Pemphigus Vulgaris Successfully Treated With Bromocriptine.

Pemphigus vulgaris (PV) is an autoimmune blistering skin condition primarily treated with immunosuppressive agents. We describe a case of PV successfully treated with nonconventional treatment, bromocriptine mesylate. Bromocriptine has been used in human trials showing beneficial therapeutic effects in managing autoimmune conditions. The results from experimental trials and the low toxicity of bromocriptine in comparison with immunosuppressive agents form a solid rationale for investigating its role in controlling PV.  J Drugs Dermatol. 2024;23(3):     doi:10.36849/JDD.7720e.

Biomarkers in Peripartum Cardiomyopathy-What We Know and What Is Still to Be Found.

Peripartum cardiomyopathy (PPCM) is a form of heart failure, often severe, that occurs in previously healthy women at the end of their pregnancy or in the first few months after delivery. In PPCM, the recovery of heart function reaches 45-50%. However, the all-cause mortality in long-term observation remains high, reaching 20% irrespective of recovery status. The incidence of PPCM is increasing globally; therefore, effort is required to clarify the pathophysiological background of the disease, as well as to discover specific diagnostic and prognostic biomarkers. The etiology of the disease remains unclear, including oxidative stress; inflammation; hormonal disturbances; endothelial, microcirculatory, cardiomyocyte and extracellular matrix dysfunction; fibrosis; and genetic mutations. Currently, antiangiogenic 16-kDa prolactin (PRL), cleaved from standard 23-kDa PRL in the case of unbalanced oxidative stress, is recognized as the main trigger of the disease. In addition, 16-kDa PRL causes damage to cardiomyocytes, acting via microRNA-146a secreted from endothelial cells as a cause of the NF-κß pathway. Bromocriptine, which inhibits the secretion of PRL from the pituitary gland, is now the only specific treatment for PPCM. Many different phenotypes of the disease, as well as cases of non-responders to bromocriptine treatment, indicate other pathophysiological pathways that need further investigation. Biomarkers in PPCM are not well established. There is a deficiency in specific diagnostic biomarkers. Pro-brain-type natriuretic peptide (BNP) and N-terminal BNP are the best, however unspecific, diagnostic biomarkers of heart failure at the moment. Therefore, more efforts should be engaged in investigating more specific biomolecules of a diagnostic and prognostic manner such as 16-kDa PRL, galectin-3, myeloperoxidase, or soluble Fms-like tyrosine kinase-1/placental growth factor ratio. In this review, we present the current state of knowledge and future directions of exploring PPCM pathophysiology, including microRNA and heat shock proteins, which may improve diagnosis, treatment monitoring, and the development of specific treatment strategies, and consequently improve patients' prognosis and outcome.

Characterization of Leptin Secretion in Premenopausal Obese Women Treated with Bromocriptine.

Leptin, a hormone secreted by adipose tissue, is primarily responsible for inhibiting hunger and maintaining energy balance. Improper leptin secretion may result in hyperleptinemia (excess secretion of leptin) or leptin resistance, both of which contribute to obesity. Diagnosing abnormal leptin secretion may help treat this underlying cause of obesity. Therefore, continuous monitoring of the level of leptin may help characterize its secretion dynamics and also help devise an appropriate treatment. In this research, we consider leptin hormone concentration data taken over a 24 hour time period from eighteen healthy premenopausal obese women before and after treatment with a dopamine agonist, bromocriptine, and deconvolve the observed leptin hormone levels to estimate the number, timing, and magnitude of the underlying leptin secretory pulses. We find that there is an overall decrease in leptin secretion, particularly during sleep, but the changes in the secretory and clearance rates, and the number of pulses underlying the secretion process are not statistically significant.Clinical relevance- This work seeks to understand the effect of bromocriptine on leptin secretory dynamics and will help further current understanding of the effect of bromocriptine in relation to obesity.

A giant invasive macroprolactinoma with recurrent nasal bleeding as the first clinical presentation: case report and review of literature.

