Pituitary-targeted medical therapy of Cushing's disease

Background: The goals of ideal medical therapy for Cushing's disease should be to target the aetiology of the disorder, as is the case for surgery, which is the current ‘gold standard’ treatment. However, no effective drug that directly and reliably targets the adrenocorticotropin-secreting pituitary adenoma has yet been found. Objective: To summarise pituitary-targeted medical treatment of Cushing's disease. Methods: Compounds with neuromodulatory properties and ligands of different nuclear hormone receptors involved in hypothalamo–pituitary regulation have been investigated. Results: The somatostatin analogue pasireotide and the dopamine agonist cabergoline, as well as their combination, show some therapeutic promise in the medical therapy of Cushing's disease. Other treatments such as retinoic acid analogues look promising and may be a possible option for further investigation. No other medical therapies seem to be reliably effective currently. Conclusion: Since a percentage of patients treated with surgery are not cured, or improve and subsequently relapse, there is an urgent need for effective medical therapies for this disorder. At present, only cabergoline and pasireotide are under active investigation.     

Pasireotide for the treatment of acromegaly

Introduction: Acromegaly is a chronic disease with high morbidity and enhanced mortality if left untreated. Treatment options include surgery, medical therapy (somatostatin analogues (SA), dopamine agonists (DA) and growth hormone receptor antagonists) and radiotherapy. Despite these treatment options, “real-life” studies have shown that approximately 50% of patients are not controlled. In this scenario, a next-generation SA, pasireotide, has recently been approved for the treatment of acromegaly.

Areas covered: 1) pasireotide’s pharmacokinetics and pharmacodynamics; 2) pasireotide’s anti-secretory and anti-proliferative effects, from preclinical studies up to phase III clinical trials; and 3) the adverse effects of pasireotide, focusing on hyperglycemia; 4) biomarkers of response to SA treatment.

Expert opinion: surgery is the primary treatment for most patients with acromegaly; however, approximately half of them will need adjuvant therapy. At present, the decision of this adjuvant treatment is made on a “trial-and-error” fashion. Nevertheless, in recent years, efforts have been made to establish biomarkers for the response to drugs involved in the treatment of acromegaly, which will change the treatment of acromegaly towards a more personalized therapeutic decision-making process. In the near future, the establishment of pasireotide response biomarkers will allow us to identify good candidates for first-line medical monotherapy with pasireotide.     

The somatostatin receptor subtype 5 in neuroendocrine tumours

Importance of the field: In recent years, scientific work has been intensified to unravel new (patho-) physiological insights, particularly regarding the functional role of somatostatin (SRIF) receptor subtype 5 (sst) and the development of novel sst₅-targeted SRIF analogues, in order to broaden medical therapeutic opportunities in patients suffering from neuroendocrine diseases.

Areas covered in this review: The scope of this review is primarily focused upon recent insights in sst₅-receptor physiology, novel sst₅-targeted treatment options predominantly directed towards pituitary adenomas, and gastroenteropancreatic neuroendocrine tumours.

What the reader will gain: An understanding of the potential that novel sst₅-targeted SRIF analogues might have in the medical treatment of Cushing’s disease and acromegaly, as demonstrated by translational research, based on pathophysiological data combined with results from clinical trials.

Take home message: The role of targeting sst₅ in gastroenteropancreatic neuroendocrine tumours remains to be established. The sst₅ subtype might function as sst₂ modulator in terms of receptor internalization and desensitization, and seems less important compared with sst₂-preferring SRIF analogues in the regulation of human insulin secretion by the pancreas. Finally, absence of sst₅ in corticotroph adenomas could be related to tumour aggressiveness in Cushing’s disease.     

Current and future medical treatments for patients with acromegaly

Introduction: Acromegaly is a relatively rare condition of growth hormone (GH) excess associated with significant morbidity and, when left untreated, high mortality. Therapy for acromegaly is targeted at decreasing GH and insulin-like growth hormone 1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant) and radiotherapy. However, despite all these treatments option, approximately 50% of patients are not adequately controlled.

