Current Drug Safety - Volume 6, Issue 2, 2011

Calcium metabolic disorders are frequent. The most frequent calcium-metabolic condition is osteoporosis with loss of mineral from the skeleton and an increased risk of fractures. Other frequent disorders are vitamin D deficiency leading to osteopmalacia and a number of other conditions both within the skeleton and in other organs. Until around 20 years ago the treatment options for osteoporosis were limited. With the advent of first the bisphosphonates, then the selective estrogen receptor modulators and strontium ranelate, and later parathyroid hormone and analogues, effective measures to prevent fractures became available. These drugs not only contributed to preventing bone loss but also to regain bone. This hot topic series in two papers demonstrate that new knowledge has uncovered a number of new signalling pathways in the bone that can be used to treat osteoporosis. These concepts offer the possibility of not only preventing bone loss but also to rebuild bone and thus with the existing therapies changing osteoporosis from a chronic incurable condition to a condition that not only can be treated but also cured through restoration of bone architecture and bone mass. The paper by Dr. Mosekilde et al. explores new anabolic therapies including treatments directed at the Wnt signalling system (sclerostin), parathyroid hormone (PTH) mimetics, and drugs that stimulate the calcium sensing receptor (CaSR) thus mimicking PTH action. These may all offer potent new treatment options for osteoporosis and a detailed outline of the development and potential is presented in the paper. The paper by Dr. Rejnmark et al. explores new antiresorptive pathways that may be used in addition to the pathways modulated by the bisphosphonates, and the selective estrogen receptor modulators. The paper explores osteoclast function in detail and presents new targets for therapy such as the RANK ligand antibodies that are already on the market, but also emerging pathways such as cathepsin-K inhibitors. Data on new selective estrogen receptor modulators such as bazedoxifene and lasofoxifene are also presented along with integrin antagonists, c-Src kinase inhibitors, inhibitors of the acidification process in the osteoclast lacunae, and GLP-2 agonists. .......

Anabolic treatment that remodels bone tissue and restores bone biomechanical competence is essential in the treatment of osteoporosis. In addition, long term antiresorptive therapy may have limitations because of the reduced renewal of bone tissue. The only pure anabolic drugs available at present are intact PTH (1-84) (Preotact®) and the truncated PTH (1-34) (Teriparatide, Forteo®) while strontium ranelate may possess antiresorptive as well as anabolic properties. The marketed antiresorptive and anabolic antiosteoporotic drugs have limitations in their use due to adverse effects or to the occurrence of rare but severe late complications. Furthermore, indications may be restricted by coexisting diseases or treatment duration may be limited. However, new anabolic drugs are being developed mimicking the effect of PTH, or targeting the calcium sensing receptor (CaSR) or the Wnt/β-catenin signalling pathway. The PTH mimetics are truncated or altered PTH fragments, parathyroid hormone related peptide (PTHrP) and calcilytics stimulating endogenous PTH secretion. Calcimimetics (e.g. strontium) and calcilytics (e.g. lithium) may also affect bone cells directly through the CaSR. The Wnt pathway that stimulates osteoblastic proliferation, differentiation and function may be activated by neutralizing antibodies to secreted inhibitors of Wnt signalling (e.g. Sclerostin or Dickkopf) or by small molecules (e.g. lithium) that inhibits the glycogen synthase kinase 3β mediated degradation of β-catenin. Finally, blocking of activin A by soluble receptor fusion proteins has been shown to increase bone mass by a dual anabolic-antiresorptive action. The present paper summarises the physiological background and the present evidence for these effects.

Bisphosphonates have for many years been the mainstay of antiresorptive treatment, acting predominantly by inducing apoptosis of mature osteoclasts. During recent years, an advanced understanding of the genetic and biological mechanism involved in bone resorption has revealed new therapeutic targets for antiresorptive treatments. Several of these new drugs act by targeting specific pathways within the osteoclastic cells and may reduce bone resorption without a concomitant decrease in bone formation. Such an uncoupling may result in a net bone formation, thereby causing a bone “anabolic” effect through an antiresorptive mechanism. Moreover, in contrast to bisphosphonates several of the new drugs are not deposited within bone and therefore their duration of action is related to their presence in plasma. Accordingly, their antiresorptive effect is quickly reversible, which may be advantageous if reversal of a suppressed bone turnover is warranted under certain clinical conditions such as osteonecrosis of the jaw. In this paper, we will review the pharmacological properties and clinical effects of the drugs that recently have been (denosumab, bazedoxifene, lasofoxifene), or currently are being tested in large phase III clinical trials (Catepsin K inhibitor), as well as drugs that have shown potential beneficial effects in phase I or II trials and may be tested in upcoming phase III trials (integrin antagonists, c-Src kinase inhibitor, inhibitors of the acidification process within the resorption lacuna, and glucagon-like peptide).