BACKGROUND: Giant prolactinoma (> 4 cm in dimension) is a rare disorder. Invasive macroprolactinoma has the potential to cause base of skull erosion and extend into the nasal cavity or even the sphenoid sinus. Nasal bleeding caused by intranasal tumor extension is a rare complication associated with invasive giant prolactinoma. We report a case of giant invasive macroprolactinoma with repeated nasal bleeding as the initial symptom. CASE PRESENTATION: A 24-year-old man with an invasive giant prolactinoma in the nasal cavity and sellar region who presented with nasal bleeding as the initial symptom, misdiagnosed as olfactory neuroblastoma. However, markedly elevated serum prolactin levels (4700 ng/mL), and a 7.8-cm invasive sellar mass confirmed the diagnosis of invasive giant prolactinoma. He was treated with oral bromocriptine. Serum prolactin was reduced to near normal after 6 months of treatment. Follow-up magnetic resonance imaging showed that the sellar lesion had disappeared completely and the skull base lesions were reduced. CONCLUSION: This case is notable in demonstrating the aggressive nature of untreated invasive giant prolactinomas which can cause a diagnostic difficulty with potential serious consequences. Early detection of hormonal levels can avoid unnecessary nasal biopsy. Early identification of pituitary adenoma with nasal bleeding as the first symptom is particularly important.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

How to manage intolerance to dopamine agonist in patients with prolactinoma.

PURPOSE: Dopamine agonists (DA) are the gold-standard for prolactinoma and hyperprolactinemia treatment. Intolerance to DA leading to drug drop out occurs in 3 to 12% of cases. We provide here a review of published data about DA intolerance and present a case report concerning the use of intravaginal cabergoline. METHODS: We review the literature on the definition, the pathogenesis, frequency and management of DA intolerance. In addition, the review provides strategies to enhance tolerability and avoid precocious clinical treatment withdrawal. RESULTS: Cabergoline is often cited as the most tolerable DA and its side effects tend to ameliorate within days to weeks. Restarting the same drug at a lower dose or switching to another DA can be used in cases of intolerance. The vaginal route can be tried specifically if there are gastrointestinal side effects in the oral administration. Symptomatic treatment could be attempted, although mainly based on a strategy used in other diseases. CONCLUSIONS: Due to limited data, no guidelines have been developed for the management of intolerance in DA treatment. The most frequent management is to perform transsphenoidal surgery. Nevertheless, this manuscript provides data derived from published literature and expert opinion, suggesting new approaches to this clinical issue.

Diagnosis and Management of Pituitary Adenomas: A Review.

Importance: Pituitary adenomas are neoplasms of the pituitary adenohypophyseal cell lineage and include functioning tumors, characterized by the secretion of pituitary hormones, and nonfunctioning tumors. Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons. Observations: Pituitary adenomas are classified as either macroadenomas (≥10 mm) (48% of tumors) or microadenomas (<10 mm). Macroadenomas may cause mass effect, such as visual field defects, headache, and/or hypopituitarism, which occur in about 18% to 78%, 17% to 75%, and 34% to 89% of patients, respectively. Thirty percent of pituitary adenomas are nonfunctioning adenomas, which do not produce hormones. Functioning tumors are those that produce an excess of normally produced hormones and include prolactinomas, somatotropinomas, corticotropinomas, and thyrotropinomas, which produce prolactin, growth hormone, corticotropin, and thyrotropin, respectively. Approximately 53% of pituitary adenomas are prolactinomas, which can cause hypogonadism, infertility, and/or galactorrhea. Twelve percent are somatotropinomas, which cause acromegaly in adults and gigantism in children, and 4% are corticotropinomas, which secrete corticotropin autonomously, resulting in hypercortisolemia and Cushing disease. All patients with pituitary tumors require endocrine evaluation for hormone hypersecretion. Patients with macroadenomas additionally require evaluation for hypopituitarism, and patients with tumors compressing the optic chiasm should be referred to an ophthalmologist for formal visual field testing. For those requiring treatment, first-line therapy is usually transsphenoidal pituitary surgery, except for prolactinomas, for which medical therapy, either bromocriptine or cabergoline, is usually first line. Conclusions and Relevance: Clinically manifest pituitary adenomas affect approximately 1 in 1100 people and can be complicated by syndromes of hormone excess as well as visual field defects and hypopituitarism from mass effect in larger tumors. First-line therapy for prolactinomas consists of bromocriptine or cabergoline, and transsphenoidal pituitary surgery is first-line therapy for other pituitary adenomas requiring treatment.

Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis.

Objective: Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the proliferation and migration properties of the endometrium in women with adenomyosis, by assessing cellular and molecular changes after six months of vaginal bromocriptine treatment. Methods: Endometrial specimens were collected during the proliferative phase from women with adenomyosis (n=6) before (baseline) and after six months of treatment with vaginal bromocriptine. Immunohistochemistry was used to determine changes in the protein expression of Ki67 in the endometrium of women with adenomyosis. Primary endometrial stromal cells isolated at baseline were expanded in vitro and exposed to different doses of bromocriptine to determine the optimal half-maximum inhibitory concentration (IC50) using CellTiter-Blue® Cell Viability Assay. Cell proliferation was assessed by bromodeoxyuridine ELISA assay and Ki67 gene expression was checked by real-time PCR. The migratory ability of endometrial stromal cells was determined by wound healing and transwell migration assays. Small RNA sequencing was applied on tissues collected from women with adenomyosis before and after bromocriptine treatment to identify differentially expressed microRNAs (miRNAs) after bromocriptine treatment. Bioinformatic methods were used for target gene prediction and the identification of biological pathways by enrichment procedures. Results: Vaginal bromocriptine treatment reduced the Ki67 protein expression in the endometrium of women with adenomyosis and did not change the prolactin mRNA expression and protein concentration of prolactin in endometrial tissues. Bromocriptine significantly inhibited the proliferative and migrative abilities of endometrial stromal cells derived from women with adenomyosis in vitro. Moreover, small RNA sequencing revealed 27 differentially expressed miRNAs between the endometrium of women with adenomyosis before and after six months of vaginal bromocriptine treatment. KEGG pathway analysis on targeted genes of 27 miRNAs showed that several signaling pathways associated with cell proliferation and apoptosis were enriched after bromocriptine treatment. Conclusion: Bromocriptine treatment exhibits an anti-proliferative effect in the endometrium of women with adenomyosis in vivo and in vitro. Bromocriptine might inhibit the proliferation of endometrial tissue in adenomyosis in part through the regulation of dysregulated microRNAs and proliferation-associated signaling pathways.

Antipyretic Efficacy of Bromocriptine in Central Fever: an Exploratory Analysis.

BACKGROUND: 'Central' fevers are thought to result from disruption of hypothalamic thermoregulatory pathways following severe brain injuries. Bromocriptine, due to its central dopamine receptor agonism, has been hypothesized to have antipyretic effect in this setting. However, clinical evidence for this off-label use is limited to a few case reports. In this retrospective cohort study, we analyzed the effect of bromocriptine administration on body temperature in acute brain injury patients with suspected central fever. METHODS: We screened a cohort of adult patients that received bromocriptine in the neurologic-intensive care unit of a tertiary care hospital between January 2018 and December 2021. Indication of central fever was ascertained by review of clinical documentation. A generalized additive mixed model (GAMM) was used to model temperature as a function of time relative to bromocriptine initiation. We adjusted for potential confounding due to the following covariates: temperature recording method (invasive vs surface), concurrent antipyretic administration within 8 h, and surface cooling device use within 4 h of temperature measurement. Temperature-time function was modeled using a cubic spline with k = 10 knots. RESULTS: A total of 33 patients were included in the analysis (14 women; mean age: 50 y, standard deviation 14 y). Median dose of bromocriptine was 7.5 mg (range 2.5-40) for a median of 13 d (range 5-160). Age and sex did not impact the function of temperature over time. Predicted temperatures were significantly (p < 0.05) higher by 0.4 °C with invasive compared to surface recording methods, lower by 0.2 °C in the presence of cooling device use and lower by 0.1 °C with concurrent antipyretic use. On adjusted analysis with the GAMM, there was decline (p < 0.05) in temperature following bromocriptine initiation by - 0.3 °C at 24 h, - 0.5 °C at 48 h, and - 0.7 °C at 72 h. CONCLUSIONS: Bromocriptine use was associated with modest but statistically significant decline in temperature, with nadir at 72 h post initiation. The findings provide a data driven basis for prospective evaluation.

