Combination of clopidogrel and statins: a hypothetical interaction or therapeutic dilemma?

BACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and clopidogrel are frequently used in the treatment of patients with various cardiovascular disorders. The possibility of a drug-drug interaction between certain statins and clopidogrel has been extensively investigated in the literature recently. Investigators have proposed that the use of statins that are metabolized by the cytochrome P450 (CYP) system may diminish the conversion of clopidogrel to its active form by inhibiting the CYP3A4 isoenzyme. This inhibition could result in a decreased antiplatelet effect of clopidogrel, which could translate into an increased risk of cardiovascular events. METHODS: We performed a MEDLINE search of the literature from 1993-2005 to evaluate and discuss the existing data on a possible interaction between clopidogrel and statins and to provide clinicians with relevant and practical recommendations. Additional studies were identified from the bibliographies of the reviewed literature. RESULTS: Several articles were discovered that discuss this potential drug-drug interaction. Whereas some studies indicated that there was not a relevant interaction between statins and clopidogrel, other studies demonstrated that the concomitant administration of some statins with clopidogrel resulted in diminished platelet inhibition activity of clopidogrel. CONCLUSIONS: Although the interaction between certain statins and clopidogrel seems to be a pharmacologic certainty, the clinical relevance of this interaction needs further clarification. While investigators continue to evaluate the clinical relevance, we provide several recommendations for clinicians responsible for treating patients who require combination therapy with statins and clopidogrel.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

INTRODUCTION: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia. AREAS COVERED: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material. EXPERT OPINION: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

Introduction: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia.

Areas covered: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material.

Expert opinion: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Sunitinib in combination with clarithromycin or azithromycin – is there a risk of interaction or not?

BackgroundMacrolides are the most widely prescribed antibiotics. Clarithromycin is a well-known inhibitor of cytochrome P450 CYP3A4 and causes numerous drug interactions that are not found for azithromycin. CYP3A4 is involved in the metabolism of the new oral multikinase inhibitor sunitinib and its active N-desethyl metabolite (SU012662). This study investigated the effects of oral single dose of clarithromycin or azithromycin on the pharmacokinetics of sunitinib.MethodsRabbits were subjected to one of three study drug groups: sunitinib + clarithromycin (n = 6), sunitinib + azithromycin (n = 6), or sunitinib (n = 6). The rabbits were treated with sunitinib in the oral dose of 25 mg. Plasma concentrations of sunitinib were measured with validated HPLC method with UV detection.ResultsComparison of the sunitinib C_max for the sunitinib + clarithromycin group with that of the sunitinib group gave a ratio of 94.4% [90% confidence interval (CI) (76.1, 117.1)]; for the sunitinib + azithromycin group, the ratio was 106.2% (90% CI 85.5, 131.7). Comparison of the sunitinib AUC_0-t of the sunitinib + clarithromycin and sunitinib + azithromycin groups with that of the sunitinib group showed ratios of 86.86% (90% CI 69.7, 108.3) and 99.8% (90% CI 80.1, 124.5), respectively.ConclusionsNo significant effect of the coadministration of clarithromycin or azithromycin on the pharmacokinetics of sunitinib in rabbits was found in this study.     

Wilcoxon-Mann-Whitney test: stratify or not?

The Wilcoxon-Mann-Whitney (WMW) test is the most commonly used nonparametric method to compare two treatments when the underlying distribution of the outcome variable is not normally distributed. In the presence of stratum effects, the van Elteren (vE) test, a stratified WMW test, can be used to adjust for the stratum effect. We provide guidance on how to choose between the two tests in the design phase of clinical trials and in the analysis of clinical data. We show by simulations that both tests preserve the type I error rate regardless of the presence of the stratum effects. Therefore, the test with greater power is preferred. In comparing powers, we found that the WMW test is better when the stratum effects are small, whereas the vE test is better when the stratum effects are large. Finally, when the stratum effects are moderate, the decision depends on the shape of the distribution and the ratio of the number of strata and the number of subjects. In this case, results presented in this article or from similar simulations may be used to determine which test is better.     

Gulf war syndrome – a syndrome or not?

After the Gulf war, new diagnostic entity was claimed: the Gulf War Syndrome (GWS). A wide spectrum of exposures is widely discussed in order to explain the reported symptoms. Investigating tentative culprits we did not find clearly conclusive data about the existence of the GWS. The origin of described symptoms can be associated to the use of pesticides and the PB pill. However, the data about the use of both are influenced by a lack of precise records. Although other agents such as nerve agent exposure could not be definitively ruled out, its link to symptoms seems to be improbable.     

Atypical antipsychotics and polydipsia: a cause or a treatment?

