Statin loading in patients undergoing percutaneous coronary intervention for acute coronary syndromes: a new pleiotropic effect?

Abstract

Intensive statin treatment has proved beneficial in patients with acute coronary syndromes. However, this benefit may apply only to those undergoing percutaneous coronary intervention (PCI). Loading, preloading or reloading with high dose(s) of a statin may decrease major adverse cardiac events, revascularization of both target and non-target vessels as well as myocardial necrosis after PCI. It seems that different actions of statins are responsible for their protective role in target vessel and non-target vessel revascularization procedures. This editorial discusses the results of statin loading trials and comments on the possible mechanisms involved.     

Clopidogrel: a CURE in acute coronary syndromes?

The standard approach to preventing acute coronary syndromes (ACSs)has been to inhibit platelet aggregation with aspirin and to inhibit blood coagulation with low molecular-weight heparin (LMWH). Even with this combination there is still a substantial short and long-term cardiovascular risk. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial [1] compared clopidogrel plus aspirin against aspirin alone in patients with ACSs. The clopidogrel regimen was a loading dose of 300 mg p.o. followed by 75 mg/day and the recommended dose of aspirin was 75 - 325 mg/day. The first primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction (MI) or stroke and this occurred significantly less often in the clopidogrel than the placebo group (9.3 vs. 11.4%). Although there were more clopidogrel patients with life-threatening bleeding (clopidogrel 2.2%, placebo 1.8%), this represented GI haemorrhages and bleeding at sites of arterial puncture rather than fatal bleeding. This trial suggests a role for clopidogrel in the long-term treatment of ACSs.     

Management of patients with acute coronary syndromes: what is the clinical role of direct thrombin inhibitors?

Despite important pharmacokinetic and biological advantages of direct thrombin inhibitors over heparin, early randomised trials failed to demonstrate a clear net clinical benefit of these agents compared with heparin because of a higher bleeding risk, particularly with hirudin, and only modest efficacy gains. More recently, however, a systematic review of the direct thrombin inhibitor trials based on individual patient data as well as the results of the 17 000-patient Hirulog Early Reperfusion or Occlusion (HERO)-2 trial have confirmed the superiority of both hirudin and bivalirudin over unfractionated heparin in patients with acute coronary syndromes and undergoing percutaneous coronary intervention. Ongoing trials should further clarify the role of bivalirudin in patients undergoing percutaneous coronary intervention in the context of glycoprotein IIb/IIIa inhibitor use, while additional studies are required to define the role of direct thrombin inhibitors used in conjunction with other newer antithrombotic and/or thrombolytic strategies in patients with acute coronary syndromes.     

What is new in the treatment of multiple sclerosis?

Multiple sclerosis (MS) is considered an autoimmune disease associated with immune activity directed against central nervous system antigens. Based on this concept, immunosuppression and immunomodualtion have been the mainstays of therapeutic strategies in MS. During the last decade new therapies have been shown to significantly improve MS disease course. The effective therapies have led to a better understanding of MS pathogenesis and further development of even more efficient therapeutic interventions. Recombinant interferon (IFN)beta represents the first breakthrough in MS therapy. Three large placebo-controlled, double-blind studies and several smaller studies have demonstrated the efficacy of different forms of IFNbeta administrated by either subcutaneous or intramuscular routes and at different doses in patients with active relapsing-remitting multiple sclerosis (RR-MS). The three IFNbeta drugs are IFNbeta-1b and two IFNbeta-1a preparations (Avonex and Rebif). Although each clinical trial had unique features and differences that make direct comparisons difficult, the aggregate results demonstrate a clear benefit of IFNbeta for decreasing relapses and probability of sustained clinical disability progression in patients with RR-MS. All forms of IFNbeta therapy had beneficial effects on the disease process measured by brain magnetic resonance imaging (MRI). IFNbeta-1a (Avonex) also showed benefit in slowing or preventing the development of MS related brain atrophy measured by MRI after 2 years of therapy. Glatiramer acetate, the acetate salt of a mixture synthetic polypeptides thought to mimic the myelin basic protein showed a significant positive results in reducing the relapse rate in patients with RR-MS. Follow up of these patients for approximately 3 years continued to show a beneficial effect on disease relapse rate. Recent MRI data supported the beneficial clinical results seen with glatiramer acetate in patients with RR-MS. Recent studies using intravenous immune globulin (IVIG) suggest that IVIG could be effective to some degree in patients with RR-MS. However, there is not enough evidence that IVIG is equivalent to IFNbeta or glatiramer acetate in the treatment of patients with RR-MS. There have also been recent therapeutical advances in secondary progressive MS (SP-MS). A recent large phase II, placebo-controlled study with IFNbeta-1b in patients with SP-MS convincingly documented that IFNbeta-1b slowed progression of the disease independent of the degree of the clinical disability at the time of treatment initiation and independent of presence of superimposed relapses. Mitoxantrone, an anthracenedione synthetic agent, was also shown to be effective as treatment for active SP-MS. It is well tolerated but the duration of treatment is limited by cumulative cardiotoxicity. There is a growing consensus that disease-modifying therapies should be initiated early in the course of the disease before irreversible clinical disability has developed. Different therapies should be considered and tailored based on patient condition. Combination therapies could be considered as a therapeutic option for patients that failed therapies with IFNbeta and/or glatiramer acetate. Currently, there are new ongoing studies testing safety and/or efficacy of different combination regimens (i.e. azathioprine with IFNbeta, IFNbeta with glatiramer acetate, or pulses of intravenous cyclophosphamide with IFNbeta). Determining the effect of different therapies on the course of the disease within large clinical studies appears easier than determining individual responsiveness. Therefore, standardised methods for evaluating individual patients receiving disease-modifying therapies and development of effective therapeutic algorithms are needed.     