Prolactin Inhibition in Peripartum Cardiomyopathy: Systematic Review and Meta-analysis.

Heart failure (HF) is one of the leading causes of maternal mortality and morbidity in the United States. Peripartum cardiomyopathy (PPCM) constitutes up to 70% of all HF in pregnancy. Cardiac angiogenic imbalance caused by cleaved 16kDa prolactin has been hypothesized to contribute to the development of PPCM, fueling investigation of prolactin inhibitors for the management of PPCM. We conducted a systematic review and meta-analysis to assess the impact of prolactin inhibition on left ventricular (LV) function and mortality in patients with PPCM. We included English language articles from PubMed and EMBASE published upto March 2022. We pooled the mean difference (MD) for left ventricular ejection fraction (LVEF) at follow-up, odds ratio (OR) for LV recovery and risk ratio (RR) for all-cause mortality using random-effects meta-analysis. Among 548 studies screened, 10 studies (3 randomized control trials (RCTs), 2 retrospective and 5 prospective cohorts) were included in the systematic review. Patients in the Bromocriptine + standard guideline directed medical therapy (GDMT) group had higher LVEF% (pMD 12.56 (95% CI 5.84-19.28, I2=0%) from two cohorts and pMD 14.25 (95% CI 0.61-27.89, I2=88%) from two RCTs) at follow-up compared to standard GDMT alone group. Bromocriptine group also had higher odds of LV recovery (pOR 3.55 (95% CI 1.39-9.1, I2=62)). We did not find any difference in all-cause mortality between the groups. Our analysis demonstrates that the addition of Bromocriptine to standard GDMT was associated with a significant improvement in LVEF% and greater odds of LV recovery, without significant reduction in all-cause mortality.

Review of Randomized Controlled Trials in Patients with Peripartum Cardiomyopathy.

INTRODUCTION: Peripartum cardiomyopathy (PPCM) is a rare but potentially lifethreatening disease, defined as idiopathic cardiomyopathy occurring towards the end of pregnancy or in the months following delivery, abortion or miscarriage. We aim to raise awareness of this condition and give an overview of current knowledge as well as an insight and comparison of clinical trials focusing on randomized controlled trials. MATERIAL AND METHODS: Systematic literature searches were conducted using PubMed up to December 2021. Studies published involving clinical trials and interventions in women with PPCM after 1970 were selected. RESULTS: Randomized controlled trials have shown that the addition of Bromocriptine to standardized heart failure therapy improves outcome in terms of recovery of Left Ventricular Ejection Fraction (LVEF), symptoms and death. Bromocriptine 2.5 mg twice daily for two weeks followed by 2.5 mg once daily for six weeks had the best trend and outcome. The addition of Levosimendan to standardized heart failure therapy had no effect, whereas the addition of Selenium improved heart failure symptoms but did not reduce risk in terms of unrecovered LVEF or death. One prospective study showed potential usage of TNF-alfa inhibitors, but was never tried in a randomized clinical trial. CONCLUSION: PPCM is a rare and potentially fatal disease. New insights on pathophysiology, genetics and clinical studies, particularly randomized controlled trials, have shown that the addition of Bromocriptine has a beneficial effect in terms of improved LVEF and death. However, some clinical studies have shown promising results using anti-inflammatory pharmacological agents with an improvement in LVEF. We suggest that targeting an anti-inflammatory route may prove beneficial in patients with PPCM. However, further research is highly warranted.

The management challenges of a case with Flupentixol-induced neuroleptic malignant syndrome.

