uterine diseases. Studies in animals and humans have documented that PRL receptors (PRL-Rs) are widely expressed on uterine cells and that PRL is directly synthesized by the endometrium under the stimulatory action of progesterone. Uterine PRL secretion is finely modulated by autocrine/paracrine mechanisms which do not depend on the same control factors implied in the regulation of PRL secretion from pituitary. On the other hand, PRL is synthesized also in the myometrium and directly promotes uterine smooth muscle cell growth and proliferation. Therefore, PRL and PRL-Rs appear to play an important role for the activation of signaling pathways involved in uterine cancers and preneoplastic lesions. Circulating PRL levels are reportedly increased in patients with cervical or endometrial cancers, as well as uterine premalignant lesions, and might be used as discriminative biomarker in patients with uterine cancers. Similarly, increased PRL levels have been implicated in the endometriosis-induced infertility, albeit a clear a causative role for PRL in the pathogenesis of endometriosis is yet to be demonstrated. This evidence has suggested the potential application of dopamine agonists in the therapeutic algorithm of women with malignant, premalignant and benign uterine lesions. This review focuses on the role of PRL as tumorigenic factor for uterus and the outcome of medical treatment with dopamine agonists in patients with malignant and benign uterine disease.

Efficacy and safety of dopamine agonists in patients treated with antipsychotics and presenting a macroprolactinoma.

In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge. Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics. This was a multicenter (France and Belgium) retrospective study. Eighteen patients treated with antipsychotics were included. Under DA, median PRL levels decreased from 1247 (117-81 132) to 42 (4-573) ng/mL (P = 0.008), from 3850 (449-38 000) to 141 (60-6000) ng/mL (P = 0.037) and from 1664 (94-9400) to 1215 (48-5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0-57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions. Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.

Modalities to overcome resistance to dopamine agonists in patients with macroprolactinomas

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Metabolic effects of dopamine agonists in patients with prolactinomas: a systematic review and meta-analysis.

ObjectivesRecent large cohort studies suggest an association between high plasma prolactin and cardiovascular mortality. The objective of this systematic review was to systematically assess the effect of reducing prolactin with dopamine agonist on established cardiovascular risk factors in patients with prolactinomas.DesignBibliographical search was done until February 2019 searching the following databases: PubMed, EMBASE, WHO and LILAC. Eligible studies had to include participants with verified prolactinomas where metabolic variables were assessed before and after at least 2 weeks treatment with dopamine agonists.MethodsBaseline data and outcomes were independently collected by two investigators. The study was registered with PROSPERO (registration number CRD42016046525).ResultsFourteen observational studies enrolling 387 participants were included. The pooled standardized mean difference of the primary outcome revealed a reduction of BMI and weight of −0.21 (95% CI −0.37 to −0.05; P = 0.01; I2 = 71%), after treatment. Subgroup analysis suggested that the reduction of weight was primarily driven by studies with high prolactin levels at baseline (P = 0.04). Secondary outcomes suggested a small decrease in waist circumference, a small-to-moderate decrease in triglycerides, fasting glucose levels, HOMA-IR, HbA1c and hsCRP, and a moderate decrease in LDL, total cholesterol and insulin.ConclusionThis systematic review suggests a reduction of weight as well as an improved lipid profile and glucose tolerance after treatment with dopamine agonist in patients with prolactinomas. These data are based on low-quality evidence.

Successful Treatment of Acromegaly and Associated Hypogonadism with First-Line Clomiphene Therapy

Clomiphene citrate (CC) has been reported as an effective add-on therapy to somatostatin analogs and dopamine agonists in patients with acromegaly accompanied by hypogonadism; its use as a single agent to treat acromegaly and associated hypogonadism following incomplete surgery has not been previously reported. We report the first case in which clomiphene was utilized as a single agent for the dual management of acromegaly and hypogonadism, not controlled by pituitary surgery alone. The treatment was well tolerated and proved to be effective after a process of treatment withdrawal and reintroduction. We propose that clomiphene may be considered as a cost-effective oral treatment option in select cases of hypogonadal acromegaly.

