Novel multifunctional dopamine D2/D3 receptors agonists with potential neuroprotection and anti-alpha synuclein protein aggregation properties

Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson’s disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of α-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths. Structural optimization led to development of several potent agonists among which (−)-8a, (−)-14 and (−)-20 exhibited potent neuroprotective properties in a cellular PD model involving neurotoxin 6-OHDA. The lead compounds (−)-8a and (−)-14 were able to modulate aggregation of α-synuclein protein efficiently. Finally, in an in vivo PD animal model, compound (−)-8a exhibited efficacious anti-parkinsonian effect.     

Reversible Mitral and Aortic Regurgitation Due to Pioglitazone

ObjectiveTo report the occurrence of pioglitazone induced reversible valvular regurgitant lesions.MethodsClinical, laboratory, and imaging data are reported on a patient with known type 2 diabetes mellitus, who was prescribed pioglitazone to achieve better glyce mic control.ResultsWe present a case report of a 50-year-old woman, in whom diabetes had been diagnosed 5 years pre viously, who developed severe mitral and aortic regurgita tion during 5 months of treatment with pioglitazone along with clinical and laboratory indications of fluid retention. Echocardiography 5 months after discontinued use of pio glitazone showed regression of regurgitant lesions and nor malization of pertinent laboratory variables.ConclusionFive months of treatment with pio glitazone could potentially induce major cardiac valvu lar dysfunction, which was reversible in our patient. This report emphasizes the importance of carefully monitoring patients during treatment with thiazolidinediones. (Endocr Pract. 2012;18:e32-e36)     

Pituitary Apoplexy in Nonfunctioning Pituitary Macroadenomas: A Case-Control Study

ObjectivePituitary apoplexy (PA) is an endocrinologie emergency characterized by headache, visual abnormalities, and hemodynamic instability in the context of hemorragic infarction of a pituitary adenoma. Our goal was to estimate the incidence, precipitating factors, clinical characteristics, and outcome of PA in a cohort of patients with nonfunctioning pituitary macroadenomas (NFPMAs).MethodsA retrospective, case-control study of 46 patients with PA and 47 controls matched for age, gender, and tumor invasiveness. Clinical, hormonal, and tumoral charactersitics, as well as the presence of potential precipitating factors and long-term outcome were evaluated using both bivariate and multivariate analysis.ResultsThe prevalence of PA was 8%. Cases and controls were similar in regards to the prevalence of diabetes, hypertension, use of antiplatelet agents, and the presence of headaches and visual field defects. Oculomotor paralysis was present in 18% of cases and in none of the controls (P = .001). Prior use of dopamine agonists was significantly more frequent among cases than in controls on both bivariate and multivariate analysis. Pituitary hormone deficiencies were more common among cases than in controls on bivariate but not on multivariate analysis. Early and late surgical treatment was carried out in 11 and 25 patients, respectively; 11 patients were managed conservatively. Visual and endocrine outcomes were similar among the 3 groups.ConclusionPA represents a life-threatening medical emergency. Prior use of dopamine agonists and the presence of oculomotor abnormalities clearly distinguished patients with NFPMA who developed PA from those who did not. (Endocr Pract 2014;20:1274-1280)     

Evolución del microprolactinoma a largo plazo con tratamiento médico

IntroductionProlactinoma is the most frequent functioning pituitary adenoma. Most commonly occurs as microprolactinoma (less than 1 cm in size), which may be cured with medical therapy, but few long-term studies are available about optimal duration of treatment with dopamine agonists to ensure cure after drug discontinuation and its withdrawal without recurrence are do not report consistent results.ObjectiveTo establish criteria for cure of microprolactinoma with medical treatment and to analyze the potential predictors involved.PatientsA retrospective study was conducted on 47 adult women with microprolactinoma followed up between 1975 and 2010; none of them had undergone prior surgery or radiotherapy, and all of them received treatment with a dopamine agonist for at least 4 years. They were divided into two groups for analysis: cured patients with at least 4 years with normal prolactin levels after drug discontinuation, and not cured patients.ResultsCure was achieved in 57.4% of patients. Only age at diagnosis was a significant predictor: there were more young patients in the cured group and youngest patients needed less time to cure. Development of empty sella turcica or normal MRI were similar regarding time to cure.ConclusionsMicroprolactinoma may be cured with dopamine agonists, and life-long treatment is not required, although more than 10 years may be required to achieve cure, 11,6 ± 5,3 years in our experience.     