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a rare and life-threatening reaction. The incidence rate of NMS has dropped because of the higher use of atypical antipsychotics, compared with the typical ones. The mortality rate in patients taking injectable antipsychotics has been also by 38%. AIM: Here, a case developing the NMS symptoms following Flupentixol (FPX) use was reported. CASE PRESENTATION: The patient was a 46-year-old man with the history of schizoaffective disorder (SAD) and recently on six-weekly doses of long-acting (LA) typical antipsychotic drugs. He was referred with a fever, sweating, a food intolerance, mutism, and disorientation in 2019. He was presented with generalized rigidity, negativism, and neck stiffness. The patient's initial creatine phosphokinase (CPK) level was 1476 IU/L, which gradually elevated to 3997 IU/L on Day 26. NMS was further diagnosed, in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and the score 9+ in the Naranjo Algorithm as the adverse drug reaction probability scale. Afterward, the patient was treated with bromocriptine at a dose of 5 mg 3 times a day, which progressively reached a maximum of 50 mg. He experienced sepsis and resistant respiratory infection several times. The case was finally discharged after 66 days of hospitalization, with a high level of consciousness, but limited verbal communication, in a fever-free condition with the oral administration of bromocriptine and lorazepam. CONCLUSION: In conclusion, there were suggestions for the management challenges of NMS in patients receiving LA injectable antipsychotic agents.

Dopamine D2 receptor agonist Bromocriptine ameliorates Aß1-42-induced memory deficits and neuroinflammation in mice.

Alzheimer's Disease (AD) is the most common neurodegenerative disease, which lacks disease-modifying therapeutics so far. Studies have shown that the dysfunction of the dopaminergic system is related to a variety of pathophysiology of AD, and the expression of Dopamine D2 receptor (DRD2) in the brains of AD patients and animal models is significantly downregulated, suggesting that DRD2 may represent a therapeutic target for AD. However, the strategy of targeting DRD2 for AD treatment still lacks some key experimental evidences. Here we show that DRD2 agonist Bromocriptine improved Aß1-42 induced neuroinflammation, neuronal apoptosis, and memory deficits in mice. For animal study, the mice have injected intracerebroventricularly (i.c.v.) with Aß1-42(410 pmol/5 µl) to induced AD cognitive deficit model (Mazzola et al., 2003; van der Stelt et al., 2006). After 7 days, Bromocriptine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) or normal saline was administered intragastrically once a day for 30 days. Behavioral tests about the Y maze and Morris water maze in mice were initiated on the twenty-fourth day of drug administration for 7 days. In vivo and in vitro mechanism research revealed that Bromocriptine, via activating DRD2, promoted the recruitment of PP2A and JNK by scaffold protein ß-arrestin 2, that repressed JNK-mediated transcription of proinflammatory cytokines and activation of NLRP3 inflammasome in microglia. Collectively, our findings suggest that Bromocriptine can ameliorate Aß1-42 induced neuroinflammation and memory deficits in mice through DRD2/ß-arrestin 2/PP2A/JNK signaling axis, which provides an experimental basis for the development of Bromocriptine as a drug for AD.

Effectivity of Bromocriptine Administration Towards Prolactin Positive Breast Cancer Receiving Anthracycline-Based Chemotherapy: A Literature Review.

Breast cancer is among the deadliest gynecology cancers in the world. However, the management of advanced-stage breast cancer is often harder as a result of chemoresistance. This review aimed to discover the effect of bromocriptine on prolactin-positive breast cancer patients who received anthracycline-based chemotherapy. It is known that anthracycline works by inhibiting topoisomerase IIα (TOP2A), forming free radicals, binding DNA, and altering cell homeostasis, hence stopping the cell cycle and inducing cell death. However, reduction of TOP2A expression and increased glutathione s-transferase (GST) and ATP-binding cassette (ATP) membrane activity increase anthracycline efflux from the cell membrane, hence reducing its effectivity. Prolactin is one of the most common chemoresistance agents whose complex with its receptor will induce JAK/STAT pathway to increase GST. The regulation of Bcl-2 and ERK was also determined by prolactin. Bromocriptine is an agonist of the D2 dopamine receptor that inhibits adenyl cyclase and a D1 dopamine weak antagonist. Bromocriptine could reduce prolactin serum and receptors in various cases. Some studies have found that bromocriptine could improve the effectiveness of chemotherapy regimens, including cancer-related hyperprolactinemia, breast cancer that underwent cisplatin, and taxanes. Therefore, bromocriptine offers potential as it could improve outcomes and reduce resistance in prolactin-positive breast cancer patients who are administered anthracycline-based neoadjuvant chemotherapy.