Medications Used for Cognitive Enhancement in Patients With Schizophrenia, Bipolar Disorder, Alzheimer's Disease, and Parkinson's Disease.

Cognitive impairment, which frequently occurs in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease, has a significant impact on the daily lives of both patients and their family. Furthermore, since the medications used for cognitive enhancement have limited efficacy, the issue of cognitive enhancement still remains a clinically unsolved challenge. We reviewed the clinical studies (published between 2007 and 2017) that focused on the efficacy of medications used for enhancing cognition in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease. Acetylcholinesterase inhibitors and memantine are the standard treatments for Alzheimer's disease and Parkinson's disease. Some studies have reported selective cognitive improvement in patients with schizophrenia following galantamine treatment. Newer antipsychotics, including paliperidone, lurasidone, aripiprazole, ziprasidone, and BL-1020, have also been reported to exert cognitive benefits in patients with schizophrenia. Dopaminergic medications were found to improve language function in patients with Parkinson's disease. However, no beneficial effects on cognitive function were observed with dopamine agonists in patients with schizophrenia. The efficacies of nicotine and its receptor modulators in cognitive improvement remain controversial, with the majority of studies showing that varenicline significantly improved the cognitive function in schizophrenic patients. Several studies have reported that N-methyl-d-aspartate glutamate receptor (NMDAR) enhancers improved the cognitive function in patients with chronic schizophrenia. NMDAR enhancers might also have cognitive benefits in patients with Alzheimer's disease or Parkinson's disease. Raloxifene, a selective estrogen receptor modulator, has also been demonstrated to have beneficial effects on attention, processing speed, and memory in female patients with schizophrenia. Clinical trials with larger sample sizes evaluating comprehensive cognitive domains are warranted to examine the efficacy of medications in cognitive enhancement in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease.

Management of prolactinomas: a survey of physicians from the Middle East and North Africa

Prolactinomas are the commonest functional tumors of the pituitary gland. There are still controversies regarding medical therapy in specific clinical situations. Patients may be managed by different specialists in the Middle East and North Africa (MENA) region and no data exist on patterns of clinical management. To ascertain the diagnostic and therapeutic approaches to prolactinomas among relevant professionals from the MENA region. An online survey of a large sample of physicians was conducted. The questionnaire covered various aspects of diagnosis and treatment of prolactinomas. 468 respondents were included; 36% were endocrinologists; 49% worked in public facilities and 81% graduated more than 10years. 40 and 30% would have seen 1-5 and more than 5 suspected or confirmed prolactinomas over a 6months period, respectively. Regarding the diagnosis, 30% of the respondents considered that prolactin levels <100ng/ml exclude the presence of a prolactinoma. 21% of respondents considered prolactin levels >250ng/ml compatible with macroprolactinomas only, whereas others accepted this to be compatible also with microprolactinomas, macroprolactinaemia and drug-induced hyperprolactinemia (50, 42 and 36% respectively). 71% of respondents favored the screening for macroprolactin in asymptomatic individuals with hyperprolactinemia. Regarding the treatment, 84% of respondents would treat microprolactinomas even in the absence of symptoms whereas 72% of the respondents would treat microprolactinomas only if symptoms exist. 60 and 49% of the respondents chose cabergoline as the drug of choice to treat macroprolactinomas and microprolactinomas respectively. Similar proportions had no preference of either cabergoline or bromocriptine as the best treatment for macroprolactinoma (27%) and microprolactinomas (32%). 46 and 75% of respondents favored treatment withdrawal 2-3years after prolactin normalization in patients with macroprolactinomas and microprolactinomas, respectively whereas 10% of respondents withdraw treatment after menopause in either case. 94% of respondents considered medical therapy as the primary treatment for microprolactinomas. In case of pregnancy, 49% considered bromocriptine as the drug of choice for women who wish to become pregnant. 65 and 38% of respondents advocated discontinuation of treatment with dopamine agonists in patients with microprolactinomas and macroprolactinomas, respectively. Finally, 48% would allow breast-feeding without restriction, 28% would restrict it to patients with microprolactinomas and 25% would not recommend it for women with prolactinomas. This is the first study of the clinical management of prolactinomas in the MENA region. Some of the practices are not in line with the latest Endocrine and Pituitary Societies guidelines. These warrant further discussions of contemporary guidelines in regional forums.

