Current Drug Safety - Volume 3, Issue 3, 2008

Antiepileptic drugs (AEDs) have traditionally been associated with osteoporosis. However, recent studies have only shown a very limited increase in the risk of fractures with the use of some but not all AEDs. Patients with epilepsy have an increased risk of fractures, but this increase is mainly linked to fractures sustained during seizures. Patients with epilepsy may also have a decreased bone mineral density but this decrease is far too small to explain the increase in fracture risk. The decrease in bone mineral density is seen mainly in children with complicating diseases and developmental disorders that lead to vitamin D deficiency. Much of the increase in fracture risk may be due to the underlying disorder and the severity of seizures rather than to the drugs used to treat epilepsy. The prevention of seizures seems to be of greater importance than any potential detrimental effects of the AEDs on the skeleton, provided that vitamin D status is kept at an optimal level. From a fracture point of view most AEDs seem to be relatively safe.

Drugs used to treat cancer may affect the skeleton in several ways, the most important being a decrease in sex steroid levels. This may induce rapid bone loss. Tamoxifen is a partial oestrogen receptor agonist and antagonist (classified as a selective oestrogen receptor modulator or SERM). As it has agonistic effects on oestrogen receptors of bone it increases bone mineral density and thus may potentially prevent fractures. In contrast aromatase inhibitors such as anastrozole lead to a decrease in bone mineral density and an increased risk of fractures. Most high-dose intravenous chemotherapeutic regimens induce rapid bone loss from effects on the gonads with induction, for example, of premature menopause. Low-dose oral agents such as methotrexate are not associated with an increased risk of fractures. Androgen deprivation therapies such as LHRH agonists in breast cancer are also associated with an increase in bone loss and an increased risk of fractures. With the increasing long-term survival of patients with cancer, preventive measures against osteoporosis must be considered.

Cardiovascular diseases are common and occur mainly in the elderly in whom osteoporotic fractures also are very common. Because of this, it is of importance to establish whether drugs used in the treatment of cardiovascular diseases affect bone, in order to minimise any possible adverse effects. In the majority of studies, treatment with thiazide diuretics, statins, digoxin, angiotensin-converting enzyme (ACE)-inhibitors, and organic nitrates have not been associated with harmful effects on bone. On the contrary, treatment with these drugs may improve bone strength but because there is a lack of randomised controlled trials (RCTs) with fracture as a primary outcome measure, these drugs should not be prescribed for fracture prevention. In RCTs, treatment with loop diuretics have been shown to increase plasma levels of parathyroid hormone and decrease bone mineral density. In epidemiological studies, treatment with loop diuretics as well as treatment with amiodarone has been associated with an increased risk of fracture. In view of the conflicting results from published studies, no conclusions can be drawn on potential bone effects of treatment with oral anticoagulants, β-blockers, and calcium channel blockers.

Many central nervous system active drugs can alter postural balance, increasing the risk of fractures. Anxiolytics and sedatives include the benzodiazepines, and these have been associated with a limited increase in the risk of fractures, even at low doses, probably from an increased risk of falls. No systematic differences have been shown between benzodiazepines with long and short half-lives. Although the increase in risk of fractures was limited, care must still be taken when prescribing for older fall-prone subjects at risk of osteoporosis. Neuroleptics may be associated with a decrease in bone mineral density and a very limited increase in fracture risk. Antidepressants are associated with a dosedependent increase in the risk of fractures. The increase in relative risk of fractures seems to be larger with selective serotonin reuptake inhibitors (SSRIs) than with tricyclic antidepressants. The reason for this is not known but may be linked to serotonin effects on bone cells and the risk of falls. With the wide use of SSRIs, more research is needed. Lithium is associated with a decrease in the risk of fractures. This may be linked to its effects on the Wnt glycoprotein family, which is a specialised signalling system for certain cell types.

Oral corticosteroids are associated with an increased risk of fractures from negative effects on sex steroids and vitamin D with a negative calcium balance, together with negative effects on the bone cells and the bone matrix. However, the increase in fracture risk with oral corticosteroids seems more linked to daily than to cumulative dose. A small daily dose may consequently be more detrimental than a large cumulative dose given as intermittent doses. Topical corticosteroids administered locally in the eyes, ears, in the mouth, on the skin, and rectally are not associated with an increased risk of fractures. Inhaled corticosteroids are not associated with an increased risk of fractures, except at very high doses that are much higher than the doses usually administered. With regard to the prevention of fractures, the use of topical corticosteroids may be preferred over oral administration where feasible. More research is needed to determine practically applicable intermittent dosing regimens for corticosteroids, replacing daily administration, to assess if this can have the same beneficial clinical effect but avoid, or at least reduce, the risk of osteoporosis and fractures.

