Current Drug Safety - Volume 3, Issue 1, 2008

With the advent of highly active antiretroviral therapy (HAART), the reduction in overall mortality and morbidity in HIV patients has been accompanied by the emergence of liver disease as a leading cause of death. Elevated liver enzymes may be due to HAART or to other risk factors, including hepatitis co-infection and alcohol use. The different components of HAART are each associated with different risks of liver toxicity. Most drugs are metabolized by cytochrome P450 enzymes in the liver, and this may be affected by liver disease. The mechanisms for drug-induced liver injury include dose-dependent toxicity, hypersensitivity reactions, idiosyncratic reactions, mitochondrial toxicity, and immune reconstitution. The diagnosis of drug-induced liver injury is exclusionary. Once diagnosed, management generally involves discontinuation of the offending drug(s). A number of studies in progress are investigating whether treatment of hepatitis co-infection can improve the tolerability of HAART.

The withdrawal of the celebrity arthritis drug, rofecoxib (Vioxx) has sparked an intense discussion and controversy about the safety of the selective COX-2 inhibitors. Laboratory, epidemiological, and clinical studies have surged and continued to evaluate and understand the safety of coxibs and traditional NSAIDs. This paper reviews the scientific and clinical basis of not only the risks, but also the benefits surrounding the use COX-2 inhibitors and NSAIDs. Discussion, debate, opinions, regulatory and clinical recommendations have evolved since the unexpected emergence of cardiac thrombotic events from the use of these drugs. The evidence by which coxibs and NSAIDs can potentially attenuate or exacerbate cardiovascular disease by affecting endothelial function is assessed; and how NSAIDs and coxibs affect renal function and blood pressure is revisited. Several investigations provide insight into their mechanism and clinical application.

Background: Age related macular degeneration (AMD) is a progressive degenerative disease affecting central vision. Recent studies have shown that that statins may lower the risk of AMD potentially due to statins' antiinflammatory and anti-oxidative properties. We sought to further explore this association and also explore the role of angiotensin- converting enzyme inhibitors (ACE-Is) with respect to the development of AMD. Methods: We conducted a nested case-control study within a cardiovascular cohort that had undergone revascularization interventions in the Province of Quebec, Canada. Cases were identified as those with an ICD-9 code for AMD. For each case, four controls were randomly chosen from the cohort and matched to the cases by age and calendar time. Conditional logistic regression was used to estimate rate ratios and adjust for potential confounders. Results: Our nested case-control study consisted of 2,867 cases and 11,468. Current users of ACE-Is or statins were at a slightly higher risk of developing AMD (1.19 [1.07-1.33]) and (1.30 [1.17-1.44]) respectively. The results were similar for those using these drugs in the year prior. Conclusions: Based on the results of our study, statin and ACE-I use may be associated with an increase in the risk of AMD. Given that our study is an observational study, further studies are required to confirm or refute these findings.

Formal retraction notice of article entitled The Benefits and Risks of Different Therapies in Preventing Postoperative Nausea and Vomiting in Patients Undergoing Thyroid Surgery (Curr Drug Saf. 2008 Jan;3(1):27-34) 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.

Inhaled corticosteroids (ICS) are the cornerstone of asthma management both in adults and in children. There are some adverse effects related to the use of these drugs in all ages. Those adverse effects can be local or systemic. From the paediatric point of view, the main worry relates to the effect on growth and on the integrity of the HPA-axis. At the recommended doses, their effect on the latter is not clinically relevant and the slight modification of cortisol levels which occurs while taking them reflects their presence in blood. Although there is a slowing down on growth velocity, this is reduced to the first months of treatment which are followed by a catch up: there is quite consistent data supporting their lack of significant effect on the final height. Other adverse effects which may appear in relation to ICS treatment in children, including infants, are mild or very sporadic. However, it is important to bear in mind that a small proportion of asthmatic children may have a certain idiosyncrasy which makes them especially sensitive to ICS. Furthermore, a close follow up is warranted when, due to the disease severity, higher than the recommended doses of ICS are administered.

Gene therapy has progressed from early clinical trials to first commercial gene therapy drugs. While there is a long history with the side-effects and adverse effects of pharmaceutical drugs, drugs based on gene delivery have presented new challenges for researchers, clinicians and regulatory authorities. On the path from early pre-clinical research to final commercial products, gene therapy tools and production methods have undergone tremendous changes to improve safety and efficacy. Deletion of adenovirus replication genes E1 and E3 has progressed to gutless adenoviruses with all viral genes removed; similarly evolution of lentiviral vectors has progressed from first generation viruses to safer third generation self-inactivating vectors. Improved chromatographic methods have eased the purification of viruses and delivery reservoirs, such as collagen or silicon collars for cardiovascular gene transfer have decreased systemic leakage of viruses; together with tissue-specific promoters and imaging of the biodistribution of viral particles, gene therapy specificity and safety can be improved even further. This review will introduce gene delivery vectors used in gene therapy and highlight key approaches used to improve their safety.