Primary polydipsia (PP) is a frequent complication that affects many chronic schizophrenic inpatients. Due to possible lethal consequences, for example, hyponatremia, coma and death, it's fundamental for the physician achieving early diagnosis and treating this condition. The first step is identifying polydipsia by clinical, biochemical and pharmacological means. Nowadays, the pathophysiology of PP remains unclear, and this limits the possibility of detecting an appropriate drug treatment. Typical antipsychotics have been associated to a worsening of polydipsic behavior, while more recently atypical antipsychotics have been reported as being useful. However results are still mixed and controversial. It appears that risperidone and olanzapine are not clearly effective; clozapine may improve symptoms, although it is difficult to manage from a therapeutic point of view; quetiapine has been poorly studied so far, nonetheless it has given interesting results. Through a case study analysis, this report presents a brief, yet selective, overview of the current state of psychopharmacology in the treatment of PP with atypical antipsychotics in schizophrenia.     

Depression and acitretin: a true association or a class labeling?

The potential relationship between systemic retinoids used in dermatology and affective disorders is controversial. Acitretin, which is widely used in the treatment of psoriasis is part of this controversy secondary to its chemical relation to isotretinoin, a drug which has been associated with a large number of anecdotal case reports of depression and suicidal ideation. Moreover, an FDA package insert precaution regarding acitretin's association with depression and suicide has elevated the level of concern for patient safety. The objective of this article is to review the evidence in the literature regarding acitretin's association with affective disorders. After 12 years of worldwide use only two cases involving acitretin have been reported in the literature. In addition, despite many anecdotal cases involving isotretinoin, there have been no clinical studies that have proven a causal relationship between isotretinoin and depression or suicidal ideation. For acitretin there have been no systematic clinical studies that examine such a relationship. Moreover, it is notable that the FDA precaution regarding depression and suicide on the package insert of acitretin predates the publication of the aforementioned two cases. This suggests that a relationship between acitretin and affective disorders is a class labeling rather than a scientifically proven association.     

Prediabetes: to treat or not to treat?

The incidence of diabetes is continuously increasing worldwide. Pre-diabetes (defined as impaired glucose tolerance, impaired fasting glucose or both) represents an intermediate state, which often progresses to overt diabetes within a few years. In addition, pre-diabetes may be associated with increased risk of microvascular and macrovascular complications. Thus, reverting a pre-diabetic state as well as preventing the development of diabetes represents enormous challenge for the clinician. Lifestyle modification in pre-diabetic individuals was found particularly effective in the prevention of diabetes. However, compliance to lifestyle modification measures can be a crucial problem in the everyday clinical practice, especially in developing countries. During the last decade many studies support the use of anti-diabetic treatment schemes in pre-diabetic subjects to be advantageous. The American Diabetes Prevention Program (DPP) as well as other minor studies and meta-analyses has convincingly demonstrated the efficacy of metformin in this patient group. In addition, results of the 10 year DPP follow up have recently been published, demonstrating the long term safety and sustainability of metformin treatment benefits in this population. In contrast to metformin, the evidence from the use of other anti-diabetic agents (thiazolidinediones, a-glucosidase inhibitors, incretin mimetics) in pre-diabetic individuals is rather inadequate and prospective data is further needed. Furthermore, large scale studies with hard clinical endpoints are needed to delineate the effect of pre-diabetes treatment on macro- and microvascular complications. In conclusion, several strategies of patient management, mainly lifestyle modification and pharmacological interventions can prevent diabetes development in subjects diagnosed with pre-diabetes or even revert pre-diabetic state. However, whether this biochemical improvement can be translated into actual clinical benefit remains to be established.     

Redox-modulated xenobiotic action and ROS formation: a mirror or a window?

A number of xenobiotics require redox reactions to form the reactive intermediates involved in the ultimate toxic events (e.g., adduct formation). The same mechanisms lead to the formation of reactive oxygen species (ROS), which can themselves exert direct toxicity including, e.g., DNA oxidative damage or glutathione depletion. The occurence of both mechanistic features in xenobiotic activation and toxicity may raise some difficulties in ascertaining the respective roles of reactive intermediates versus ROS-related mechnisms. An example is provided by the toxicity mechanisms of mitomycin C (MMC) and diepoxybutane (DEB), which are commonly referred to as 'cross-linkers'. Their toxic actions, however, are well-known to be modulated via redox parameters, such as oxygen tension, antioxidants levels, or thioredoxin overexpression. The diagnostic assessment of Fanconi's anaemia (FA) relies on MMC and DEB sensitivity, which is usually referred to as 'cross-linker sensitivity'; thus the redox-dependent toxicities of MMC and DEB may have direct implications for the definition of FA phenotype. Another major aspect in ROS formation relies on the extensive evidence pointing to the requirement for oxidative, as well as nitrosative activities in triggering a number of key events in cell division and differentiation, and in early embryogenesis. In turn, antioxidants that may prevent ROS-associated cellular damage in adult cells may prove to exert adverse or fatal outcomes when administered in early life stages. The overall information available on xenobiotic redox biotransformation and on the physiopathological roles of ROS points to the need of addressing ad hoc studies that should take into account the multiplicity of mechanistic events involved.     

