Current Clinical Pharmacology - Volume 6, Issue 1, 2011

Background: Takotsubo cardiomyopathy (TCM) is a syndrome of transient cardiac dysfunction precipitated by intense emotional or physical stress. Excessive sympathetic stimulation is believed to be central to the pathogenesis of this condition, thus drugs with sympathetic effect could precipitate TCM. The aim of this study was to conduct a comprehensive literature search to identify drugs that could precipitate TCM. Methods: Published case reports of TCM associated with drug-used were identified by a comprehensive literature search using the Medline/PubMed database, from January 1990 to November 2010. Search terms included Takotsubo cardiomyopathy, Tako-tsubo cardiomyopathy, stress cardiomyopathy, transient-left-ventricular ballooning syndrome, ampulla cardiomyopathy, apical ballooning syndrome, OR broken heart syndrome; together with “iatrogenic”, “drug-induced”, OR “induced by”. Only publications in English or Spanish, in Humans, and with links to full text were retrieved. Then, articles that recognized any drug as a possible drug-induced TCM were selected. Additionally, citation lists from identified articles were subsequently reviewed to identify additional relevant articles. Results: Overall, 401 different references were retrieved and 42 selected. Additionally, 5 articles were identified from citation list of selected articles. Thus, 47 articles with one report of more drugs as a possible trigger of 58 cases of SCM were reviewed, in which 20 different drugs were recognized as possible drug-induced TCM. Conclusion: There are some reports that linked the drug-used, mainly associated to sympathetic overstimulation, with the development of TCM. Consequently, drug-induced TCM would be considered in patients with TCM, particularly those in which no clear emotional or stress trigger could be identified.

Intrahepatic cholestasis of pregnancy is the most common liver disease occurring in the second half of pregnancy, characterized by pruritus and elevated serum bile acids often coupled to abnormal liver tests. Maternal prognosis is favourable with a complete symptom resolution after delivery, while preterm deliveries, fetal respiratory distress and stillbirths may occur. The goal of the pharmacological treatment of the disease is to improve maternal symptoms and biochemical alterations and, most importantly, to reduce fetal adverse events. The present manuscript will review the current knowledge on the pharmacological treatment of intrahepatic cholestasis of pregnancy.

Tigecycline is the first of a new class of antibiotics named glycylcyclines and it was approved for the treatment of complicated intra-abdominal infections and skin and skin structure infections and community-acquired bacterial pneumonia. Notwithstanding this, the tigecycline's pharmacological and microbiological profile encourage physicians' use of the drug in other infections. The aim of this study was to characterize the indications type, pathogens, and outcomes of patients who were treated with tigecycline. We analyzed the tigecycline prescriptions in 209 patients in 23 Latin American centres using an electronic form included in the website LatinUser™ (http://www.clinicalrec.com.ar). Sixty-six patients (31.5%) received tigecycline for approved indications, and 143 (68.5%) for “off label” indications (47% with scientific support and 21.5% with limited or without any scientific support). The most frequent “off label” use was ventilator-associated pneumonia (VAP) (76 patients). The etiology of infections was established in 88 patients (42%). Acinetobacter spp. (54.5%, in 65% of cases carbapenemsresistant), methicillin-resistant Staphylococcus aureus (12%), and extended spectrum β-lactamases-producing Enterobacteriaceae (10%) were the most common microorganisms isolated. Overall, attending physicians reported clinical success in 144 of the 209 patients (69%). Global mortality proportion was 35.5% (74/209 patients). Our study shows that the off label use of tigecycline is frequent, especially in VAP due to multidrug-resistant pathogens, where the therapeutic options are limited (e.g.: carbapenems-resistant Acinetobacter spp.). Physicians must evaluate the benefits/risks to use this antibiotic for indications that lack rigorous scientific support.

Objectives: Diclofenac a non-steroidal anti-inflammatory drug (NSAID) is widely used for the management of various musculoskeletal conditions. An injectable test formulation of diclofenac sodium (75 mg/mL) was prepared to facilitate reduction in injection volume as compared to already marketed formulations of diclofenac sodium (75 mg/3mL). The objective of this study was to compare the bioavailability of test formulation with the reference formulation given intramuscularly in healthy volunteers. Methods: This two way randomized crossover study was performed in 14 healthy, adult, Indian, male human subjects to compare bioavailability. The formulations were administered intramuscularly (intragluteal) to the volunteers in a two way randomized fashion with a wash out period of 6 days. Blood samples were collected till 6.0 h following drug administration. The samples were analyzed using pre-validated HPLC method. Results: The mean Cmax and Tmax for the test and reference formulations were 2.14 μg/mL, 1.91 μg/mL and 0.49 h, 0.50 h respectively. The mean AUC0-t for test and reference formulations were 3.79 μg.h/mL, and 3.43 μg.h/mL respectively. The mean AUC0-∞ for test and reference formulation were 4.03 μg.h/mL and 3.65 μg.h/mL respectively. The mean (90% CI) Cmax, AUC0-t and AUC0-∞ ratio (Test:Reference) were 1.15 (100.25-132.99), 1.10 (100.34-119.96) and 1.09 (100.78- 118.88), respectively. Conclusion: The test formulation shows a comparable AUC0-t and AUC0-∞ but a higher Cmax in comparison to the reference when given intra-gluteally. The lower volume of the test formulation offers advantage of injection at other sites, like deltoid region. Absence of propylene glycol in the test formulation could be advantageous in terms of improved tolerability. Hence, such formulations of previously well established molecules provide a new direction towards developing better and convenient dosing alternatives.