Acute Liver Failure with Thyrotoxicosis Treated with Liver Transplantation

ObjectiveWe describe a young woman with previously undiagnosed thyrotoxicosis who presented with acute liver failure (ALF).MethodsWe present a case report and review the relevant literature.ResultsAn extensive evaluation excluded possible causes of ALF other than thyrotoxicosis. The management of thyrotoxicosis posed several unique challenges in the setting of ALF, particularly because we did not want to use potentially hepatotoxic thionamides. The patient was treated with prednisone and propranolol and was started on potassium iodide when she was listed for liver transplantation. She underwent an uncomplicated liver transplant and subsequent thyroidectomy and is doing well.ConclusionThis well-characterized case describes thyrotoxicosis as a possible cause of ALF after thoroughly excluding other possible causes and illustrates the challenges of simultaneously managing both disorders. To our knowledge, this is the first report of ALF possibly resulting from untreated thyrotoxicosis that was successfully treated with liver transplantation. (Endocr Pract. 2013;19:e57-e60)     

A Case of Nonischemic Cardiomyopathy Associated with Autoimmune Polyglandular Syndrome Type III

Objective:To report a case of nonischemic dilated cardiomyopathy associated with autoimmune polyglandular syndrome (APS) type III.MethodsA review of our patient’s medical records was undertaken, and her clinical history, investigations, and outcome are described. In addition, a literature review of nonischemic dilated cardiomyopathy occurring in association with autoimmune polyendocrinopathies was performed.ResultsAPS is diagnosed once a patient has developed at least 2 organ specific autoimmune diseases. APS III involves a combination of autoimmune diabetes and Graves’ disease without adrenal insufficiency. Autoimmune cardiomyopathies are not described as a feature of this condition; however, there are a few reported cases of patients with autoimmune polyendocrinopathies developing a nonischemic dilated cardiomyopathy. In this case, a 30-year-old female developed vitiligo, Graves’ disease, and latent autoimmune diabetes of the adult (LADA) over a 5-year period before presenting with conscious ventricular tachycardia (VT). This evolved into acute severe biventricular failure within a few weeks, which failed to resolve after adequate treatment of her other autoimmune conditions.ConclusionAlthough nonischemic cardiomyopathies have been associated with APS in a few published cases, this is the first case to our knowledge in a patient with APS III. (Endocr Pract. 2014;20:e183-e186)     

Danger of Hypoglycemia Due to Acute Tramadol Poisoning

ObjectiveTo report a case of prolonged hypoglycemia after acute tramadol poisoning.MethodsWe describe a patient’s clinical presentation and outcome with prolonged hypoglycemia attributable to acute tramadol poisoning. In addition, the possible mechanism for the hypoglycemia is discussed, and a brief review of the pertinent literature is presented.ResultsA 54-year-old woman had previously under- gone a partial hepatectomy because of involvement of her liver by a gastrointestinal stromal tumor. After ingestion of 3,000 mg of tramadol with suicidal intent, she developed prolonged hypoglycemia that necessitated treatment with continuous intravenous glucose infusion for 24 hours. Reports in the literature have described central nervous system depression, nausea, vomiting, tachycardia, seizures, and even death from tramadol overdoses.ConclusionThis report alerts clinicians to the potential danger of severe hypoglycemia in tramadol poisoning. (Endocr Pract. 2012;18:e151-e152)     

Atypical Femoral Fracture in an Osteogenesis Imperfecta Patient Successfully Treated with Teriparatide

