Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development

Antiplatelet therapy is the cornerstone of treatment for patients who present with acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI). Clopidogrel, in combination with aspirin, is associated with improvement in long-term clinical outcomes in these patients and is currently the antiplatelet therapy of choice. However, a significant number of patients experience recurrent ischemic events, which have been in part attributed to variability in individual response profiles to currently recommended treatment regimens. The presence of variable degrees of responsiveness, thus inadequate platelet inhibition in some patients, underscores the need for novel agents with more potency and less variable platelet inhibitory effects. Prasugrel (CS-747; LY640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate (ADP) P2Y₁₂ receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared with clopidogrel. Recent findings from large-scale Phase III testing showed prasugrel to be more efficacious in preventing ischemic events in ACS patients undergoing PCI; however, this is achieved at the expense of an increased risk of bleeding. This article reviews the currently available data regarding the efficacy and safety of prasugrel.     

Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development

Antiplatelet therapy is the cornerstone of treatment for patients who present with acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI). Clopidogrel, in combination with aspirin, is associated with improvement in long-term clinical outcomes in these patients and is currently the antiplatelet therapy of choice. However, a significant number of patients experience recurrent ischemic events, which have been in part attributed to variability in individual response profiles to currently recommended treatment regimens. The presence of variable degrees of responsiveness, thus inadequate platelet inhibition in some patients, underscores the need for novel agents with more potency and less variable platelet inhibitory effects. Prasugrel (CS-747; LY640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate (ADP) P2Y(12) receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared with clopidogrel. Recent findings from large-scale Phase III testing showed prasugrel to be more efficacious in preventing ischemic events in ACS patients undergoing PCI; however, this is achieved at the expense of an increased risk of bleeding. This article reviews the currently available data regarding the efficacy and safety of prasugrel.     

Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies

Nefopam is a non‐opioid, non‐steroidal, centrally acting analgesic drug used to prevent postoperative pain, primarily in the context of multimodal analgesia. This paper reviews preclinical and clinical studies in which nefopam has been combined with opioids, non‐steroidal anti‐inflammatory compounds, and paracetamol. This report focuses on the literature during the last decade and discusses the translational efforts between animal and clinical studies in the context of multimodal or balanced analgesia. In preclinical rodent models of acute and inflammatory pain, nefopam combinations including opioids revealed a synergistic interaction or enhanced morphine analgesia in six out of seven studies. Nefopam combinations including non‐steroidal anti‐inflammatory drugs (NSAIDs) (aspirin, ketoprofen or nimesulide) or paracetamol likewise showed enhanced analgesic effects for the associated compound in all instances. Clinical studies have been performed in various types of surgeries involving different pain intensities. Nefopam combinations including opioids resulted in a reduction in morphine consumption in 8 out of 10 studies of severe or moderate pain. Nefopam combinations including NSAIDs (ketoprofen or tenoxicam) or paracetamol also demonstrated a synergic interaction or an enhancement of the analgesic effect of the associated compound. In conclusion, this review of nefopam combinations including various analgesic drugs (opioids, NSAIDs and paracetamol) reveals that enhanced analgesia was demonstrated in most preclinical and clinical studies, suggesting a role for nefopam in multimodal analgesia based on its distinct characteristics as an analgesic. Further clinical studies are needed to evaluate the analgesic effects of nefopam combinations including NSAIDs or paracetamol.     

Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia

Rationale Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. Materials and methods The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-d-aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed. Results Asenapine (0.05–0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05–0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC. Conclusions These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.     