Areas covered: In this paper, the authors discuss: 1) efficacy and safety of current medical therapy 2) the efficacy and safety of the new multireceptor-targeted somatostatin ligand pasireotide 3) medical treatments currently under clinical investigation (oral octreotide, ITF2984, ATL1103), and 4) preliminary data on the use of new injectable and transdermal/transmucosal formulations of octreotide.

Expert opinion: This expert opinion supports the need for new therapeutic agents and modalities for patients with acromegaly.     

Drugs in the medical treatment of Cushing's syndrome

Cushing's syndrome is a complex endocrine condition with potential serious complications if untreated or inadequately treated. Transsphenoidal surgery with resection of a pituitary adenoma is successful in 75 – 80% of patients, but approximately 20 – 25% show persistence of Cushing's, and a similar proportion may experience recurrence within 2 – 4 years post-op. When surgery fails, medical treatment can temporarily suppress excessive cortisol production and ameliorate its clinical manifestations while more definitive therapy becomes effective. We describe pharmacological approaches to the treatment of Cushing's syndrome. Drugs used to suppress cortisol secretion are mostly inhibitors of steroidogenesis. Ketoconazole, fluconazole aminoglutethimide, metyrapone, mitotane and etomidate are in that category. Ketoconazole is in current use while other drugs, although mostly available in the past, continue to have a potential role either alone or in combination. Drugs that suppress adrenocorticotropic hormone (ACTH) secretion are less popular as standard treatment and include cyproheptadine, valproic acid, cabergoline, somatostatin analogs, PPAR-γ agonists, vasopressin antagonists. Some of these drugs have been tested in limited clinical trials but there is potential therapeutic benefit in analogs with better specificity for the class of receptors present in ACTH-secreting tumors. A third category of drugs is glucocorticoid receptor antagonists. Mifepristone is currently being tested in clinical trials in patients with persistent or recurrent Cushing's disease and in patients with metastatic adrenal cortical carcinoma or ectopic ACTH syndrome not amenable to surgery. We also review replacement therapy after surgery and non-specific drugs to treat complications in patients with severe hypercortisol.

The review provides a complete survey of the drugs used in the medical treatment of Cushing's, and new advances in the development of pituitary-active drugs as well as receptor blockers of glucocorticoid action. It also provides avenues for exploration of new drugs active on somatostatin, dopamine and vasopressin receptors. There are effective pharmacological agents capable of chronically reversing biochemical and clinical manifestations of hypercortisolemia in Cushing's syndrome but new drugs are needed with action at the pituitary level.     

Memantine ER,a once-daily formulation for the treatment of Alzheimer's disease

Importance of the field: Alzheimer's disease is a progressive, degenerative brain disease. As the disease progresses, patients and caregivers face increasing problems with medication adherence. Given its relentlessly progressive nature, newer and more effective therapies for Alzheimer's disease are needed. Memantine 10 mg twice daily is the FDA-approved regimen for the treatment of moderate to severe Alzheimer's disease.

Areas covered in this review: The goal of this article is to review the once-daily memantine ER 28 mg formulation for the treatment of Alzheimer's disease, which, by simplifying the dosage regimen, decreases the problems of medication adherence. A new extended-release formulation has been developed to improve adherence and possibly efficacy without compromising an excellent tolerability and safety profile. There is also a possibility of dose-dependent improvement/superiority in cognitive, global and behavioral measures as well as in verbal fluency with higher-dose (28 mg/day) memantine.

What the reader will gain: Readers will become knowledgeable about this new dose and preparation of memantine. However, these advantages remain provisional and more research is needed to evaluate patient adherence, outcomes and caregiver burden related to twice-daily versus once-daily administration in patients with moderate to severe Alzheimer's disease.

