Current Drug Safety - Volume 4, Issue 2, 2009

If the man in the street were to be asked this question, his response might well be as follows. “Of course it must be serious. Is your question a serious one?” It seems self-evident that suicidality must be taken seriously. However, like many things that appear to be self-evident, the seriousness of the concept of suicidality should be questioned. The first step in trying to answer the question posed in the title of this editorial must be to define the concept of “suicidality”. The “Wiktionary” (web-based dictionary) defines suicidality as “the tendency of a person to commit suicide” or “a fatality that is an instance of suicide”. The Oxford English dictionary defines suicidality as “the quality or condition of being suicidal”. Do these terms accurately reflect the meaning of the word “suicidality” as used in the medical literature? It would appear that the answer is, emphatically, no. A commonly used definition in the medical literature is “suicidal acts or ideation”. Silverman et al. use the operational definition “considered suicide, attempted suicide” [1]. In a review of the reported link between suicidality and the use of SSRIs, we defined the term as “suicidal ideation, self-harm and suicide attempt” [2]. In other papers, suicidality is not defined but, by implication, it appears to be defined as “suicidal ideation, intent or attempt”. Are these definitions simply too broad to be of practical use? Suicidal ideation might include anything from a transient thought that life is not worth living to a persistent determination to end life with a clear plan, using a means that is very likely to be effective, such as jumping off a high building. Similarly, suicide attempt might cover anything from being seen in an accident and emergency department for having taken more than the recommended dose of aspirin through to shooting oneself in the head with non-fatal consequences. Most people who make apparent suicidal gestures do not seriously wish to end their lives but instead want to draw attention to their difficult predicament. Should this situation be classified as “suicide attempt” or should another term, such as “deliberate self-harm” be preferred? The problem with the term “deliberate self-harm” is that it would normally include a much wider variety of behaviours, for example, self-cutting, that are carried out with no intention of suicide.

The effects exerted by P1 and P2 as well as by A1 and A2 agonists and antagonists purinoceptor on the acute opiate withdrawal induced by morphine were investigated in vitro. Following a 4 min in vitro exposure to morphine, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. The P1 purinoceptor agonist, adenosine, was able dose-dependently to reduce morphine withdrawal whereas α,β- methylene ATP (APCPP), a P2 purinoceptor agonist, increased morphine withdrawal. Caffeine, a P1 purinoceptor antagonist, was able significantly and in a concentration dependent manner to increase morphine withdrawal whereas quinidine, a P2 receptor antagonist, reduced it. Also, the adenosine A1 receptor agonist, N6-Cyclopentyladenosine (CPA) was able to reduce dose-dependently naloxoneprecipitaded withdrawal whereas the selective adenosine A2A receptor agonist CGS 21680 increased the naloxoneprecipitated withdrawal phenomenon. Dipyridamole, a blocker of adenosine reuptake, induced a significant reduction of morphine dependence. Caffeine, an adenosine receptor antagonist, significantly increased the naloxone-precipitated withdrawal effect in a concentration dependent manner. The same effect was observed with 8-phenyltheophylline (8PT), an A1 adenosine receptor antagonist, whereas 3,7-dimethyl-1-propargylxanthine (DMPX), an A2 adenosine receptor antagonist, reduced the naloxone-precipitated withdrawal phenomenon. The results of our experiments indicate that P1 and P2 as well as A1 and A2 purinoceptor agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the purinergic system and opioid withdrawal.

To determine the frequency and the direct costs of adverse drug reactions, in an ambulatory population of the City of Buenos Aires, Argentina and its area of influence. A retrospective study was done during a period of three months on approximately 300.000 residents of the Buenos Aires area, gathering data according to the selected variables by means of the electronic capture of prescriptions dispensed in pharmacies of the area. This method enables the detection and registration of potential conflicts that may arise between a prescribed drug and factors such as: patient's demographic, clinical and drug profile. The analysis unit was defined as the happening of a moderate or severe adverse event reported by the system. The selected variables were the incidence of these effects and the direct cost was calculated as the value of the drugs that induced the adverse event. The events were classified according to the following interactions: a) drug- drug, b) drug-pediatrics, c) drug- gender, d) drug- pregnancy and abuse of controlled substances. The observed frequency shows great variability and the shortage of available data for ambulatory populations. We found 6.74% of reported events over the total of processed items, which generated an additional cost equivalent to 4.58% of the total pharmaceutical expenses. This study has only evaluated the cost occured by the use of a drug that will lead to an adverse reaction. Moderate and severe reactions were included regardless of the important indirect costs, hospitalization costs, tests, physician fees, etc.