Tigecycline: a review of preclinical and clinical studies of the first-in-class glycylcycline antibiotic

Tigecycline is a novel glycylcycline antibacterial agent discovered and developed by Wyeth Research. The U.S. Food and Drug Administration (FDA) recently approved the agent for use in patients with complicated skin infections, skin-structure infections and intra-abdominal infections. Tigecycline is currently under review by regulatory agencies worldwide. Global clinical trials are underway to further assess the efficacy of tigecycline for community- and hospital- acquired pneumonia. Because of the expanded broad spectrum of activity of tigecycline with proven utility against Gram-positive, Gram-negative, anaerobic and atypical pathogens in addition to resistant organisms of clinical importance--community- and hospital-acquired methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., penicillin-resistant Streptococcus pneumoniae and Escherichia coli and Klebsiella pneumoniae expressing extended-spectrum beta-lactamases--this novel antibiotic has come into clinical use at a critical time and will be a welcome asset to the current armamentarium.     

Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450.

The biotransformation of prasugrel to R-138727 (2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid) involves rapid deesterification to R-95913 (2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone) followed by cytochrome P450 (P450)-mediated formation of R-138727, the metabolite responsible for platelet aggregation. For identification of the P450s responsible for the formation of the active metabolite, the current studies were conducted with R-95913 as the substrate. Incubations required supplementation with reduced glutathione. Hyperbolic kinetics (K(m) 21-30 microM), consistent with a single enzyme predominating, were observed after incubations with human liver microsomes. Correlation analyses revealed a strong relationship between R-138727 formation and CYP3A-mediated midazolam 1'-hydroxylation (r(2) = 0.98; p < 0.001) in a bank of characterized human liver microsomal samples. The human lymphoblast-expressed enzymes capable of forming R-138727, in rank order of rates, were CYP3A4>CYP2B6>CYP2C19 approximately CYP2C9>CYP2D6. A monoclonal antibody to CYP2B6 and the CYP3A inhibitor ketoconazole substantially inhibited R-138727 formation, whereas inhibitors of CYP2C9 (sulfaphenazole) and CYP2C19 (omeprazole) did not. Scaling of in vitro intrinsic clearance values from expressed enzymes to the whole liver using a relative abundance approach indicated that either CYP3A4 alone or CYP3A4 and CYP2B6 are the major contributors to R-138727 formation. R-95913 and R-138727 were also examined for their ability to inhibit metabolism mediated by five P450s. R-138727 did not inhibit the P450s tested. In vitro, R-95913 inhibited CYP2C9, CYP2C19, CYP2D6, and CYP3A, with K(i) values ranging from 7.2 microM to 82 microM, but did not inhibit CYP1A2. These K(i) values exceed circulating concentrations in humans by 3.8- to 43-fold. Therefore, neither R-95913 nor R-138727 is expected to substantially inhibit the P450-mediated metabolism of coadministered drugs.     

Biological basis of sex differences in drug abuse: preclinical and clinical studies

The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific. Electronic Publication     

Tretinoin: A review of preclinical toxicological studies

Tretinoin (all-trans-retinoic acid) has shown efficacy in the treatment of acute promyelocytic leukemia. The preclinical toxicological profile of tretinoin was similar to that of other retinoids. The compound had a relatively low acute toxicity; repeated doses resulted in a substantial increase in toxicity that was a function of dose and duration of exposure. Bone fractures, elevated alkaline phosphatase, and testicular degeneration were produced by repeated doses of tretinoin. Teratogenicity was demonstrated in several species. Tretinoin was inactive in the Ames test but appeared to induce sister-chromatid exchanges in human diploid fibroblasts. Insufficient data are available to evaluate the carcinogenic potential of tretinoin. © 1993 wiley-Liss, Inc.     

Ticagrelor: a novel antiplatelet agent for patients with acute coronary syndrome

Ticagrelor is an oral, reversible blocker of the P2Y12 adenosine receptor. In clinical trials the antiplatelet agent reduced significantly vascular mortality and death from any cause when compared to clopidogrel in patients with acute coronary syndrome.     