Proton pump inhibitors and clopidogrel: is it a significant drug interaction?

Importance of the field: Clopidogrel is indicated as part of a dual antiplatelet therapy (DAT) with aspirin for the prevention of cardiac related events in acute coronary syndromes particularly in patients undergoing percutaneous coronary intervention. Recently, there have been reports of a clinically significant drug interaction between clopidogrel and proton pump inhibitors (PPI), which are frequently co-prescribed to prevent DAT associated gastrointestinal (GI) bleeding.

Areas covered in this review: This review evaluates the risk of GI bleeding associated with DAT and the rationale for the use of PPI. This review also describes the pharmacokinetic and pharmacodynamic basis for the interaction and evaluates its significance on clinical outcomes. An extensive literature search on PubMed from January 1980 to August 2009 was performed. Additionally, abstracts and presentations from key cardiology meetings and press releases were reviewed for relevant studies related to the interaction.

What the reader will gain: At the end of the review, readers should have a complete understanding of the interaction and steps that can be taken to limit the interaction.

Take home message: There is a mechanistic basis and pharmacodynamic data supporting an interaction between PPIs, particularly omeprazole and clopidogrel. The clinical significance of this interaction is, however, still a subject of intense debate and ongoing research.     

Pharmacists and their customers: a personal or anonymous service?

Aims — To explore the existence and nature of the pharmacist‐customer relationship. Methods — A qualitative approach was adopted. Semi‐structured interviews were conducted with 20 customers recruited from two pharmacies differing in type and location: Pharmacy A, a multiple chain pharmacy in a more affluent area, and pharmacy B, a small chain pharmacy. Key findings — Customers' views differed according to the pharmacy from which they were recruited. Pharmacy B customers had a personal relationship with the pharmacist and used the pharmacy as a health care resource, while pharmacy A customers did not have a personal relationship with the pharmacist and used the pharmacy simply for medicine supply. Several pharmacy A customers had their own different local pharmacist whom they used for more personal advice and counselling. Both groups described disadvantages of multiple chain pharmacies. Consumerist behaviour was identified among customers whereby they preferred to control the provision of advice, assess it and act upon it. However, lack of information was mentioned by several interviewees, which suggested that different types of customers have different needs from the pharmacy. The pharmacist has therefore to recognise these different needs and to meet them accordingly to provide services, whether anonymous or personal, within their “extended role.” While most customers viewed pharmacists as drug experts and considered managing minor ailments to be part of their job, they were less supportive of a more extended role in the therapeutic monitoring of drug therapy. This presents a serious barrier to pharmacists wishing to extend their role into a more patient‐oriented and clinical domain. Conclusion — This study reinforces the importance of considering customers' views when policies and strategies concerning the development of the “extended role” are considered. Recognising customers' views helps the profession to adapt and respond to changing consumer behaviour. Issues identified through this in‐depth exploration of public perceptions of pharmacists have implications for the extension of pharmacists' roles into areas favoured and appreciated by customers.     

IL-6 and arthritis: a detrimental or beneficial mediator?

Acute inflammation is accompanied by changes in the concentrations of several plasma proteins. Cytokines play a crucial role in the regulation of inflammatory events. Inflammatory disorders such as rheumatoid arthritis are characterized by an overproduction of several cytokines including interleukin-6 (IL-6). Recent data suggest that IL-6 and other members of the IL-6-cytokine family have anti-inflammatory and immunosuppressive properties, and therefore may negatively regulate inflammatory processes.     

Biochemical and pharmacological characterization of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline: a biologically relevant neurotoxin?

Acute and long-term effects of exposure to reactive compounds as the result of environmental pollution, workplace conditions or dietary intake are suspected to be involved in the etiology of a variety of disorders, including neurodegenerative disorders such as Parkinson's disease. The recognition in 1970s that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxic by-product of illicit meperidine synthesis, elicits parkinsonian symptoms in primates, including man, prompted the search for naturally occurring analogs which might be involved in human disease. It has been suggested that one candidate, 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a potent dopaminergic neurotoxin, might be formed endogenously in humans following the administration of the hypnotic chloral hydrate or after the exposure to the industrial solvent trichloroethylene. Such spontaneous formation has, indeed, been recently reported. The biochemical and pharmacological characteristics of TaClo and related compounds are thus reviewed here, and their potential significance for human neurodegenerative disease discussed.