Take home message: A new, once-daily, higher-dose preparation of memantine seems to be well tolerated and may provide additional benefits for selected patients with Alzheimer's disease.     

Efficacy and safety of drugs for ulcerative colitis

Importance of the field: Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon that carries considerable burden and morbidity for patients and presents a constant challenge in management for gastroenterologists. Continued advances in medical therapies provide a range of treatment options for patients, but with this is the need to balance the potential benefits of a particular medication with its side effect profile in both the short and the long term.

Areas covered in this review: This article will review the current drugs used in the treatment of UC, including 5-amninosalicylates, antibiotics, steroids, immunomodulators and biologics, with particular attention to their indications, efficacy and toxicity profile.

What the reader will gain: The reader will gain a comprehensive understanding of the various medical therapies used in the treatment of UC with focus on efficacy and toxicity profiles, allowing providers to choose appropriate medical therapies for their patients.

Take home message: The particular agent used depends upon the extent and severity of disease, with mild-to-moderate disease treated with conventional therapy including 5-amninosalicylates. Steroids are used in the short term to bring active disease into remission, and the more aggressive immunomodulators and biologics are reserved for more severe disease given their toxicity profiles.     

Emerging drugs for acromegaly

Introduction: Acromegaly is a rare disease that severely impacts patients' health all the while, being a slowly progressing illness. In the past decades, advancements in treatment modalities, especially development of new drugs, as well as focused guidelines has improved management of acromegaly. Still, many patients are considered not sufficiently treated and there remains an ongoing need for further development.

Areas covered: This article reviews new medical treatments currently under clinical investigation (such as pasireotide, oral octreotide and somatoprim) and under experimental development (such as octreotide implants, CAM2029 and ATL-1103).

Expert opinion: As it seems unlikely that one single agent may achieve cure in 100% of cases, there is an urgent need for new agents that help patients where current medication fails. Imperatively, this means we have to improve our understanding of the underlying pathogenetic and molecular mechanisms.     

Emerging drugs for Cushing’s disease

Introduction: Considering the effects of uncontrolled hypercortisolism on morbidity and mortality, there is a clear need for effective medical therapy for patients with Cushing’s disease (CD). Therefore, the search for new medical effective tools remains active, and already promising results have been obtained.

Areas covered: The importance of the design and conduct of trials to validate old drugs or to test new compounds is discussed. The results of the ongoing clinical trials, targeting the specific properties of drugs, such as ketoconazole, LCI699, mifepristone, etomidate and pasireotide, are also reported. The authors also emphasise the advantages and drawbacks of each particular drug, and the potential combined use of agents with complementary mechanisms of action.

Expert opinion: CD is an excellent example of a situation where effective therapy is essential, but where the balance of risk and benefit must be carefully judged. Metyrapone is the drug of choice when rapid control of the hypercortisolaemia is required, ketoconazole represents a good second-line drug, although in the future LCI699 may be a better alternative. Mifepristone can also be used in the rare situation when previous drugs are inappropriate. Etomidate is useful where immediate parenteral action is required. For drugs working directly on the pituitary, cabergoline is occasionally effective and pasireotide can be attempted in patients with mild CD.     

Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects

Introduction: Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs.

Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs.

Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.     

Safety evaluation of zotepine for the treatment of schizophrenia

Importance of the field: Atypical antipsychotics have become the first-line treatment for patients suffering from schizophrenia in the industrialized world. Given the frequent necessity of a life-long enduring antipsychotic treatment, the compounds' safety profile is of great importance for patients and caregivers. Zotepine is an antipsychotic with atypical properties and previous data have suggested a very favorable side effect profile.

Areas covered in this review: The aim of this review is to provide a broad knowledge base on the safety profile of zotepine deriving from currently available research results published in English medical databases. The focus of this research reports starts in the 1990s with zotepine's approval in Europe.