Is there any future for felbamate treatment?

Felbamate (2-phenyl-1,3-propanediol dicarbamate), a representative of novel antiepileptic drugs (AESs), proved to have broad-spectrum anticonvulsive activity. Particularly beneficial efficacy was found against partial seizures and Lennox-Gastaut syndrome. Therefore, felbamate started to be indicated not only as an adjunctive antiepileptic drug but also in monotherapy. Unfortunately, it was also evidenced that the drug may induce aplastic anemia or hepatic failure. The former complication was frequently described in patients with previously diagnosed hematopoetic disturbances. Thirty-four cases of well-documented bone marrow suppression, occurred fatal in thirteen cases. Subsequently, felbamate's usage was essentially restricted and at present felbamate is not a first-line AED. However, excluding anemia-prone individuals, new possibilities may open for felbamate position in add-on therapy of drug-resistant epilepsy. Experimental studies provide a good theoretical basis for this kind of treatment.     

Antibiotics for myocardial infarction? A possible role of infection in atherogenesis and acute coronary syndromes

The role of inflammatory mechanisms in the initiation, progression and clinical expression of atherosclerosis is increasingly appreciated. With this awareness, the possibility that acute or chronic infection may initiate or modulate these processes in an active area of investigation. Infectious organisms may influence the atherosclerotic process through direct local effects on the coronary endothelium, on vascular smooth muscle cells and on macrophages in the atherosclerotic lesion. Infection may also exert systemic effects by inducing the elaboration of cytokines, the creation of a hypercoagulable state and by activating monocytes, causing possible transmission of infectious material to atherosclerotic lesions. Macrophages may then elaborate multiple mediators which destabilise plaque, promoting rupture and progression. Seroepidemiological data have identified associations between clinically active atherosclerosis and evidence of infection with Helicobacter pylori, Chlamydia pneumoniae and some herpesviridae. In addition, pathological examinations have demonstrated the presence of infectious organisms in coronary artery plaques. Cytomegalovirus, for example, has been identified pathologically to be associated with transplant vasculopathy and with an increased risk of restenosis following coronary intervention. Finally, recent pilot trials have demonstrated that macrolide antibacterial treatment directed against C. pneumoniae reduces the risk of recurrent coronary events. Infectious organisms may therefore influence atherogenesis through multiple pathways, and pathological and seroepidemiological investigations provide evidence of this association. Future large-scale clinical trials are needed to further evaluate the evidence of causality and the efficacy of antibacterial therapy for coronary artery disease.     

CGRP receptor antagonists: a new choice for acute treatment of migraine?

The neuropeptide calcitonin gene-related peptide (CGRP) is believed to play a central role in the underlying pathology of migraine. Serum levels of CGRP, elevated during a migraine attack, return to normal as pain alleviates. Recently, a causative role for CGRP in migraine has been suggested. Based on these findings, it was proposed that blockade of postsynaptic CGRP receptors, and hence the physiological effects of CGRP, should effectively abort a migraine attack. This review will discuss the therapeutic potential of olcegepant, the first non-peptide CGRP receptor antagonist available for human studies, within the context of current neurovascular theories on migraine pathology.     