[Peripartum Cardiomyopathy]. / Peripartale Kardiomyopathie.

Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening heart disease, with onset in the last month of pregnancy or in the first months after delivery in previously heart-healthy women. PPCM patients typically present with heart failure due to left ventricular (LV) dysfunction with an LV ejection fraction (EF) < 45 %. In the last years clinical and experimental studies contributed to a better understanding of the pathophysiology and the clinical course of PPCM. In the context of oxidative stress, the nursing hormone prolactin is cleaved into a smaller antiangiogenic and proapoptotic 16k Da form, leading to myocardial dysfunction. In an animal model this can be prevented by treatment with the dopamine agonist bromocriptine, which suppresses prolactin release. This therapeutic approach was confirmed in several clinical studies. Therefore, the current guidelines recommend a treatment consisting of a heart failure treatment according to current guidelines in combination with the dopamine agonist bromocriptine. If the diagnosis is made early and the treatment is started immediately, the prognosis is good compared to other forms of cardiomyopathies, as LV function recovers in most cases.In the acute phase the severity of heart failure differs among PPCM patients. Some patients present with mild forms, whereas some PPCM patients display severely reduced LV function and cardiogenic shock. Especially the latter cases are still challenging, as treatment with ß1-adrenergic receptor agonists is associated with progression of heart failure and a worse cardiac outcome. Therefore, patients with cardiogenic shock complicating PPCM should be treated in centers experienced in mechanical circulatory support in combination with bromocriptine treatment.

Surgery as a first-line option for prolactinomas.

INTRODUCTION: Treatment of prolactinomas with dopamine agonists has been the established first-line treatment option for many years, with surgery reserved for refractory cases or medication intolerance. This approach may not be the best option in many cases. AREAS COVERED: Review of the epidemiology, biology, and treatment options available for prolactinomas, including best available data on outcomes, costs, and morbidities for each therapy. These data are then used to propose a 'surgery-first' treatment approach for a subset of prolactinomas as an alternative to primary medical management. EXPERT OPINION: Based on the available data, there is a strong rationale that transsphenoidal surgery should be considered a first-line treatment option for both micro- and macro-prolactinomas that do not demonstrate high grade cavernous sinus invasion on MRI imaging, with dopamine agonists administered as a secondary therapy for tumors not in remission following surgery, and for giant tumors. This 'surgery-first' approach assumes the availability of skilled and experienced pituitary surgeons to ensure optimal outcomes. This approach should result in high cure rates and reduced DA requirements for patients not cured from initial surgery. Further, it will reduce medical costs over a patient's lifetime and the chronic morbidities associated with protracted dopamine agonist usage.

Neuroleptic malignant syndrome associated with acute organophosphate poisoning: Case report / Síndrome neuroléptico maligno asociado con intoxicación aguda por un organofosforado: reporte de caso.

Neuroleptic malignant syndrome is a rare and potentially fatal clinical condition frequently associated with the use of antipsychotics. In the literature, there is only one case report associated with the intake of organophosphates. We present the case of a patient who presented with a clinical picture compatible with neuroleptic malignant syndrome, after the ingestion of an organophosphate (chlorpyrifos). A 57-year-old man who consulted for attempted suicide, acute deterioration of consciousness, torpid neurological evolution, and associated autonomic instability associated with rigidity, persistent hyperthermia, and elevated CPK. Bromocriptine treatment was offered, which resolved the clinical picture. The association with the ingestion of an organophosphate was established, and he was discharged without sequelae. The diagnosis of neuroleptic malignant syndrome is clinical and should be considered in any case of exposure to substances that may lead to dysregulation of dopaminergic neurotransmission in order to initiate timely therapy and impact outcomes.