Medications to treat pain are in widespread use and any change in the risk of fracture may consequently have a significant impact at a population level. Strong analgesics of the opiate and opiate-like group are associated with an increased risk of fractures probably from an increased risk of falls resulting from the dizziness induced by these drugs. However, not all strong analgesics are associated with an increased risk of fractures. The differences are not readily explained from variations in pharmacokinetic properties. Weak analgesics mainly interact with the prostaglandin system; these drugs include non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid and acetaminophen. Acetaminophen is associated with an increased risk of fractures while acetylsalicylic acid is not. Some but not all NSAIDs are associated with an increased fracture risk, and the differences are not explained by variations in pharmacokinetic properties. More research is needed to determine if some analgesics are safer than others with respect to fracture risk.

Osteoporotic fractures, particularly hip fractures, can have a devastating impact on the well-being of the elderly population. Recently, two population-based observational studies reported a highly important association between the use of potent acid suppressive therapy and an increased risk of hip fractures. The mechanisms underlying such an association are not clear. However, a careful review of the existing evidence seems to suggest that the main physiologic consequences of proton pump inhibitor therapy may each have a theoretical influence on bone metabolism. Specifically, inhibition of the osteoclastic proton pumps may reduce bone resorption, while profound acid suppression could potentially hamper intestinal calcium absorption, and secondary hypergastrinemia may enhance bone resorption through the induction of parathyroid gland hyperplasia. However, the existing data are clearly too limited for us to draw any definitive conclusions, and more studies are urgently needed to delineate the physiologic relevance of these theoretical mechanistic links, individually and collectively.

Introduction: Aripiprazole is a new antipsychotic agent that has proven safe and efficacious in controlled clinical trials. However, few published data on its effectiveness and safety when used in augmentation and combination are available. Methods: Our study aimed to determine the functional effectiveness and safety of different combinations of aripiprazole with other psychotropics in resistant patients. All acute not selected (15) patients treated with aripiprazole and other psychotropics between February 2005 and May 2007 are included. Results: Mean follow-up 20.4 days. Main diagnosis was schizophrenia (40%) and mean dose of aripiprazole was 25 mg/d. Resistant patients received initially multiple psychotropics (mean 3.3) and their functional status was very low. A significant functional improvement was observed after admission in most (12) of them. Only three patients experienced mild to moderate improvement; another three patients showed extrapyramidal symptoms. No dermatological reactions or adverse effects were observed with lamotrigine association. Discusions: The combination of aripiprazole with other psychotropics was well tolerated. No significant new adverse reactions were observed. In a short term follow-up, our results show a good tolerability of aripiprazole in combination with other psychotropics of different groups.

Developmental immunotoxicity (DIT) recently emerged as a significant concern for drug safety and was the topic of several recent scientific forums in Europe, North America and Asia. The heightened concern is based on several observations: 1) many childhood diseases with recent increases in prevalence, such as asthma, allergic disease, leukemia and certain infections, have clear linkages to the immune system and immune dysfunction, 2) the developing immune system has been shown to be a particularly sensitive target for xenobiotic-induced adverse outcomes, 3) immunotoxicity assessment following adult exposure to xenobiotics is ineffective for predicting immunotoxic risk in the non-adult and 4) in several cases developmental immunotoxicity to low-level xenobiotic exposure can take the form of immune dysfunction in the absence of readily detected morphometric/histological alterations. The present review examines harmonized preclinical drug safety guidelines for immunotoxicity in light of environmentally-mediated childhood disease trends as well as research-based mechanisms for DIT. Because none of the guidelines was designed to address risk of DIT, suggestions are offered for closing the early-life immune dysfunction data gap. A longer-term goal is to help narrow the difference between current guideline expectations and the known sensitivity of the developing immune system for potential adverse outcomes.

Approximately 7000 deaths occur yearly in the United States as a result of medication errors, and 1.5 million people are harmed by adverse drug events at a cost of $3.5 billion per year. Computerized order entry has been shown to decrease the number of medication errors by 55% to 80 % in the hospital. This has led many to advocate the use of electronic medical records in both the inpatient and outpatient setting. However, there is little evidence at present that electronic medical records reduce adverse drug events in the outpatient setting. This may be largely due to the quality of medication lists in the medical record: Among complicated patients, complete agreement between the medication list and what the patient is actually taking occurs in only 5% of patients. Unless there is improved medication reconciliation, it will be difficult to realize the potential safety benefits of information technology. An accurate medication list requires a healthcare team dedicated to obtaining and maintaining this information.

Formal retraction notice of article entitled Clinical Strategies for Preventing Postoperative Nausea and Vomitting after Middle Ear Surgery in Adult Patients (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.