What the reader will gain: This paper incorporates data on placebo-controlled studies of zotepine as well as studies with comparator compounds also beyond the diagnostic boarder of schizophrenia regarding zotepine's safety.

Take home message: The take home message of this safety evaluation of zotepine is that compared to typical compounds zotepine induces less extrapyramidal side effects; however, in terms of comparing zotepine's safety with other atypical antipsychotics more studies are needed to draw final conclusions.     

Pharmacological management of polycystic kidney disease

Introduction: Autosomal-dominant polycystic kidney disease (ADPKD) represents a therapeutic challenge as effective treatment to retard the growth of cysts in the kidneys and the liver has not been available despite decades of intense basic and clinical research.

Areas covered: Several clinical trials have been performed in recent years to study the effect of diverse drugs on the growth of renal and hepatic cysts, and on functional deterioration of the glomerular filtration rate. The drug classes that have been tested in randomized clinical trials include the mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, the somatostatin analogues (octreotide, lanreotide, pasireotide), and most recently, the vasopressin V₂ receptor antagonist, tolvaptan. The results with the mTOR inhibitors were disappointing, but more encouraging with the somatostatin analogues and with tolvaptan. Additional drugs are being tested, which include among others, the SRC-ABL tyrosine kinase inhibitor, bosutinib, and the traditional Chinese herbal medication, triptolide. Additional therapeutic strategies to retard cyst growth aim at blood pressure control via inhibition of the renin–angiotensin system and the sympathetic nervous system.

Expert opinion: Given the accumulated knowledge, it is currently uncertain whether drugs will become available in the near future to significantly change the course of the relentlessly progressing polycystic kidney disease.     

Safety evaluation of tirofiban

Importance of the field: Heightened platelet activity is pivotal in the thrombosis underlying acute coronary syndrome (ACS). The glycoprotein IIb/IIIa inhibitor tirofiban is a powerful platelet inhibitor with demonstrated efficacy and safety across the spectrum of ACS. Despite tirofiban's impact on the platelet compared with placebo, only an excess in minor and importantly not major bleeding has been observed. Thrombocytopenia with tirofiban seems to be extremely rare and immediately reversible on infusion discontinuation.

Areas covered in this review: The review includes the rationale for potent antiplatelet therapy in the management of ACS, particularly patients at high risk for ischemic complications. Additionally, it provides an overview of tirofiban's pharmacology and summary of the clinical efficacy and safety data of two dosing regimens.

What the reader will gain: The reader will gain a perspective on the efficacy and safety data from the key trials of tirofiban.

Take home message: Tirofiban is safe and effective in patients with ACS. The single bolus dose regimen produces potent platelet inhibition resulting in significant improvement in clinical events over placebo when initiated just prior to percutaneous coronary intervention and at first medical contact. When compared with abciximab, tirofiban demonstrates similar efficacy though significantly lower rates of thrombocytopenia.     

Levodopa in Parkinson's disease: from the past to the future

Importance of the field: Levodopa is the mainstay of symptomatic treatment for Parkinson's disease (PD). Although other treatments have been developed in the last 30 years, most patients use levodopa in view of its superior efficacy in controlling PD symptoms. Unfortunately, levodopa is associated with long-term motor complications (motor fluctuations and dyskinesias). The main causes of these undesirable effects are the narrowing of the therapeutic window with the natural progression of the disease, pulsatile dopaminergic stimulation due to the short half-life of the drug and erratic absorption. Several studies suggest that PD control could be enhanced by changing the mode of levodopa delivery so as to ensure continuous and stable supply of the drug to the brain. The objective of this text is to review the ascertained strengths and limitations of levodopa in PD, starting from its history, and propose novel modes of usage designed to cover currently unmet medical needs.

Areas covered in this review: Medline literature search (from 1973 to date).

What the reader will gain: A perspective on the evolution of PD pharmacological treatment.

Take home message: Levodopa still is the best treatment for PD. Truly stable and controlled formulations that ensure clinical response should be developed to reduce the undesirable effects that restrict its efficacy.     