ObjectiveWe report a case of a successfully healed atypical femoral fracture (AFF) following treatment with teriparatide in a patient with osteogenesis imperfecta (OI). To our knowledge, no successful treatment of AFFs with teriparatide in this subpopulation has ever been described.MethodsThis is a case report of an AFF treated with teriparatide.ResultsThe patient was treated with hormone replacement therapy for 18 years and bisphosphonates for 9 years before suffering a spontaneous AFF in the form of a dislocated noncomminute transverse fracture of the right femoral shaft, and an open reduction and internal fixation (ORIF) with a T2 Femoral Nail was done. Due to nonunion and another fracture distal to the nail, the patient was reoperated on with exchange ORIF and off-label treatment with teriparatide 20 μg/day was started. An X-ray 1 month later showed early signs of fracture healing. A subsequent X-ray 6 months after the last operation showed a solid healing of both right femoral fractures.ConclusionThis is a rare case that highly suggests a potential fracture healing effect of teriparatide treatment and highlights a potential significant practical therapeutic consideration in relation to the management of AFF with delayed healing. (Endocr Pract. 2014;20:e187-e190)     

A Protracted and Affressive Variant of Lymphocytic Hypophysitis with Mammillary Body Involvement and Cognitive Dysfunction

ObjectiveOur objective was to describe the 14-year course of a patient with a protracted and aggressive variant of lymphocytic hypophysitis.MethodsThis is a case report.ResultsDespite several trials of pulse steroids, this young female patient demonstrated persistent inflammation of the pituitary gland with eventual extension into the mammillary bodies with clinical cognitive decline. To our knowledge, there is no other reported case of lymphocytic hypophysitis with autoimmune inflammation extending beyond the infundibulum.ConclusionThis case broadens the clinical spectrum of lymphocytic hypophysitis. (Endocr Pract. 2014;20:e225-e229)     

Everolimu Resolving Hypoglycemia,Producing Hyperglycemia,and Necessitating Insulin Use in A Patient With Di Etes and Nonresectable Malignant Insulinoma

ObjectiveTo present a case of management of refractory hypoglycemia due to malignant insulinoma with use of everolimusresulting in recurrent insulin-requiring diabetes.MethodsThis report describes a case of a nonresectable malignant insulinoma in a 78-year-old patient with long-standing type 2 diabetes mellitus. Endogenous hyperinsulinism was confirmed by a fasting test, which revealed a glucose level of 35 mg/dL and an insulin value of 23.7 μIU/mL. Endoscopic ultrasonography, magnetic resonance imaging, and computed tomography identified a pancreatic mass, infiltration of the superior mesenteric vein, and metastatic lesions in the liver.ResultsAfter chemoembolization of the metastatic lesions, hypoglycemia recurred, despite combined treatment with somatostatin analogues, dexamethasone, and diazoxide. Everolimus, an orally administered mammalian target of rapamycin, was used at a daily dose of 5 mg. After 6 months, the hypoglycemia was controlled, and the patient presented with a C-peptide level of 0.2 ng/mL and secondary hyperglycemia that necessitated insulin treatment.ConclusionThe orally administered drug everolimus controlled hypoglycemia due to a malignant insulinoma in a patient with prior insulinrequiring diabetes. Secondary hyperglycemia was an acceptable drug effect (to the patient and managing physicians), in light of the complex and often poorly tolerated treatments available for this rare condition. (Endocr Pract. 2011;17:e17-e20)     

Effect of the Preoperative Use of Dopamine Agonists in the Postoperative Course of Prolactinomas: A Systematic Review

ObjectiveSince the 1980s, it has been discussed whether the preoperative treatment of prolactinomas with dopamine agonists (DAs) is beneficial or detrimental regarding postoperative residue or recurrence. Many neurosurgeons have emphasized the difficulties caused by fibrosis during the ablation of such prolactinomas.MethodsFrom February to December 2012, the authors searched electronic databases and book chapters published from 1991 to 2012; a total of 3,771 articles and 37 book chapters were searched. Ten articles that explicitly addressed this issue were identified.ResultsFive articles reported that preoperative treatment did not affect postoperative status. One article described a positive influence of preoperative treatment with DAs (P < .01), and 3 articles found a negative influence (P = .040, P = .02, no significance value reported). One article described histopathological evidence of tumor fibrosis that was found intraoperatively after preoperative DA treatment.ConclusionsThis systematic review did not identify any strong evidence that preoperative treatment of prolactinomas with DAs is harmful or beneficial. Therefore, further studies are needed. (Endocr Pract. 2014;20:70-74)     