Objective: This study was conducted with four objectives in mind, including: (1) characteristics of selfmedication; (2) storage of drugs at home; (3) factors associated with storage of drugs at home; and (4) comparison of the level and sources of knowledge between over-the-counter (OTC1) and prescription-only (POM2) medication consumers. Methods: A cross-sectional survey was conducted in 2007 using a semi-structured questionnaire on 300 clients of 21 drugstores (from a total of 214 drugstores in the city of Tabriz, Iran). Results: The highest demand for drugs was for analgesics (from OTC drugs) and antibiotics (from POM drugs). Of 325 requests for medications by 300 customers of drugstores in Tabriz, aged 15 years or higher, 50.8% (165 requests) were for OTC drugs and 49.2% (160 requests) were for POM drugs, twenty-five cases requested both OTC and POM medications. There were 246 customers (82%) who reported that they stored drugs at home. Physicians were reportedly the most common source of information about medications, while the highest-quality information was obtained from pharmacists. Conclusion: The frequency of home storing of medications was very high in this study. Customers, especially the lower education groups, had very little information about the side effects of drugs and differentiation of OTC and POM medications. Wayward use of antibiotics was very high among the drugstore clients. It seems that the information provided by the pharmacists can be one of the most effective ways for advancing the level of knowledge among the consumers of medications.

Aim: The aim of this study was to identify predictors of worsening renal function (WRF) among hospitalized patients in the internal medicine department. Settings and Design: A one-year, hospital-based prospective study. Methods and Material: This study was carried out at the internal medicine department of Al-Watani governmental hospital, Palestine. Inclusion criteria were: hospitalization for at least 48 hours and availability of at least three serum creatinine (Scr) measurements. WRF was defined, per hospital stay, as an elevation in Scr of ®0.5 mg/dL from baseline value if baseline Scr value was < 3mg/ dL and 1mg/dL if the baseline value was ® 3mg/dL. Baseline measurements were made at hospital admission. Statistical Analysis: Regression analysis (enter method) was carried out on two sets of variables: non-medication variables (Model I) and medication variables (Model II). Statistics was performed using SPSS version 15. Results: Three hundred and sixty one patients were included in this study. The prevalence of WRF among those who met the inclusion criteria was 40.2%. In the majority of cases, WRF started within the first 48 hrs of admission. Analysis of data indicated that eight variables were significantly associated with WRF: renal dysfunction (P< 0.0001), diabetes mellitus (P= 0.005), hypertension (HTN) (P< 0.0001), congestive heart failure (CHF) (P= 0.021), elderly (being > 65 years) (P= 0.003), number of diagnosis (P< 0.001), furosemide (P = 0.001) and calcium channel blockers (P= 0.01) administration at admission. Regression analysis indicated that HTN (P =0.033) and renal dysfunction (P= 0.007) were predictors of WRF in model I, while furosemide administration (P= 0.01) was the only predictor of WRF in model II. Conclusion: Hypertension, renal dysfunction and furosemide administration at hospital admission are predictors of WRF among hospitalized patients. Clinical characteristics available at hospital admission can be used to identify patients at increased risk for WRF. Patients receiving certain medications, especially loop diuretics, require close observation for potential development of WRF.

Objective: We report a case of neuroleptic malignant syndrome in a woman who assumed risperidone for schizoaffective disorders. Case Summary: A 45-year-old woman affected by schizoaffective disorders was admitted to Infectious Disease unit of Crotone Hospital because of a diagnosis of a fever of unknown origin. Clinical evaluation documented confusion and dysphoria, whereas chemical blood evaluation revealed acidosis and liver dysfunction. After few days she was transferred to the Operative Unit of Internal Medicine of San Giovanni in Fiore Hospital because of an increase in liver transaminases. Clinical evaluation showed the persistence of fever (38.8 degrees Celsius), with an increase in CPK, and liver enzymes. Pharmacological evaluation indicated a probable relationship between risperidone and NMS and led to a diagnosis of neuroleptic malignant syndrome associated with risperidone in a woman with schizophrenia. About seven days later, we recorded a complete resolution of her psychiatric symptoms. Discussion: We postulate a possible interaction between risperidone and neuroleptic malignant syndrome and we suggest to use risperidone with caution in both young and middle aged people.