No Untoward Effect of Long‐Term Ketoconazole Administration on Electrocardiographic QT Interval in Patients with Cushing's Disease

Ketoconazole is listed among drugs that prolong QT interval and may increase the risk of torsade de pointes, a severe ventricular arrhythmia. This compound has recently been approved for treatment of Cushing's syndrome, a severe endocrine disorder. These patients harbour several risk factors for prolonged QT interval, for example hypokalaemia and left ventricular hypertrophy, but no study has evaluated whether administration of ketoconazole affects their QT interval. The aim of this study was to assess the QT interval in patients with Cushing's disease during long‐term administration of ketoconazole. Electrocardiograms from 15 patients with Cushing's disease (12 women, 3 men, age: 37.8 ± 2.66 years) on ketoconazole treatment (100 mg–800 mg qd) for 1 month to 12 years were reviewed retrospectively. QT interval was measured and corrected for heart rate (QTc). Measurements before and during ketoconazole treatment were compared and any abnormal QTc value recorded. Concurrent medical therapies were also documented. On average, QTc was superimposable before and during ketoconazole treatment (393.2 ± 7.17 versus 403.3 ± 6.05 msec. in women; 424.3 ± 23.54 versus 398.0 ± 14.93 msec. in men, N.S.). QTc normalized on ketoconazole in one man with prolonged QTc prior to treatment; no abnormal QTc was observed in any other patient during the entire observation period, even during concurrent treatment with other QT‐prolonging drugs. In conclusion, long‐term ketoconazole administration does not appear to be associated with significant prolongation of QT interval in patients with Cushing's disease. ECG monitoring can follow recommendations drawn for other low‐risk QT‐prolonging drugs with attention to specific risk factors, for example hypokalaemia and drug interactions.     

Pharmacotherapy of systemic sclerosis

Importance of the field: Systemic sclerosis (SSc) is an uncommon autoimmune disease with variable degrees of fibroproliferation in blood vessels and certain organs of the body. There is currently no cure. The purpose of this article is to review the current literature regarding pathogenesis and treatment of complications of SSc.

Areas covered in this review: All available articles regarding research related to SSc pathogenesis and treatment listed in the PubMed database were searched; relevant articles were then reviewed and used as sources of information for this review.

What the reader will gain: This review attempts to highlight for the reader some current thought regarding mechanisms of SSc pathogenesis and how autoimmunity relates to vascular changes and fibrogenesis of the disease, as well as providing a review of results of completed clinical trials and current ongoing clinical trials that address organ-specific or global therapies for this disease. This can aid physicians who provide medical care for patients with SSc.

Take home message: SSc is a complex autoimmune disease, the pathogenesis of which, although not completely understood, is under active study; new insights into pathogenesis are continually being discovered. Although there is no effective disease-modifying treatment for patients with SSc, quality of life, morbidity and mortality can be improved by using targeted therapy directed at affecting the consequences of damage to lungs, blood vessels, kidneys and the gastrointestinal tract. Innovative approaches to treating SSc are under intense investigation.     

Treating gestational trophoblastic disease

Importance of the field: Gestational trophoblastic disease is one of the few human malignancies that is curable, even in advanced stages of the disease. However, appropriate management and follow-up are essential components in curing this disease.

Areas covered in this review: Observational, retrospective and prospective studies evaluating the efficacy of medical and surgical management of gestational trophoblastic disease were analyzed to provide a comprehensive review of current and new treatment modalities. We searched PubMed, Medline and the Library of Congress from January 1965 to January 2010.

What the reader will gain: The reader will obtain information on how to classify gestational trophoblastic neoplasia (GTN) into low- and high-risk groups, as well as learn the medical and surgical management of low- and high-risk GTN and recurrent GTN. The effectiveness of treatment regimens and subsequent fertility is also reviewed.