Hypoparathyroidism (HypoPT) is one of the few major hormone deficiency diseases that are not usually treated with the missing hormone. Bovine parathyroid hormone (PTH) has been purified and used as an experimental treatment, as long as in 1928 by Fuller Albright. Treatment, however, was abolished mainly because of antibody formation and costs. The recent approval of fully humanized truncated parathyroid hormone (Teriparatide, PTH (1-34)) and intact parathyroid hormone (Preotact, PTH(1-84)) for treatment of osteoporosis, has made the PTH drugs more accessible and thereby made clinical trials with PTH treatment of HypoPT feasible. Recent clinical trials have shown that treatment with PTH (1-34) and PTH (1-84) can stabilize plasma calcium, normalize plasma phosphate and reduce urine excretion of calcium. Furthermore, it seems that some patients with hypoPT experience an improved quality of life when treated with PTH compared with conventional treatment with 1α-hydroxylated vitamin D metabolites and calcium supplements.

Background: Primary hyperparathyroidism (PHPT) and vitamin D insufficiency are two very frequent conditions. In cases where the combination of both vitamin D insufficiency and PHPT is diagnosed, vitamin D repletion is an option. However, only limited evidence exists for this treatment. Objective: The aim of this review is to describe different aspects of concomitant vitamin D insufficiency and PHPT and in this setting to evaluate existing evidence on safety and possible outcome of vitamin D treatment. Methods: Background literature was found based on a search in pubmed.com and scirus.com. Results: Multiple association studies support the hypothesis that the clinical presentation of PHPT is more severe in patients with vitamin D insufficiency. Treatment with vitamin D in PHPT may decrease PTH levels and bone turnover and potentially increase bone mass in various compartments. However, some patients experience increasing plasma or urine levels of calcium, triggering either vitamin D withdrawal or surgery. Conclusion: Measurement of vitamin D in PHPT is important to fully assess the disorder. The causality of the frequent coexistence of vitamin D insufficiency and PHPT is not fully understood. Vitamin D treatment is recommended and may decrease PTH levels in PHPT. However, there is no randomized controlled trial to prove any beneficial effect. For safety reasons, it is recommended to monitor plasma and urinary calcium during treatment. Furthermore, the effect of vitamin D repletion on other outcomes like quality of life, muscle function and CNS symptoms should be assessed.

Hyperparathyroidism is a condition with elevated parathyroid hormone (PTH). The increase may be due to a) primary hyperparathyroidism which is caused by adenoma of one or more parathyroid glands or hyperplasia of all four glands, b) secondary hyperparathyroidism, which may be caused by deficiency in vitamin D or uremia, and 3) tertiary hyperparathyroidism, which most often is the result of a long-standing, severe secondary hyperparathyroidism, which has turned autonomous once the cause of the secondary hyperparathyroidism has been removed. Many new treatment options have been introduced in recent years. Cinacalcet is a calcium sensing receptor agonist, which by stimulating the receptor decreases PTH and calcium levels. It may be used in primary hyperparathyroidism, secondary hyperparathyroidism caused by uremia, which may not be controlled with calcium and activated vitamin D. It may also be used in tertiary hyperparathyroidism. Newer analogues of vitamin D such as paricalcitol have also been introduced, which may have an advantage over traditional compounds such as alphacalcidol and calcitriol.