Combination of Exercise Training and Dopamine Agonists in Patients with RLS on Dialysis: A Randomized, Double-Blind Placebo-Controlled Study.

Both exercise training and treatment with dopamine agonists (DA) have been used with success for the amelioration of uremic restless legs syndrome (RLS) symptoms. However, no data are available combining those two approaches. The aim of the current randomized, double-blind, placebo-controlled study was to investigate the effects of a 6 month intradialytic exercise training in combination with a low dose of DA in patients suffering from uremic RLS symptoms. Fourteen stable patients with RLS on hemodialysis were randomly assigned to the exercise training plus DA group and the exercise training plus placebo group. Both combinations were found to equally reduce uremic RLS symptoms by approximately 60%. The combination of low dose of DA with aerobic exercise training could be considered an alternative approach to high DA dosage regimes in reducing RLS symptoms' severity.

A long-term echocardiographic study of the course of valvular dysfunctions following discontinuation of ergot-derived dopamine agonists in patients with Parkinson's disease

BackgroundAn increased risk of restrictive valvular heart disease (VHD) has been widely reported in patients with Parkinson's disease (PD), as a possible consequence of the chronic use of ergot-derived dopamine agonists (EDA), such as pergolide and cabergoline. An aspect that remains poorly investigated is the extent of reversibility of the valvular dysfunction after drug discontinuation. MethodsFifteen patients with PD (8 male and 7 female) on chronic treatment with pergolide or cabergoline in which a cardiac mono or multivalvular fibrosis with or without regurgitation was detected on echocardiographic examination were enrolled in the study from March to December 2007. Because of this the EDA were discontinued and replaced by a non-EDA or l-dopa. A second echocardiography has been performed after a median duration of follow-up of 54months in order to assess the course of valvular abnormalities i.e. regurgitation, thickening of mitral valve anterior leaflet (MAL) and mitral valve tenting area. ResultsAt the follow-up echocardiographic assessment a complete regression of MAL thickening in 7 out of 13 patients and of the aortic fibrosis in 7 out 10 patients was observed. A statistically significant improvement of mitral and tricuspid valve regurgitation score, sum of regurgitations, thickening of MAL and mitral valve tenting area was found. None of the patients showed a worsening of VHD after drug withdrawal. ConclusionsThis long-term study confirms an improvement of the restrictive VHD after withdrawal of EDA in PD patients. However, only a partial reversibility of cardiac valvular abnormalities was observed.

Effect of exercise training and dopamine agonists in patients with uremic restless legs syndrome: a six-month randomized, partially double-blind, placebo-controlled comparative study