Nonischemic Cardiomyopathy Associated with Autoimmune Polyglandular Syndrome Type II

ObjectiveTo report a case of nonischemic cardiomyopathy associated with autoimmune polyglandular syndrome type II (APS-II).MethodsWe describe our patient’s clinical features, evaluation, and outcome. In addition, a literature review of cardiomyopathy associated with polyendocrinopathy syndromes is presented.ResultsThe component disorders of APS-II are Addison’s disease in combination with either autoimmune thyroid disease or type 1 (insulin-dependent) diabetes. Although numerous other autoimmune conditions have been reported in conjunction with APS-II, cardiomyopathy has not been previously described as part of this syndrome. The current patient was a 32-year-old man who, during a 5-year period, was diagnosed as having type 1 diabetes mellitus, Crohn’s disease, and Addison’s disease. In 2001, he presented with severe heart failure that progressed rapidly and eventually necessitated cardiac transplantation.ConclusionAlthough autoimmune cardiomyopathy has been associated with other autoimmune disorders, to our knowledge this is the first reported case of cardiomyopathy in association with an autoimmune polyglandular syndrome. Patients with this syndrome should undergo clinical evaluation for heart failure. (Endocr Pract. 2007;13:59-62)     

A Rare Case of Central Precocious Puberty Due to Hypothalamic Hamartoma Diagnosed In Utero

ObjectiveTo report a rare case of central precocious puberty attributable to hypothalamic hamartoma that was diagnosed in utero.MethodsWe present the clinical, laboratory, and imaging data pertaining to our case and discuss the diagnostic features and recommended treatment of central precocious puberty in patients with hypothalamic hamartoma.ResultsA 3-month-old male child had had excessively rapid growth velocity and weight gain since birth. On investigation, the patient was diagnosed as having hypothalamic hamartoma with central precocious puberty. On inquiry, his mother described a history of prenatal ultrasonography and fetal magnetic resonance imaging suggesting the presence of a cystic lesion in his brain at 9 months of gestation. Because of continued rapid growth and acceleration of puberty during a 4-month observation period, we decided to treat the patient with leuprolide acetate. The patient responded well to treatment, with stabilization of growth.ConclusionTo the best of our knowledge, this patient is the youngest in the medical literature diagnosed to have central precocious puberty and also to receive treatment with leuprolide acetate. (Endocr Pract. 2010;16:237-240)     

Severe Ectopic Cushing Syndrome Caused by Adenoid Cystic Carcinoma of a Salivary Gland

ObjectiveWe present a rare case of Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS). To our knowledge only two similar cases have been previously reported.MethodsThis is a case report of EAS by a metastatic lingual adenoid cystic carcinoma (ACC).ResultsThe patient was diagnosed of a Cushing syndrome caused by tumoral EAS two years after initial cancer diagnosis. Clinical presentation included asthenia, insomnia, hypertension, acne, and hyperpigmentation developing in a period of two months. Laboratory and imaging testing revealed hypokalemic metabolic alkalosis, hypercortisole- mia, high ACTH, nonsuppresion by 8 mg dexamethasone, and a normal pituitary magnetic resonance imaging (MRI). With a high clinical suspicion of EAS, combined medical treatment was started but was unsuccessful. Bilateral adrenalectomy could not be performed given the patient’s rapid deterioration. Immunostained tissue from the original tumor was positive for synaptophysin.ConclusionThis rare case of EAS illustrates the challenge that this condition may confer regarding diagnosis and management. (Endocr. Pract. 2013;19:e118-e121)     