Take home message: GTN is highly responsive to chemotherapy. However, surgery is an important adjunct in select cases. Even in advanced-stage or recurrent disease, cure can be achieved and fertility preserved.     

Pramipexole extended-release (once-daily formulation) for the treatment of Parkinson's disease

Importance of the field: Immediate-release pramipexole (P-IR) is indicated three times daily for the symptomatic treatment of early and advanced Parkinson's disease (PD). An extended-release formulation of pramipexole (P-ER) has been developed to allow a once-daily formulation and to provide more stable dopaminergic stimulation.

Areas covered in this review: This review summarizes clinical pharmacology and pharmacokinetics of P-ER for the treatment of early and advanced PD. The advantages and disadvantages of the strategies available at present for achieving continuous dopaminergic stimulation in the treatment of PD are discussed first. The pharmacological properties are then summarized. Finally, the clinical pharmacology and pharmacokinetics of P-ER are described.

What the reader will gain: The reader will gain knowledge of the development of P-ER, its current place in the pharmacotherapy of PD, and future directions.

Take home message: P-ER has been shown to be efficacious in early and advanced PD and it has the same clinical profile when administered once daily as P-IR administered three times daily. An overnight switching of P-IR to dose-equivalent P-ER is successful in 80% of patients with early PD.     

Pharmacotherapy of Zollinger–Ellison syndrome

Introduction: The role of pharmacotherapy in the management of patients with Zollinger–Ellison syndrome (ZES) is often equated with the medical management of acid hypersecretion. However, pharmacotherapy is also increasingly involved in the other management areas of these patients.

Areas covered: This paper reviews the role of pharmacotherapy in all aspects of the management of patients with ZES. Newer aspects are emphasized. This includes the difficulty of diagnosing ZES in patients taking proton pump inhibitors. Also covered is the role of pharmacotherapy in controlling acid hypersecretion and other hormonal hypersecretory states these patients may develop, including hyperparathyroidism in patients with multiple endocrine neoplasia type 1 and ZES; tumor localization; and the treatment of advanced metastatic disease. The last includes chemotherapy, liver-directed therapies, biotherapy (somatostatin/interferon), peptide radio-receptor therapy and molecular-targeted therapies including the use of mTor inhibitors (everolimus) and tyrosine kinase inhibitors (sunitinib).

Expert opinion: Pharmacotherapy is now involved in all aspects of the management of patients with ZES, with the result that ZES has progressed from being considered an entirely surgical disease initially to the present where medical treatment plays a major role in almost all aspects of the management of these patients.     

Pharmacotherapy of diabetes in cystic fibrosis patients

Importance of the field: Cystic fibrosis-related diabetes (CFRD) is a unique type of diabetes. In this article I review the pathophysiology of CFRD to gain insight as to why these patients have clinical features of both type 1 and 2 diabetes (DM). The reader will also learn that, although CFRD is different from type 1 and 2 DM, the development of diabetes-induced complications is similar to other types of DM. These complications can include retinopathy, nephropathy and neuropathy resulting from uncontrolled hyperglycemia; however, hyperglycemia and/or insulin deficiency in people with CFRD may exacerbate underlying CF problems, such as decreased pulmonary function and weight loss.

Areas covered in this review: Review medical therapy of CFRD including the over-riding goal of maintaining blood glucose levels in a range as close to normal as possible. The other important goal for diabetes management is to prevent diabetes complications and to encourage psychological wellbeing of the patient. However, as reviewed in this article, the underlying medical condition of people with CF and the basic metabolic differences caused by the disease often provide challenges in maintaining optimal diabetes control.

What the reader will gain: The reader will gain an understanding of how CFRD physically affects the patient with CF and the various pharmacologic therapies available for treatment of this type of diabetes. Furthermore they will gain insight into areas where more research is needed.

Take home message: Cystic fibrosis-related diabetes is unique to CF and thus deserves disease specific medical therapy.