Introduction: Model-based drug development (MBDD) is recognized as an initiative able to improve success rates in the development of new anti-cancer agents. The use of pharmacodynamic (PD) biomarkers may be valuable in this context. The implementation of biomarkers in MBDD in oncology is the subject of this review. Methods: Literature was searched for articles and relevant conference abstracts concerning application of biomarkers in MBDD in oncology. First, papers are discussed concerning the use of biomarkers in modeling and simulation analyses in preclinical and early clinical phases of drug development. Subsequently, articles concerning late-stage clinical drug development are discussed. Results: Only a limited set of articles and conference presentations were identified. As expected, the majority of publications are concerned with targeted anti-cancer drugs. In the early development of novel anti-cancer agents, most publications concerned to the evaluation of dosing regimens for further clinical evaluation, or the identification of the required levels of target modulation. In general, combined analysis of clinical and preclinical data provide the most informative analyses. The use of biomarkers in late-stage drug development has mainly been confined to the prediction of phase III outcome on the basis of tumor growth data obtained from phase II trials, with tumor growth as biomarker for outcome. Conclusion: The use of suitable biomarkers in MBDD, has shown its merits in oncology, especially in early clinical development. Considering the low number of reports in literature, we would propose a more active use of presented techniques during all developmental phases of new anticancer agents.

Gastroesophageal reflux (GER) is defined as the passage of gastric contents into the esophagus. It occurs in healthy infants and can be considered physiological process. Uncomplicated GER can present with recurrent vomiting or regurgitation without any other symptoms and is usually managed by educating, reassuring, and guiding the parent without other intervention. GER disease (GERD) refers to the appearance of troublesome symptoms or complications (erosive esophagitis, ulceration, Barrett's esophagus) and may warrant acid suppression. Proton Pump Inhibitors (PPIs) are the most effective pharmacologic agents available for the treatment of children with GERD. In the pediatric practice only omeprazole, lansoprazole and esomeprazole are available over the first year of life. The empiric use in infants with nonspecific symptoms (excessive crying, regurgitation, feeding refusal, chronic cough) is frequent without randomized controlled study. Our paper will focus on the correct indications, dosages, duration of treatment and safety of PPI use in pediatric population.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, and its prevalence is rising worldwide. Bronchodilators remain the cornerstone of COPD treatment, especially inhaled β2-adrenergic receptor agonists and inhaled anticholinergics. Long-acting bronchodilators are considered more effective and convenient than short-acting bronchodilators for maintenance treatment in patients with moderate to very severe COPD. There are currently 3 long-acting inhaled bronchodilators available in the United States: the β2-adrenergic receptor agonists formoterol and salmeterol, and the anticholinergic, tiotropium. All 3 long-acting bronchodilators have been shown to be effective and well tolerated for the management of patients with stable COPD in clinical studies. The combination of β2-adrenergic receptor agonists and anticholinergics has been shown to provide superior bronchodilatory effect than either agent alone, possibly because of the different mechanisms of action of these agents. The current treatment guidelines recommend the use of one or more long-acting bronchodilators for patients with moderate to severe stable COPD who remain symptomatic with single-agent bronchodilator therapy. The objective of this article is to review clinical data on combined bronchodilator therapy with β2-adrenergic receptor agonists and anticholinergics in patients with COPD.

The study aimed to assess 75% of drug utilization (DU75%) in participating hospitals and identify quality indicators which should be used to monitor performance within the hospitals. In the European Surveillance of Antimicrobial Consumption (ESAC; http://www.esac.ua.ac.be) project anatomic therapeutic chemical (ATC), defined daily dose (DDD) and route of administration (RoA) were used for drug categorization. Data were collected for: antibacterials for systemic use; intestinal antibiotics; rifampicin; and nitroimidazole derivatives. Each hospital's annual data were analyzed separately (hospital-year) adding up to a total of 97 hospital-year data-sets. The drug most persistently present within DU75% was ciprofloxacin (84/97 hospital-years). Co-amoxiclav was the drug which most frequently ranked first (28 times). The number of drugs constituting the DU75% by substance ranged from 7-15 (median 12) and 8- 19 (median 15) by RoA which identified oral amoxicillin most frequently ranking first (17 times). In many hospitals the oral route accounted for most of the DU75%. Therefore, the extent of oral use was identified as a quality indicator which could be monitored using DU75% methodology. Since substantial variation both in extent and distribution of antibiotic use was observed, DU75% methodology is best adapted for intra-hospital consumption trend analyses or for hospitals with comparable characteristics and formularies. The number of drugs within DU75% was identified as another quality indicator. Thus, aspiring to decrease the consumption of overused drug classes should be set by the hospitals as a quality indicator on prescribing patterns.