The association of antidepressants with suicidal thought in people aged up to 25 year is a thorny issue. Balancing risk with benefit must always be at the core of any decision to treat and when the risk is an increased risk of suicide then a balanced decision can be difficult to make. Some clinicians who have been successfully treating patients using antidepressants have felt skepticism with these studies, finding them to be not reflective of their personal clinical experience. It may be wondered by some whether highlighting the link between suicidal thoughts and antidepressants may paradoxically lead to an increase in suicide by reducing the number of cases treated, however there is no evidence that this has occurred. The association between antidepressants and suicidal thought may be unpalatable, but as with all new research the only way it can be judged is by the evidence to support it. The weight of evidence to demonstrate the association between antidepressants and suicidal thought in young people is convincing although the risk is low, estimated at one case of emerging suicidal ideation or suicide attempt for every 143 pediatric patients treated [1]. This risk is too low to displace antidepressants as the first line of treatment for depression but is too high a risk to be ignored. The risk is also too low to be recognized based on clinical experience alone as it is low enough to be imperceptible amongst suicides which occur due to depressive illness independent of antidepressant treatment. Only large studies are sufficiently powered to detect suicidal thought associated with antidepressant treatment. Clearly further studies would be helpful, especially if they can help characterize those at greatest risk. This is why the study by Lucy Goldsmith and Joanna Moncrieff in this issue of Current Drug Safety is an important step towards improving our understanding of antidepressant safety. These researchers find a link between increased suicidal impulses and emotional blunting and emotional instability. Treating clinicians are urged to monitor for risk of suicide after initiation of antidepressant treatment, typically more frequently for the first four weeks of treatment and as indicated thereafter. However, if there is no history of suicidal thought or attempt and the patient does not admit to suicidal thought, suicidality may be missed by the treating clinician, ending in tragedy. Studies that provide new insights into this serious problem may lead to improvements in the effectiveness of monitoring patients for suicide risk, ultimately leading to better outcomes for patients.

Although antidepressants are known to produce some adverse mental effects, their full range of psychoactive effects has not been systematically described. It has been suggested that some antidepressants are associated with increased suicidal thoughts and actions, but the issue remains controversial, and the mechanism of association, if any, is unclear. In the current study we examined descriptions of the major psychoactive and physical effects experienced by users of two commonly used antidepressants, fluoxetine and venlafaxine, as reported on a patient-oriented web site. We categorised responses into common psychoactive effects and explored associations among those effects, including reported increases in suicidal ideation. In the 468 descriptions we examined, the most commonly reported drug-induced psychoactive effects were sedation, impaired cognition, reduced libido, emotional blunting, activation (feelings of arousal, insomnia and agitation) and emotional instability. There were no differences between the two drugs in the prevalence of reporting of these effects. Activation effects were associated with involuntary movements, suggesting a physical basis. Emotional blunting was associated with cognitive impairment, reduced libido and sedation. Emotional instability, which included the reported side effects of increased anxiety, anger, aggression and mood swings, was related to activation effects and was more commonly reported by younger respondents. Increased suicidal thoughts were rare but were associated with both types of emotional effect. The effects identified are consistent with other data, and suggest that some antidepressants may induce emotional effects that are experienced as unpleasant, may impact on the symptoms of mental disorders, and may account for the suggested occurrence of increased suicidal impulses in some users.

Formal retraction notice of article entitled Current Review of Ramosetron in the Prevention of Postoperative Nausea and Vomiting (Curr Drug Saf. 2011 Apr;6(2):122-7) by Dr Y. Fujii. This article is being retracted as a result of: Failure of Dr. Fijii's institution as well as of himself to rationalize the legitimacy of the study and/or its data as stipulated in request by the Editors-in-Chief of the journals extended on April 9, 2012. Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Use of zolpidem, a short-acting imidazopyridine hypnotic, has not been associated with teratogenic effects in usual clinical doses. We report a case of fetal neural tube defects occurring in a female dependent on zolpidem and consuming high doses in the first trimester of pregnancy. Possible mechanisms by which high dose zolpidem may lead to teratogenicity are discussed. Clinicians are advised to be aware of the risks of high-dose zolpidem abuse in early pregnancy.

Controversial reports exist regarding the administration of spinal anesthesia in achondroplastic dwarfs regarding safety, dose, drug choice, in obstetric patients. Bony characteristics such as vertebral anomalies, lordosis and lumbar scoliosis, limited mouth opening and cervical spine instability make the administration of anesthesia to these patients truly a challenge. Here we demonstrate that low dose meperidine and bupivacaine spinal anesthesia in an achondroplastic parturient for ceserean section, was administered successfully after careful evaluation, consideration of risks, and awareness of potential complications.