Confirmation of Hypoglycemia in the “Dead-In-Bed” Syndrome,as Captured by a Retrospective Continuous Glucose Monitoring System

ObjectiveTo report a case that substantiates the presence of hypoglycemia at the time of death of a young man with type 1 diabetes, who was found unresponsive in his undisturbed bed in the morning.MethodsWe describe a 23-year-old man with a history of type 1 diabetes treated with an insulin pump, who had recurrent severe hypoglycemia. In an effort to understand these episodes better and attempt to eliminate them, a retrospective (non-real-time) continuous subcutaneous glucose monitoring system (CGMS) was attached to the patient. He was found dead in his undisturbed bed 20 hours later. The insulin pump and CGMS were both downloaded for postmortem study.ResultsPostmortem download of the data in the CGMS demonstrated glucose levels below 30 mg/dL around the time of his death, with only a minimal counterregulatory response. This finding corresponded to a postmortem vitreous humor glucose of 25 mg/dL. An autopsy showed no major anatomic abnormalities that could have contributed to his death.ConclusionTo our knowledge, this is the first documentation of hypoglycemia at the time of death in a patient with the “dead-in-bed” syndrome. This report should raise the awareness of physicians to the potentially lethal effectsof hypoglycemia and provide justification for efforts directed at avoiding nocturnal hypoglycemia. (Endocr Pract. 2010;16:244-248)     

Panhypopituitarism secondary to a macroprolactinoma manifesting with pancytopenia:case report and literature review

ObjectiveTo present a case of pancytopenia associated with hypopituitarism secondary to a macroprolactinoma.MethodsWe report the clinical features on presentation and results of laboratory investigation. Findings on magnetic resonance imaging are illustrated. The response to hormone replacement therapy is summarized.ResultsA 46-year-old man was referred with pancytopenia and secondary hypothyroidism. Laboratory investigation revealed hypopituitarism and a substantially increased prolactin level. Magnetic resonance imaging of the head demonstrated a macroprolactinoma. Hematologic investigation disclosed no other cause for the pancytopenia. Hormone replacement therapy was initiated with hydrocortisone, levothyroxine, and testosterone. Cabergoline was used to induce regression of the prolactinoma. A rapid improvement was seen in the cytopenias, with normalization of the blood cell counts after 8 months of treatment. This result has been sustained during 29 months of follow-up.ConclusionPancytopenia associated with hypopituitarism has been reported in the literature as a rare occurrence limited to isolated case reports, predominantly associated with Sheehan syndrome. To our knowledge, this is the first reported case of pancytopenia macroprolactinoma. This finding is noteworthy because associated with a prolactin alone has been reported to support hematopoiesis in animal studies. (Endocr Pract. 2011;17:e32-e36)     

Unusual Case of Metastatic Neuroendocrine Tumor

ObjectiveTo report a rare case of metastatic growth hormone (GH)-secreting pituitary carcinoma causing acromegaly.MethodsWe present a case report and review the available literature on this topic.ResultsA 68-year-old woman presented with persistent acromegaly after treatment for a GH-secreting pituitary adenoma. Evaluation of long-standing cervical adenopathy revealed findings consistent with a metastatic neuroendocrine tumor. Further work-up revealed additional thyroid, parathyroid, and cervical masses. After operative treatment including total thyroidectomy, subtotal parathyroidectomy, partial thymectomy, and right modified radical neck dissection, the patient’s symptoms diminished, and her GH levels approached the normal range. Surgical pathology findings were consistent with a GH-secreting pituitary carcinoma metastatic to the cervical lymph nodes, multinodular thyroid hyperplasia with a focus of papillary microcarcinoma, and parathyroid hyperplasia.ConclusionOverall, pituitary carcinomas are extremely rare. To date, about 100 cases have been reported in the world’s literature, and of these, only 19 cases originated from GH-secreting cells. Our examination of the symptoms, signs, diagnosis, and treatment of our patient, in comparison with the previously reported cases, should enhance awareness of this unusual disease process. (Endocr Pract. 2007;13:72-76)