BackgroundRestless Legs Syndrome is very common in hemodialysis patients however there are no comparative studies assessing the effectiveness of a non-pharmacological treatment to a classical treatment on parameters related to syndromes’ severity and quality of life.MethodsIn this randomized, partially double blind, placebo controlled trial, thirty two hemodialysis patients with restless legs syndrome were randomly assigned into three groups: 1) the exercise training group (N = 16), 2) the dopamine agonists group (ropinirole 0.25 mg/d) (N = 8) and 3) the placebo group (N = 8). The intervention programs lasted 6 months. Restless Legs Syndrome severity was assessed using the international severity scale, physical performance by a battery of tests, muscle size and composition by computed tomography, body composition by Dual Energy X Ray Absorptiometry, while depression score, sleep quality, daily sleepiness and quality of life were assessed through questionnaires.ResultsExercise training and dopamine agonists were effective in reducing syndrome’s symptoms by 46% (P = 0.009) and 54% (P = 0.001) respectively. Within group changes revealed that both approaches significantly improved quality of life (P < 0.05), however, only the dopamine agonists significantly improved sleep quality (P = 0.009). Within group changes showed a tendency for lean body mass improvements with dopamine agonists, this reached statistical significance only with the exercise training (P = 0.014), which also reduced fat infiltration in muscles (P = 0.044) and improved physical performance (P > 0.05) in various tests. Between group changes detect significant improvements with both exercise and dopamine agonists in depression score (P = 0.003), while only the dopamine agonist treatment was able to significantly improve sleep quality, compared to exercise and placebo (P = 0.016).ConclusionsA 6-month exercise training regime was as effective as a 6-month low dosage dopamine agonist treatment in reducing restless legs syndrome symptoms and improving depression score in uremic patients. Further research is needed in order to show whether a combination treatment could be more beneficial for the amelioration of RLS.Trial registrationNCT00942253

The effect of the ANKK1/DRD2 Taq1A polymorphism on weight changes of dopaminergic treatment in prolactinomas

Treatment with dopamine agonists in patients with prolactinomas has been associated with weight loss in short term studies. However, long-term studies on weight changes are lacking. Taq1A is a restriction fragment length polymorphism considered as a gene marker for the DRD2 gene. The presence of at least one A1 allele is linked to reduced brain dopaminergic activity due to reduced receptor binding and lower density of the dopamine 2 receptor. We aimed at testing the hypothesis that the dopaminergic treatment in prolactinoma patients leads to sustained weight loss and that the presence of diminished weight loss response under dopamine agonists is associated with the minor A1 allele of Taq1A.We included n=44 patients (17 male and 27 female, 26 macroadenomas and 18 microadenomas) with prolactinomas treated with dopamine agonists. Outcome measures were weight and body mass index (BMI) change under dopaminergic treatment after 2years with regard to Taq1A status and sex. We observed that the dopaminergic treatment leads to a significant mean weight loss of 3.1±6.25kg after 2years. Regarding Taq1A polymorphisms, 21 patients were carriers of at least one A1 allele and 23 patients had a genotype of A2/A2. However, the presence of the A1 allele was neither associated with the mean BMI at baseline nor with an altered weight loss response under dopamine agonist therapy. Our results implicate that the dopaminergic treatment leads to a sustained weight loss in patients with prolactinomas after 2years. However, there was no association to the A1 allele of Taq1A, observation that needs to be analysed in larger cohorts.

Cardiac effects of hyperprolactinemiatherapy withdopamine agonists

A number of publications of the 1990s found an association between the development of disease of the heart valves and the use of dopamine agonists in patients receiving treatment for Parkinson’s disease. Therefore, it became necessary to investigate the possible risks of valve disease in patients with hyperprolactinemia receiving treatment with dopamine agonists, in order to improve the recommendations.

Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas

Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood-brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene. We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case-control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy. i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood-brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found. This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

Dopaminergika-induziertes Pathologisches Glücksspiel

Problems with impulse control and pathological gambling are known as possible side effects of dopaminergic therapy in patients with Parkinson's disease. We report 2 cases of pathological gambling induced by dopamine agonists in patients without Parkinson's disease. The first patient, a 46-year-old man, was treated with ropinirole for restless legs syndrome and had lost huge amounts of money in the context of internet-based poker game. Another 46-year-old male patient developed pathological gambling under treatment with cabergoline administered for prolactinoma. The two cases implicate pathological gambling as a possible consequence of dopaminergic treatment and support the increasing evidence regarding pathological gambling as an adverse drug reaction of dopaminergic treatment, also in patients who do not suffer from Parkinson's disease.