El síndrome neuroléptico maligno es una condición clínica rara y potencialmente letal que frecuentemente se asocia con el uso de antipsicóticos. En la literatura especializada se encontró únicamente un reporte de caso relacionado con la ingestión de organofosforados. Se presenta un paciente con un cuadro clínico correspondiente al síndrome neuroléptico maligno posterior a la ingestión de clorpirifós. Como resultado de un intento de suicidio con el mencionado organofosforado, el hombre de 57 años presentó deterioro agudo del estado de consciencia, evolución neurológica tórpida e inestabilidad autonómica asociada a rigidez e hipertermia persistentes, así como incremento de la creatina-fosfocinasa (creatine phosphokinase, CPK). Se le administró tratamiento con bromocriptina, con lo cual el cuadro clínico remitió, y fue dado de alta sin secuelas. El diagnóstico del síndrome neuroléptico maligno es clínico y debe contemplarse en cualquier caso de exposición a sustancias que puedan resultar en una desregulación de la neurotransmisión dopaminérgica, con el fin de iniciar el tratamiento oportuno y contrarrestar efectivamente los efectos.

Treatment of Prolactinoma.

Prolactinomas are the commonest form of pituitary neuroendocrine tumor (PitNET), representing approximately half of such tumors. Dopamine agonists (DAs) have traditionally been the primary treatment for the majority of prolactinomas, with surgery considered the second line. The aim of this review is to examine the historical and modern management of prolactinomas, including medical therapy with DAs, transsphenoidal surgery, and multimodality therapy for the treatment of aggressive prolactinomas and metastatic PitNETs, with an emphasis on the efficacy, safety, and future directions of current therapeutic modalities. DAs have been the mainstay of prolactinoma management since the 1970s, initially with bromocriptine and more recently with cabergoline. Cabergoline normalizes prolactin in up to 85% of patients and causes tumor shrinkage in up to 80%. Primary surgical resection of microprolactinomas and enclosed macroprolactinomas performed by experienced pituitary neurosurgeons have similar remission rates to cabergoline. Aggressive prolactinomas and metastatic PitNETS should receive multimodality therapy including high dose cabergoline, surgery, radiation therapy (preferably using stereotactic radiosurgery where suitable), and temozolomide. DAs remain a reliable mode of therapy for most prolactinomas but results from transsphenoidal surgery in expert hands have improved considerably over the last one to two decades. Surgery should be strongly considered as primary therapy, particularly in the setting of microprolactinomas, non-invasive macroprolactinomas, or prior to attempting pregnancy, and has an important role in the management of DA resistant and aggressive prolactinomas.

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects.

Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body's systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3ß, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1ß, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3ß (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1ß, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.

Bromocriptine quick-release as adjunct therapy in youth and adults with type 1 diabetes: A randomized, placebo-controlled crossover study.

AIM: To evaluate the potential for glycaemic, renal and vascular benefits of bromocriptine quick release (BCQR) in adolescents and adults with type 1 diabetes. MATERIALS AND METHODS: Forty adolescents and 40 adults with type 1 diabetes aged 12-60 years old were enrolled in a double-blind, placebo-controlled, random order crossover study of 4 weeks of treatment in the morning with BCQR (titrated weekly from 0.8 mg to 1.6 mg to 3.2 mg, minimum dose 1.6 mg). Study assessments after each phase included blood pressure (BP), lipids, peripheral arterial stiffness and autonomic function, mixed meal tolerance test, continuous glucose monitoring (CGM), creatinine, estimated glomerular filtration rate, estimated insulin sensitivity, insulin dose and indirect calorimetry. RESULTS: Adolescents displayed baseline hyperglycaemia, insulin resistance, metabolic dysfunction and increased renal filtration compared with adults. In both age groups, continuous glucose monitoring measures, estimated insulin sensitivity and insulin dose did not differ with BCQR treatment. In adolescents, BCQR decreased systolic BP, diastolic BP and triangular index and increased serum creatinine. In adults, systolic BP, mean arterial pressure, systemic vascular resistance, and mixed meal tolerance test glucose and glucagon-like peptide 1 areas under the curve were lower, and the orthostatic drop in systolic BP was greater with BCQR. CONCLUSIONS: Greater hyperglycaemia, insulin resistance, metabolic dysfunction and renal hyperfiltration in adolescents argues for increased attention during this high-risk age period. Although BCQR had little impact on glycaemia or insulin sensitivity, initial vascular and renal responses suggest potential benefits of BCQR in adolescents and adults with type 1 diabetes requiring further study.