The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression

Major depressive disorder (MDD) poses a significant health problem and is estimated to be the third most costly and disabling disorder in the United States. Pharmacotherapy of depression has been successful, but improvements in response rates, remission rates, side effects, compliance and faster onset of therapeutic action have become prime objectives in drug development. There is considerable support for the hypothesis that dysfunctional serotonergic or noradrenergic neurotransmission may be etiological in depressed patients. Duloxetine is a balanced and potent reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) being studied as an antidepressant medication. In this review, we highlight the preclinical pharmacology, pharmacokinetic profile, and effects of duloxetine in the pharmacotherapy of depression. Evidence for 5-HT and NE reuptake inhibition by duloxetine comes from in vitro and in vivo transporter binding and functional uptake studies. Taken together with efficacy data from in vivo microdialysis, electrophysiological and behavioral studies, it is evident that duloxetine is balanced as a dual serotonin norepinephrine uptake inhibitor in vivo. The clinical efficacy and safety of duloxetine in the treatment of MDD has been studied in 6 multicenter, randomized, double-blind, placebo-controlled trials. In these studies, duloxetine was found to be effective in the treatment of emotional/psychological and painful physical symptoms associated with depression. More importantly, duloxetine appears to have better response rates and remission from depressive symptoms, perhaps due to its ability to treat a wider range of symptoms.     

Levetiracetam: the profile of a novel anticonvulsant drug-part I: preclinical data

The objective of this article was to review and summarize the available reports on the preclinical profile of the novel anticonvulsant drug levetiracetam (LEV). Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article provides detailed information on the anticonvulsant effects of LEV in various animal models of epilepsy and on its pharmacology in laboratory animals. The mechanism of action of LEV is reviewed, with special regard to its recently discovered binding site, the synaptic vesicle protein 2A. In general, LEV is shown to be a safe, broad-spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties and a distinct mechanism of action. The clinical studies with LEV will be discussed in the second part of this review article to be published subsequently.     

Resveratrol: a review of preclinical studies for human cancer prevention

The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.     

亚胺培南肾毒性和西司他丁肾保护的基础和临床研究进展

亚胺培南是一种碳青霉烯类抗生素,在临床上和西司他丁组成复方制剂,用于多重耐药和重症感染的治疗。肾毒性是亚胺培南的常见不良反应,在儿童和老年等肾功不全群体中,应用亚胺培南导致肾脏毒性的风险更大。西司他丁具有肾保护活性,可降低顺铂、万古霉素、环孢素A等药物的肾毒性。本文对近年来亚胺培南肾毒性和西司他丁肾保护作用的研究进展进行综述,从基础研究和临床应用的角度,揭示亚胺培南和西司他丁在肾脏产生不同效应的可能机制,为亚胺培南和西司他丁的临床安全合理应用提供理论基础和科学建议。     

Pharmacokinetic,pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current ‘gold standard’ antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists. The candidates include various blockers of the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosine triphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor (intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplatelet compound that can be administered both intravenously and orally); BX 667, an orally active and reversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 and E5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number of drugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxane receptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrand factor-dependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIb binding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor. The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered, randomized, controlled trials.     

Buserelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical profile

The gonadotrophin releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); gonadorelin] agonist buserelin is a promising new agent in the treatment of a variety of disorders in gynaecology and andrology, paediatrics and oncology. While a single dose of buserelin stimulates the release of pituitary gonadotrophins, multiple doses produce reversible pituitary desensitisation, and this specific blockade of gonadotrophin support to the gonads provides the basis for the drug's efficacy in conditions dependent on sex hormone secretion. Thus, buserelin provides comparable efficacy to orchidectomy or high dose estrogens in the treatment of hormone-sensitive prostate cancer and exhibits a lower incidence of adverse effects. During the early phase of treatment it may be particularly useful in combination with antiandrogens. Buserelin also appears promising in hormone-sensitive premenopausal breast cancer. Extensive studies have proven the value of buserelin in endometriosis, where it produces a transient remission with gradual recurrence of the disease on cessation of treatment. Surgical intervention is necessary in severe disease after buserelin-induced involution of the lesions. In patients with uterine leiomyoma, preliminary data suggest that buserelin may be beneficial in rendering surgery more conservative by reducing fibroid size, although it appears unlikely to preclude surgical intervention. The use of buserelin to induce a state of reversible hypogonadotrophism before administration of exogenous gonadotrophins is a promising strategy in the treatment of infertility associated with polycystic ovary syndrome and other conditions of infertility with underlying ovarian dysfunction; such a strategy also clearly enhances the efficiency of in vitro fertilisation programmes. Initial studies suggest its potential usefulness as a female contraceptive when administered intermittently in conjunction with a progestogen. Buserelin represents a first-line treatment of central precocious puberty. In endometriosis the adverse effect profile of buserelin is generally favourable, with hypoestrogenic effects such as hot flushes and vaginal dryness, and decreased libido, predominating. There is no apparent detrimental effect on lipid metabolism. The potential for adverse hypoestrogenic effects on bone mineral content with long term administration remains to be clarified. Thus, the GnRH agonist buserelin represents an advance in the treatment of a variety of gynaecological and andrological as well as paediatric and oncological conditions, infertility and other sex-hormone dependent conditions, with a low incidence of adverse treatment effects.     

Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies

INTRODUCTION: Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4. AREAS COVERED: This review focuses on the rationale for the use of eritoran tetrasodium in sepsis as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Preclinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms 'eritoran' and 'E5564' are discussed. EXPERT OPINION: Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis are currently under investigation. Even if the ongoing Phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies would be necessary to define its clinical usage.     

Torasemide (LUPRAC): a review of its pharmacological and clinical profile

Loop diuretics potently excrete water and electrolytes and therefore have been widely prescribed for the treatment of various kinds of edema for a long time. The potent diuretic action of loop diuretics, however, often causes hypokalemia, and therefore potassium sparing diuretics have also been supplied as a concomitant drug. Torasemide (LUPRAC), a novel diuretics, shows not only an effective loop diuretic action but also a potassium sparing action due to its anti-aldosteronergic effect. Torasemide also has a high bioavailability and is only slightly influenced by meals in humans. In addition, its pharmacodynamic features contribute to its stable diuretic action without any individual differences. In animal experiments, torasemide showed about a tenfold more potent diuretic action in comparison with furosemide, an authentic loop diuretic. On the one hand, the increase in the urinary potassium excretion by torasemide was relatively slight compared to the increase in urinary sodium excretion and, as a result, the urinary sodium to potassium (Na+/K+) ratio increased. The diuretic profile of torasemide was equal to that of the concomitant use of furosemide and an anti-aldosteronergic drug, spironolactone. Torasemide showed a significant efficacy and safety in comparison with furosemide in the patients with edema in both domestic and foreign clinical studies. Moreover, torasemide also showed a decreased rate of cardiac death in comparison to furosemide in patients with chronic heart failure in a large-scale clinical study (TORIC Study). The difference in cardiac death between these two diuretics has been suggested to depend on the anti-aldosteronergic effect of torasemide. In Japan, no new loop diuretics have been developed in over 10 years. Torasemide is therefore expected to be useful as an effective diuretic for diseases with edema.     

Meloxicam (Mobic): a review of its pharmacological and clinical profile

Meloxicam (Mobic) is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid, exhibiting selectivity for cyclooxygenase (COX)-2 over COX-1. Meloxicam has shown potent anti-inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models. It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat, but also of bone and cartilage destruction. The therapeutic range of meloxicam in the rat, with regard to inhibition of adjuvant arthritis, was several times greater than that of other NSAIDs. Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers. In clinical studies, meloxicam has shown reliable efficacy against rheumatoid arthritis, osteoarthritis, lumbago (low back pain), scapulohumeral periarthritis, and neck-shoulder-arm syndrome with low gastrointestinal toxicity.