Traditional medicine use is common in developing countries and increasingly popular in the western world. Despite the popularity of traditional medicines, scientific research on safety and efficacy is limited. However documented fatalities and severe illness due to lead poisoning are increasingly recognized to be associated with traditional medicine use. As society becomes more globalized, it is imperative for pharmacists and health care providers to learn about the safety of traditional medical practices. The information presented educates and alerts pharmacists and health care providers about the potential of traditional medicines to cause lead encephalopathy. Case reports were located through systematic literature searches using MEDLINE, CINAHL, AMED, CISCOM, EMBASE and The Cochrane library from 1966 to the February 2007. Reference lists of identified articles and the authors' own files were also searched. Inclusion criteria were cases of human lead encephalopathy associated with traditional medical practices. There were no restrictions regarding the language of publication. Data were subsequently extracted and summarized in narrative and tabular form. We found 76 cases of lead encephalopathy potentially associated with traditional medicine. Ayurvedic medicines were associated with 5 cases (7%), Middle eastern traditional medicines with 66 cases (87%) and 5 cases (7%) with other traditional medicines. Of the 76 cases, 5% were in adults and 95% were in infants and young children. Of the 4 adult cases, at least one was left with residual neurological impairment. In infants and young children, among 72 cases 8 (11%) were fatal, and at least 15 (21%) had residual neurological deficits. Traditional medicine users should be screened for lead exposure and strongly encouraged to discontinue metal128;“containing remedies. Therefore, the United States Food and Drug Administration and corresponding agencies in other countries should require and enforce heavy metal testing for all imported traditional medicines and "dietary supplements".

Busulphan (1, 4-bis [methanesulfonyl-y] butane) is a bi-functional alkylating agent that, in combination with cyclophosphamide, has been commonly used in conditioning regimens before hematological stem cell transplantation (HSCT) for nearly 20 years. Busulfan has a very narrow therapeutic index, and acute toxicity may be related to absorption and disposition of the drug and metabolites. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in infants and small children. An intravenous busulfan formula was approved nearly 40 years after the approval of the oral formulation. Busulfan levels expressed as the area under the concentration-time curve (AUC) higher than 1500 μM * minute were reported to increase the risk of developing veno-occlusive disease (VOD), while low levels may result in engraftment failure or disease relapse. VOD occurs in 11-40% of patients undergoing HSCT and is associated with death in 3.3% of patients. Measurement of individual plasma busulfan levels during oral or intravenous dosing to obtain an AUC is likely to provide the necessary elements to monitor the drug disposition, ensuring efficacy and preventing toxicity of patients undergoing HSCT. It is also important to consider the busulfan drug-drug interactions and adverse drug reactions that can develop during the therapeutic process. Busulfan therapeutic drug monitoring and dose-adjustment should be performed in specialized laboratories staffed by well-trained personnel.

Gadolinium is widely employed as a contrast agent for magnetic resonance imaging (MRI) and has generally been considered to be safe. As with iodinated radiocontrast, concern for contrast-induced nephropathy existed with gadolinium- contrast as it possessed many similar qualities (hyperosmolar, renal excretion via glomerular filtration). Early studies in low risk patients suggested a benign renal profile, however, recent studies raise the possibility of nephrotoxicity. In addition, reports of a previously rare condition entitled nephrogenic systemic fibrosis (NSF) have recently emerged in patients with advanced kidney disease and have been linked to exposure to gadolinium-contrast. Nephrogenic systemic fibrosis is a debilitating disorder in which progressive and severe fibrosis of the skin and other systemic organs that leads to significant disability and is associated with increased mortality. Initially reported most commonly in end stage renal disease (ESRD) patients receiving dialysis, it is also described in patients with severe acute kidney injury (AKI) and advanced chronic kidney disease (stages 4 and 5) not requiring dialysis. In addition to underlying kidney disease, the risk of developing NSF is increased with larger doses of gadolinium (or multiple exposures), exposure to specific gadolinium chelates (non-ionic, linear), underlying pro-inflammatory states (in particular vascular endothelial dysfunction), and perhaps some currently unrecognized cofactors. No clearly effective therapies exist for NSF, although recovery from AKI and establishment of normal kidney function with renal transplantation appear to reverse or stabilize the disease in some cases. Avoidance of gadolinium exposure appears to be the best approach for patients who maintain risk factors. When gadolinium exposure occurs, aggressive hemodialysis following exposure may be useful as gadolinium is efficiently removed by this extracorporeal technique. Peritoneal dialysis clearance of gadolinium is poor, but aggressive peritoneal dialysis prescriptions have not been studied for gadolinium removal.

Postpartum psychosis is a rare but serious psychiatric illness that follows delivery. Although controversy continues to surround its diagnostic status, it is generally considered an episode of bipolar disorder with accompanying psychotic features. The consequences of untreated postpartum psychosis can be serious due to the associated risk of suicide and infanticide; however, its close temporal association with childbirth should provide an opportunity to undertake prophylactic measures in women at risk for developing postpartum psychosis. This article reviews the literature concerning acute and prophylactic pharmacological treatment and suggests a comprehensive approach for management of postpartum psychosis.

Pathogens can infect almost all tissues and cause serious infections. Objective was to evaluate efficacy and safety of fixed-dose combination of Ceftriaxone-Vancomycin in patients with various infections. Patients (n=305) suffering from different bacterial infections (serious respiratory tract disease, bronchitis, gastrointestinal tract infections, urinary tract infection, cellulites and meningitis) were enrolled. Patients were randomized into two groups depending on severity of illness. Group A (n=106) and Group B (n=199) patients were given intravenous dose of fixed-dose combination 1.5 g B.D. and 3.0 g B.D. respectively for 3-10 days. Hemoglobin, total leukocyte count, erythrocyte sedimentation rate, urea, creatinine levels serum glutamyl oxaloacetic transaminase and glutamyl pyruvic transaminase activities were recorded before and on completion of the treatment. Most of patients (70%) were cured in seven or less than seven days of the treatment. Significant decrease in total leukocyte count, erythrocyte sedimentation rate levels were observed indicating patients were cured from the infections. No significant alterations were observed in hemoglobin, serum urea, creatinine levels, glutamyl oxaloacetic transaminase and glutamyl pyruvic transaminase activities on completion of treatment. The fixed-dose combination of Ceftriaxone128;“Vancomycin, is found to be effective in treating various bacterial infections without any toxic effect on liver and kidney. Patients well tolerated the drug without major adverse effects.