Protease inhibitors (PIs) inhibit the cytochrome P450 CYP3A4 [1]. Because the metabolism of pravastatin is independent of the cytochrome P450 CYP3A4, this drug has become the preferred statin for treatment of dyslipidemia associated with human immunodeficiency virus (HIV) infection, with no cases of serious toxicity such as rhabdomyolysis reported to date. We report an HIV-infected patient receiving antiretroviral regimen consisting of atazanavir, ritonavir, emtricitabine and tenofovir who developed severe rhabdomyolysis approximately 4 months after increasing his pravastatin dose from 40 to 80 mg daily. His symptoms resolved within 10 days after the discontinuation of pravastatin and antiretroviral therapy. To our knowledge, this is the first case of rhabdomyolysis possibly caused by pravastatin in an HIV-infected patient.

Drug-induced photoirritation can be defined as an inflammatory reaction of the skin after topical or systemic administration of pharmaceutical substances. In many cases of drug-induced phototoxicity, skin reactions can be triggered by doses of sunlight regarded as harmless and most often in the ultraviolet A (320-400 nm). Several classes of drugs including antibacterials, thiazide diuretics, non-steroidal anti-inflammatory drugs, quinolones, and tricyclic antidepressants, even though nontoxic by themselves, may become reactive under exposure to environmental light, leading to undesired side effects. At least three types of drug-induced phototoxic skin reactions, including the photoirritant, photogenotoxic and photoallergic skin responses, have been recognized, and their mechanisms and pathologic features are quite different. The development of effective methodology to evaluate the photochemical/biological properties has been attempted over the past few years, since it would be a key consideration to predict and avoid the phototoxic risk in the early phase of the drug discovery process. The aim of this review is to describe the clinical features, pathogenesis and photochemical characteristics of drug-induced phototoxicity, and the current developments in research tools for predicting phototoxic potential of new drug entities are also addressed.

Although cohort studies which are based on intention-to-treat (ITT) approach offer a simple design with data which are simpler to analyse and results easier to interpret, such studies also intrinsically assume that any time-varying treatment effect that exits can be adequately estimated by a fixed-effect component. However, such an assumption may not reflect real-life drug use. Reflection of real-life clinical practice is a major strength of epidemiologic safety studies. The failure to properly reflect reality may result in effect under-estimation leading to false and irreproducible conclusions due to exposure misclassification. In effect, the use of nested case-control design is a concession that ITT in cohort design may not be adequate. But the nested design also has its own sources of bias, including confounding by indication. We present an overview of the counter-matched version of the nested case-control, case-crossover, case-in-time, case series and case-cohort designs as alternatives in prospective post-authorization safety studies.

Purpose: To identify potential safety profiles for small molecule multi-targeted kinase inhibitors for the treatment of advanced cancer. Methods: A systematic review was performed on published papers and meeting abstracts reporting safety outcomes in cancer patients for selected multi-kinase inhibiting small molecules with mainly anti-angiogenic activity. Specifically, we focused on single agent safety or early phase clinical development studies. Results: Of 1,923 studies identified in a MEDLINE search, 26 primary studies met eligibility criteria. Meeting materials included 7 papers, 6 posters, and 27 abstracts. When grade I-IV safety results of all 23 kinases were summed together, diarrhea, fatigue, nausea, rash, anorexia, vomiting, hand/foot syndrome, and hypertension were common, occurring in greater than 10% of patients. When only grade III and IV events are pooled together, fatigue and hypertension remain relatively common (>5%). When total adverse events were stratified by kinase or by kinase family, differences in safety profiles emerged. Conclusions: The results of this systematic review suggest that adverse events are common and varied for patients treated with a multi-kinase inhibitor. However, unlike some systemic cytotoxic therapies, serious and severe adverse events for multikinase inhibitors are less frequent. Sub-analyses by target kinase or kinase family demonstrate that certain groups of multi-kinase inhibitors can be associated with different safety profiles with unique adverse events.

The activation of T cells depends upon two signals, antigen-specific signal through the T cell receptor and nonantigen- specific costimulatory signal through antigen present cell surface molecules. In clinical transplantation, activated T cells orchestrate the immune response and result in allograft acute rejection. Allograft chronic rejection is also a serious complication and a major cause of late allograft loss after the transplantation. Costimulatory molecules involve in determining T cell activation, cytokine production, vascular endothelial cell damage, and induction of transplant tolerance. An emerging therapeutic strategy provides methods for inhibiting undesired T-cell activation, proliferation and function by blocking costimulatory interactions. This review article describes the roles of costimulation pathways in the progression of acute and chronic allograft rejection, particularly focuses on the recent development and application of costimulatory blockers in experimental and pre-clinical transplantation.