Is there a role for immunoconjugates in the treatment of AIDS?

The use of antibodies to deliver therapeutic agents to specific cells is a well-established concept in the treatment of malignancy. Therapeutic effects have been shown in both animal models and human clinical trials. By analogy, antibodies and other ligands may be used to treat AIDS by targeting cells that are actively producing HIV and spreading the infection. Immunoconjugates with specificity for HIV antigens or structures on the surface of HIV-infected cells have been made. These agents have undergone extensive in vitro testing. In tissue culture they can eliminate infected cells and halt the production of HIV. A number of agents have been shown to enhance the efficacy of anti-HIV immunoconjugates. Because animal models of HIV-infection are problematic, there has been little preclinical testing. Nevertheless, several clinical trials have begun.     

Pharmacologic treatment of constipation: what is new?

Constipation is a common gastrointestinal disease affecting 2-27% of the population in Western hemisphere. Approximately in half of patients the diagnosis of functional constipation is made after having ruled out secondary causes. Treatment of chronic functional constipation primarily addresses education on toilet habits, dietary advice, and patient reassurance. Further therapies are guided according to functional subtype slow-transit constipation, dyssynergic defecation, and constipation-predominant irritable bowel syndrome (IBS-C). Traditionally, the pharmacologic treatment of constipation uses primarily bulking agents and/or laxatives (osmotic or secretory). However, often these therapies do not provide the desired improvement, have a short-lived efficacy and/or are accompanied by side-effects such as bloating and abdominal cramps. Thus, there is a clinical need for new, more potent drugs particularly for patients who are not satisfactorily treated by conventional therapies. This review discusses recent developments in the pharmacologic treatment of chronic constipation including recently FDA-approved lubiprostone, emerging 5-HT receptors modifiers, investigational substances, and probiotics.     

CBD for the treatment of pain: What is the evidence?

Cannabidiol (CBD) has become widely available owing to recent changes in federal and state regulations. Although it is marketed for many health conditions, a recent survey found that the most common reason for taking CBD was for the treatment of pain. The endocannabinoid system (ECS) is present at essentially all levels of the anterolateral system, which is responsible for the perception and modulation of pain. In addition to its effects on the ECS, CBD interacts with other important signaling systems involved in the regulation of pain. Thus, there is a physiological basis to investigate CBD for the treatment of pain. Although CBD has been found to reduce pain in several animal models of inflammatory and neuropathic pain, studies to date lack sufficient rigor to provide more than modest evidence for the analgesic activity of CBD. To date, only 1 controlled clinical study has been published evaluating the effect of CBD in the treatment of pain. This study was fraught with numerous deficiencies in design, such that the results are uninformative. Because studies to date have found a high level of variability in the content of CBD products, product quality is a major concern. Although limited preclinical studies suggest that CBD may alter the metabolism of drugs metabolized by cytochromes P450, the lack of clinical studies makes it impossible to assess the clinical significance of these observations. At present, there is insufficient evidence to recommend CBD for the treatment of pain. The safety of the compound in patients with chronic illness remains untested, and pharmacists should caution patients about its use in the absence of clinical supervision.     

Resectable non-small cell lung cancer in the elderly: is there a role for adjuvant treatment?

Over the past 2 years, systemic chemotherapy has emerged as the standard adjuvant approach for resectable non-small cell lung cancer (NSCLC). In aggregate, a 5.3% improvement in 5-year survival has been observed with platinum-based combination chemotherapy in patients with NSCLC, with benefits being most pronounced in stage II and IIIa disease. Recent data suggest that the elderly (up to age 75 years) derive benefits from such therapy similar to those seen in younger patients. Unfortunately, although patients aged >or=70 years constitute 50% of those with newly diagnosed NSCLC, <10% of enrollees in clinical trials are in this age group. To help offset the spectre of increased risk in this age group, two potential strategies exist: (i) substitution of carboplatin for cisplatin; and (ii) increased use of neoadjuvant treatment to avoid perioperative co-morbidities and difficulties with compliance that can hamper appropriate administration of adjuvant treatment. To date, there have been no elderly-specific adjuvant trials in NSCLC. Over time, this omission is likely to be corrected.